Improvements in cell block processing: The Cell-Gel method

La Fortune KA, Randolph ML, Wu HH, Cramer HM. Cancer 2017; 125(4): 267–276

BACKGROUND: The ability to produce adequate cell blocks profoundly impacts the diagnostic usefulness of cytology specimens. Cell blocks are routinely processed from fine-needle aspiration specimens or concentrated fluid samples. Obtaining directed passes for the sole purpose of producing a cell block is common practice, particularly when the cytopathologist anticipates the need for ancillary immunocytochemical stains and/or molecular studies.
METHODS: The authors developed an effective and inexpensive process for producing cell blocks that consistently yields abundant cellular material, which they have termed the Cell-Gel method. This method can be simplified into 3 main steps: (1) preparing the sample; (2) constructing the cell block; and (3) processing the cell block. Highlights of the protocol include using a hemolytic fixative for sample preparation and disposable base moulds for cell block construction.
RESULTS: The cell block failure rate in the current study decreased from 18% with the HistoGel Tube method (January 2014 – December 2014) to 6% with the Cell-Gel method (January 2015 – December 2016). The authors evaluated 110 cell blocks processed with the HistoGel Tube method and 110 cell blocks processed with the Cell-Gel method, for a total evaluation of 220 cell blocks.
CONCLUSIONS: The authors have developed an effective and inexpensive protocol for producing cell blocks that consistently yields abundant cellular material. The Cell-Gel method uses a hemolytic fixative and disposable base moulds to produce adequate cell blocks. When the method was implemented, the cell block failure rate of the study laboratory decreased by approximately 67%.

Lung carcinoma predictive biomarker testing by immunoperoxidase stains in cytology and small biopsy specimens: advantages and limitations

Zhou F, Moreira AL. Arch Pathol Lab Med 2016; 140(12): 1331–1337

CONTEXT: In the burgeoning era of molecular genomics, immunoperoxidase (IPOX) testing grows increasingly relevant as an efficient and effective molecular screening tool. Patients with lung carcinoma may especially benefit from the use of IPOX because most lung carcinomas are inoperable at diagnosis and only diagnosed by small tissue biopsy or fine-needle sampling. When such small specimens are at times inadequate for molecular testing, positive IPOX results still provide actionable information.
OBJECTIVE: To describe the benefits and pitfalls of IPOX in the detection of biomarkers in lung carcinoma cytology specimens and small biopsies by summarizing the currently available commercial antibodies, pre-analytic variables, and analytic considerations.
DATA SOURCES: PubMed.
CONCLUSIONS: Commercial antibodies exist for IPOX detection of aberrant protein expression due to EGFR L858R mutation, EGFR E746_A750 deletion, ALK rearrangement, ROS1 rearrangement, and BRAF V600E mutation, as well as PD-L1 expression in tumour cells. Automated IPOX protocols for ALK and PD-L1 detection were recently approved by the Food and Drug Administration as companion diagnostics for targeted therapies, but consistent interpretive criteria remain to be elucidated, and such protocols do not yet exist for other biomarkers. The inclusion of cytology specimens in clinical trials would expand patients’ access to testing and treatment, yet there is a scarcity of clinical trial data regarding the application of IPOX to cytology, which can be attributed to trial designers’ lack of familiarity with the advantages and limitations of cytology. The content of this review may be used to inform clinical trial design and advance IPOX validation studies.

DUX4 immunohistochemistry is a highly sensitive and specific marker for CIC-DUX4 fusion-positive round cell tumor

Siegele B, Roberts J, Black JO, Rudzinski E et al. Am J Surg Pathol 2017; 41(3): 423–429

The histologic differential diagnosis of pediatric and adult round cell tumours is vast and includes the recently recognized entity CIC-DUX4 fusion-positive round cell tumour. The diagnosis of CIC-DUX4 tumour can be suggested by light microscopic and immunohistochemical features, but currently, definitive diagnosis requires ancillary genetic testing such as conventional karyotyping, fluorescence in situ hybridization, or molecular methods. We sought to determine whether DUX4 expression would serve as a fusion-specific immunohistochemical marker distinguishing CIC-DUX4 tumour from potential histologic mimics. A cohort of CIC-DUX4 fusion-positive round cell tumours harbouring t(4;19)(q35;q13) and t(10;19)(q26;q13) translocations was designed, with additional inclusion of a case with a translocation confirmed to involve the CIC gene without delineation of the partner. Round cell tumours with potentially overlapping histologic features were also collected. Staining with a monoclonal antibody raised against the C-terminus of the DUX4 protein was applied to all cases. DUX4 immunohistochemistry exhibited diffuse, crisp, strong nuclear staining in all CIC-DUX4 fusion-positive round cell tumours (5/5, 100% sensitivity), and exhibited negative staining in nuclei of all of the other tested round cell tumours, including 20 Ewing sarcomas, 1 Ewing-like sarcoma, 11 alveolar rhabdomyosarcomas, 9 embryonal rhabdomyosarcomas, 12 synovial sarcomas, 7 desmoplastic small round cell tumours, 3 malignant rhabdoid tumours, 9 neuroblastomas, and 4 clear cell sarcomas (0/76, 100% specificity). Thus, in our experience, DUX4 immunostaining distinguishes CIC-DUX4 tumours from other round cell mimics. We recommend its use when CIC-DUX4 fusion-positive round cell tumour enters the histologic differential diagnosis.


Role of quantitative p16INK4A mRNA assay and digital reading of p16INK4A immunostained sections in diagnosis of cervical intraepithelial neoplasia

Vasiljević N, Carter PD, Reuter C et al. Int J Cancer 2017; 141(4): 829–836

Visual interpretation of cervical biopsies is subjective and variable, generally showing fair to moderate inter-reader agreement in distinguishing high from low grade cervical intraepithelial neoplasia (CIN). We investigated the performance of two objective p16 quantitative tests in comparison with visual assessment: (i) p16-mRNA assay and (ii) digital analysis of sections stained for p16 protein. The primary analysis considered 232 high-risk human papilloma virus positive (HPV+) samples from diagnostic cervical specimens. A p16 RT-qPCR (p16-mRNA assay) was run on mRNA extracted from formalin-fixed paraffin-embedded sections. Two p16 immunohistochemistry (IHC) readings, a visual read by a histopathologist (Visual IHC) and a digital read of a high-resolution scan (Digital IHC), were done on adjacent sections. The worst reviewed CIN grade (agreed by at least two histopathologists) from up to two biopsies and a loop excision was taken, with CIN2/3 as the primary endpoint. Visual IHC attained a specificity of 70% (95%CI 61–77) for 85% (95%CI 77–91%) sensitivity. The four-point Visual IHC staining area under the curve (AUC) was 0.77 (95%CI 0.71–0.82), compared with 0.71 (95%CI 0.64–0.77) for p16-mRNA and 0.67 (95%CI 0.60–0.74) for Digital IHC. Spearman rank-order correlations were: visual to p16-mRNA 0.41, visual to digital 0.49 and p16-mRNA to digital: 0.22. The addition of p16-mRNA assay to visual reading of p16 IHC improved the AUC from 0.77 to 0.84 (P=0.0049). p16-mRNA testing may be complementary to visual IHC p16 staining for a more accurate diagnosis of CIN, or perhaps a substitute in locations with a lack of skilled pathologists.

Biomarkers for pathology diagnosis of uterine cervix malignant glandular lesions

Lee S, Rose MS, Sahasrabuddhe VV et al. Int J Gynecol Pathol 2017;36(4): 310–322

Immunohistochemistry is widely used to support a pathology diagnosis of cervical adenocarcinoma despite the absence of a systematic review and meta-analysis of the published data. This systematic review and meta-analysis was performed to investigate the sensitivity and specificity of immunohistochemistry biomarkers in the tissue-based diagnosis of cervical adenocarcinoma histotypes compared with normal endocervix and benign glandular lesions. The systematic review and meta-analysis used a PICOT framework and QUADAS-2 to evaluate the quality of included studies. The literature search spanned 40 years and ended June 30, 2015. Abstracts of identified records were independently screened by two of the authors who then conducted a full-text review of selected articles. Sensitivity and specificity of immunohistochemistry expression in malignant glandular lesions of the cervix classified per WHO 2003 compared with 5 benign comparators (normal/benign endocervix, and benign endocervical, endometrioid, gastric, and mesonephric lesions) were calculated. Of 902 abstracts screened, 154 articles were selected for full review. Twenty-five articles with results for 36 biomarkers were included. The only biomarker with enough studies for a meta-analysis was p16 and the definition of positive p16 staining among them was variable. Nevertheless, any positive p16 expression was sensitive, ranging from 0.94 to 0.98 with narrow confidence intervals (CIs), for adenocarcinoma in situ (AIS) and mucinous adenocarcinomas in comparison with normal/benign endocervix and benign endocervical and endometrioid lesions. Specificity for AIS and mucinous adenocarcinomas was also high with narrow CIs compared with benign endocervical lesions. The specificity was high for AIS, 0.99 (0.24, 1.0), and mucinous adenocarcinoma, 0.95 (0.52, 1.0), compared with normal/benign endocervix but with wider CIs, and low with very wide CIs compared with benign endometrioid lesions: 0.31 (0.00, 0.99) and 0.34 (0.00, 0.99), respectively. Results from single studies showed that p16, p16/Ki67 dual stain, ProExC, CEA, ESA, HIK1083, Claudin 18, and ER loss in perilesional stromal cells were useful with high (≥0.75) sensitivity and specificity estimates in ≥1 malignant versus benign comparisons. None of the biomarkers had highly useful sensitivity and specificity estimates for AIS, mucinous adenocarcinomas, or minimal deviation adenocarcinoma/gastric adenocarcinoma compared with benign gastric or mesonephric lesions or for mesonephric carcinoma compared with normal/benign endocervix, benign endocervical, endometrial, or mesonephric lesions. Any expression of p16 supports a diagnosis of AIS and mucinous adenocarcinomas in comparison with normal/benign endocervix and benign endocervical lesions. The majority of studies did not separate mosaic/focal p16 staining from diffuse staining as a distinct pattern of p16 overexpression and this may have contributed to the poor performance of p16 in distinguishing AIS and mucinous adenocarcinomas from benign endometrioid lesions. Single studies support further investigation of 8 additional biomarkers that have highly useful sensitivity and specificity estimates for ≥1 malignant glandular lesions compared with ≥1 of the 5 benign comparators.

GATA3 expression in triple-negative breast cancers

Byrne DJ, Deb S, Takano EA, Fox SB. Histopathology 2017; 71(1): 63–71

AIMS: GATA-binding protein 3 (GATA3) is a well-studied transcription factor found to be essential in the development of luminal breast epithelium and has been identified in a variety of tumour types, including breast and urothelial carcinomas, making it a useful immunohistochemistry marker in the diagnosis of both primary and metastatic disease.
METHODS AND RESULTS: We investigated GATA3 protein expression in a 106 primary triple-negative breast carcinomas (100 basal-like, six non-basal-like) using Cell Marque mouse monoclonal anti-GATA3 (L50-823). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to quantify mRNA expression in 22 triple-negative breast cancers (TNBCs) (20 primary and two cell lines), four luminal (three primary and one cell line) and five human epidermal growth factor receptor 2 (HER2) (four primary and one cell line) amplified tumours. In 98 TNBCs where IHC was assessable, 47 (48%) had a 1+ or greater staining with 20 (21%) having high GATA3 expression when using a weighted scoring.
CONCLUSION: Our study has demonstrated that GATA3 expression is common in primary triple-negative breast carcinomas. It also suggests that although GATA3 is an estrogen receptor (ER) regulated gene, it still proves useful in differentiating between primary and metastatic tumours in patients with a history of breast cancer regardless of its molecular subtype.

Accuracy of fine needle cytology in histological prediction of papillary thyroid carcinoma variants: a prospective study

Cipolletta Campanile A, Malzone MG, Losito NS et al. 2017; 28(3): 187–197

Fine needle cytology (FNC) is a crucial procedure in the preoperative diagnosis of thyroid tumours. Papillary thyroid carcinoma (PTC), in its classic variant (cPTC), is the most common malignant neoplasm of the thyroid. Several histological variants of PTC have been described, each one with its own characteristics and prognosis. The ability of FNC to identify the variants represents a challenge even for a skilled pathologist. The aim of this study was to evaluate the diagnostic cytological accuracy of FNC in PTC and to look for specific features that could predict the different variants. This was a single centre prospective study on 128 patients who received a diagnosis of PTC on FNC. The smears were blindly reviewed by two cytopathologists to create a frequency score (0, 1, 2, 3) of the features for each variant. The cytological parameters were divided into three groups: architectural, nucleo-cytoplasmic, and background features. Univariate analysis was performed by chi-square test with Yates correction and Fisher exact test as appropriate. Multiple regression analysis was performed among the variables correlated at the linear correlation. The correlation study between cytology and histology showed an accuracy of FNC in classic, follicular, and oncocytic PTC variants of 63.5, 87.5, and 87%, respectively. Familiarity with cytological features may allow an early diagnosis of a given PTC variant on FNC samples. This is fundamental in a preoperative evaluation for the best surgical approach and subsequent treatment.

Over the last 60 years, medicine has made major advances in diagnosis, treatment and surgery. Radiography and Fluoroscopy imaging are essential to medical science. As a result, Original Equipment Manufacturers (OEM’s) need to deliver ever more sophisticated turnkey platforms for their systems which are dedicated to end-users. Thales has designed a platform that meets all of these needs.

ArtPix DRF, a unique Imaging Platform for Dynamic X-Ray applications

ArtPix DRF is an advanced imaging platform that helps OEMs bring Radio-Fluoroscopy systems to market by reducing integration, certification, time and cost through flexibility and reactivity. This increases customer gain by optimizing margins and has several key advantages such as image quality and design. The system is designed to deliver outstanding performance in fluoroscopy and radiography, enhancing radiology department workflow & productivity.

State of the art dynamic and static images

ArtPix DRF introduces a real 10-bit image pipeline and a set of unique algorithms based on parallel computing, providing real-time, full HD images as well as flexibility of adjustments on demand. Users can customise the imaging platform to suit their preferences, including user-interface, display configuration, image quality and room peripherals. A proprietary image processing allows adjustments according to the regions of the world, user experience expectations and preferences. 

Multiple advanced applications are embedded in this solution

ArtPix DRF is based on a user-friendly application that controls the generator and remote tables. For the physician, it also includes a patient vicinity controlled application to enhance treatment. The system offers increased value to OEM’s by featuring a vast choice of advanced clinical options such as: Tomosynthesis, stitching, radiation-less positioning, etc.

Integration and daily use are facilitated thanks to an intuitive setup, calibration and application

The setup, calibration, generator settings and stations can be easily configured by an X-ray technician guided by ArtPix DRF, allowing the system environment to be easily adjusted. Thanks to these options and the flexibility to change all of the configurations, time and money are saved by practitioners and therefore, a higher number of patients can be seen. The platform has been designed to tackle IT and patient information vulnerabilities. The system is compliant with the latest information security standards.

The people we rely on to keep us healthy rely on Thales to provide pioneering fluoroscopy solutions. Thales’ 60 years of experience in the domain, combined with its ability to remain at the forefront of innovation, has made the Group the leading choice for many radiological system manufacturers. With the launch of the world’s 1st 4343 panel dedicated to fluoroscopy in 2007, the company is perceived as a precursor in this domain. Nowadays, and thanks to its long term expertise, Thales is increasingly engaged in the development of image chain platforms in order to provide complete and efficient solutions for systems integrators and end-users. Discover ArtPix DRF at the ECR congress from 1-4 March 2018, Thales booth N°410 – Foyer D.

Diagnostic and prognostic MRI is recommended for infants for a range of conditions. These include gestational age below 30 weeks, in premature infants suspected of metabolic disease, and in term infants who might have sustained perinatal brain injuries or who show Stage 2 or 3 hypoxic-ischemic encephalopathy.

MRI preferred imaging solution for numerous conditions
Although ultrasound (US) is used as first-line imaging in certain cases like intracranial hemorrhage, MRI is indicated for most other infant brain and head neuroimaging. This has been the case for some time. One example is a report published in 1990 in the French-language journal ‘Pediatrie’ by a team from the CHU Hautepierre hospital in Strasbourg, which discusses the advantages of MRI over ultrasound in areas such as brain injury. The report, nevertheless, also points out the problems with neonatal MRI, such as the need for immobilization and lack of accessibility.  Such difficulties have persisted over the years.
Indeed, in the early 1990s, Britain’s Hammersmith Hospital installed a 1T MRI scanner in the NICU. However, it had a limited field of view and was replaced with a conventional adult-sized 3T system. In fairly short order, the 3T system was found not only challenging to use in the NICU due to its long bore and problems of access to infants, but also expensive to operate.

Guidelines for infant MRI imaging
At present, a multitude of guidelines recommend that MRI is used to follow up ultrasound diagnosis of parenchymal brain injury, post-hemorrhage ventricular dilatation as well as US (or clinical) suspicion of abnormalities in the posterior fossa and at the brain’s convexity. Other conditions in infants that indicate MRI imaging include brain inflammation (meningitis, encephalitis, brain abscess etc.) and seizures, abnormal consciousness and/or asymmetry which cannot be satisfactorily explained by US findings.
The case for MRI after ultrasound has also been studied extensively. One report from the Medical University of Vienna in 2010 stated that among infants undergoing cranial ultrasounds after clinical seizure, MRI was able to identify a causative pathology in 42% of cases where US findings were unspecific.

Conventional MRI “not designed” for infants
As mentioned in an ‘Advances in Neonatal Care’ analysis in 2005, it takes a single look at a typical MRI scanner to know that “it was not designed for an infant.”
Technically, a baby’s head size poses one of the first challenges. Standard MR head coils lead to sub-optimal picture quality and adult knee coils are often used instead.
Cooperation between neonatal team and radiologists
Given the very small size of a neonate brain, it is especially important to have high signal-to-noise ratios (SNR) for delineation of anatomical details. This was one of the major limitations of smaller, customized low-field MRIs designed for NICUs. At Royal Hallamshire Hospital in Sheffield, for example, a 0.17T system with 15mT/m gradients was installed in the early 2000s, but its low SNR made it impossible to use emerging  MRI techniques such as diffusion tensor imaging and MR spectroscopy in neonates.

The best way forward has instead been seen in tailoring MR protocols to the neonatal brain. This is however a complex task. MR protocols involve a wide range of technical factors: echo time, repetition time, flip angle, slice numbers, slice thickness, scan duration, field of view etc. Achieving this “requires close cooperation between the neonatal team, radiographers and radiologists,” according to a study at Ireland’s University of Cork, published in 2012 in the ‘British Journal of Radiology’.

The challenge of transfers
The transfer of infants from a continuously-monitored NICU to MRI suites has been one of the most vexatious problems. As discussed in the 2005 edition of ‘Advances in Neonatal Care’ cited above, MRI scanners “are often situated far away from the NICU.”
The move of infants to an MRI room involves multiple transfers – from NICU bed to incubator to scanning table, and then backwards. These have to be made in a relatively short period of time, which can add dramatically to physiological stress.
Specific problems during transfer include the chance of extubation and arterial or venous decannulation. Excessive movement in a premature infant is also known to adversely affect cerebral blood flow. This, in turn, can defeat the very purpose of an MRI, by altering results.

Sedation and hypothermia
The question of whether or not to sedate infants before transfer is also a major challenge. Sedation has risks. Moreover, a sedated neonate requires continuous monitoring during an MRI.
There are problems after the transfer, too. Once in the MRI room, infants must be removed from the warmth of the incubator to a cooler scanning table. Towards this, they are usually swaddled in blankets, accompanied sometimes by neonatal thermal packs to prevent heat loss. The American College of Radiology (ACR) also recommends use of temperature probes for infants to take an auxiliary temperature before and after the examination.
Even as the MRI begins, NICU staff need to be on alert to decide if an examination must be halted. This may be due to the impact of the transport, cold, stress, sedation etc..

MRI-compatible incubators
Since the early 2000s, attention has focused on MRI-compatible incubators. These are equipped with an integrated head coil and accompanied by auditory shielding, temperature and humidity regulators, a ventilation support system and monitors specifically certified for the massive magnetic environment of the MRI.
In February 2004, ‘Pediatrics’ published a report on the imaging of seven non-sedated neonates via the use of an MRI-compatible incubator. The authors noted that the “constant environment reduces the risk of adverse events occurring during the transport and imaging of the neonate.”
Not all problems, however, were mastered by the incubator. For instance, the infant was not easily visible from the control room and required the presence of a staff member in the vicinity. In addition, in spite of temperature and humidity controls, additional monitoring was required for electrocardiography and oxygen saturation.
Nevertheless, interest in MRI-compatible neonatal incubators has continued.
In September 2010, the ‘European Journal of Paediatric Neurology’ published results of a study which found that MRI-compatible incubators reduced the mean gestational age of patients from 44 to 39.7 weeks, and in parallel, more than doubled incubator use from 14.8% to 36% for ventilated neonates.
Advantages of the MRI-compatible neonatal incubator also included halving the time required for handling the infant, a reduction of total procedure time by an average of 20 minutes, and in imaging time by four minutes. Such time savings arose from the fact that there was no need to stabilize the infant. Furthermore, no MRI procedure was terminated due to insufficient sedation or infant instability; previously, one in 10 infants had required additional sedation during the procedure.
Equipment compatibility and safety
In May 2013, researchers from Australia’s Royal Brisbane and Women’s Hospital published results of a three-year review on MRI-compatible incubators in the ‘Journal of Paediatrics and Child Health’. Although the overall conclusions were positive, with no adverse incident reported over the period, the authors drew attention to several “practical issues”.
The first was a 30-45 minute pre-warming period required to reach an appropriate temperature setting for babies. The second consisted of difficulties in reading the incubator’s patient monitor interface, including key data such as cot temperature, pulse rate and oximetry readings. Once again, as with the February 2004 ‘Pediatrics’ study mentioned previously, the Royal Brisbane researchers recommended “that staff remain in the scan room throughout the procedure to monitor the well-being of the baby.”
The biggest challenge, however, concerned compatibility of equipment connected to the incubator. For instance, though the ventilator was MRI-compatible, it was not designed to provide humidified or preheated gas. The researchers also noted the need to improvise very specific procedures, for example, in extending infusion lines from pumps located outside the imaging room, which were not MRI-compatible.
Indeed, the need to use MRI-compatible or MRI-safe accessories, ranging from thermal packs and temperature probes to noise protectors, remains one of the biggest drawbacks with MRI-compatible incubators outside the NICU. The authors of the Royal Brisbane study point to “difficulties in sourcing a gas supplier to refill the portable MRI-compatible air and oxygen cylinders because of their special status outside the usual medical gas cylinder refilling programme.”
The scale of such problems becomes dramatic when intubation or resuscitation is required. In such cases, the infants need to be rapidly removed from the MR system and its magnetic fringe. The only alternative is to ensure that, rather than just accessories, the entire range of medical equipment – from syringes and infusion pumps to laryngoscopes and suction equipment – is MRI-compatible.

More research needed
In February 2015, ‘Advances in Neonatal Care’ published results from a systematic review of 13 research studies, two quality improvement projects, as well as practice guidelines and articles on neonatal MRI imaging by the Norwegian Neonatal Network and Oslo University Hospital.
The authors concluded that although results seemed promising and increasingly consistent, “more research is needed before conclusive recommendations” could be established about MRI-compatible incubators and associated techniques.

Alternatives emerge
Recently, a system from Aspect Imaging known as Embrace Neonatal MRI has sought to close the gap between NICU imaging requirements and the capabilities of current MRI-compatible incubators.  Embrace received authorization from United States Food and Drug Administration (FDA) in July 2017, and in November obtained a CE marking for European Union sales.
Unlike conventional MRI machines, the new system does not require a safety zone or a radio-frequency shielded room. Since it is fully enclosed, medical device implants or equipment in the NICU in close proximity are not required to be MRI-compatible.  Other advantages include an always-on permanent magnet; it therefore requires no electrical, cryogenic or water cooling (click here for more details on this product).

Other approaches to neonate imaging are also under evaluation.
Cincinnati Children’s Hospital in the US, for example, has installed a commercial 1.5-T MRI system in its NICU, based on an orthopedic system coupled to custom-built components – most significantly, a high-end scanner. The unit’s gradient coil is about 2.5 times shorter than a conventional adult-sized system. In January 2014, the ‘American Journal of Roentgenology’ published results of a study at the hospital on imaging neonates. Although its scope was small (15 infants), the authors concluded that the system was capable of producing “high quality” images of neonates, not only of the brain but also the abdomen and chest.
As with other efforts to date, the modified system also attained several collateral objectives, such as ease of installation and operation in an NICU, improved visual contact and physical access to the infant, along with the use of advanced imaging techniques, ECG and respiratory gating and triggering.  One of “the most important benefits”, according to the authors, consisted of “the reduction of risk associated with transport of the neonate to and from the NICU.” As discussed previously, this has been the single biggest challenge for neonate imaging and a driver of most design and technology development for over 25 years.