Towards in vivo characterization of thyroid nodules suspicious for malignancy using multispectral optoacoustic tomography.

PURPOSE: Patient-tailored management of thyroid nodules requires improved risk of malignancy stratification by accurate preoperative nodule assessment, aiming to personalize decisions concerning diagnostics and treatment. Here, we perform an exploratory pilot study to identify possible patterns on multispectral optoacoustic tomography (MSOT) for thyroid malignancy stratification. For the first time, we directly correlate MSOT images with histopathology data on a detailed level. METHODS: We use recently enhanced data processing and image reconstruction methods for MSOT to provide next-level image quality by means of improved spatial resolution and spectral contrast. We examine optoacoustic features in thyroid nodules associated with vascular patterns and correlate these directly with reference histopathology. RESULTS: Our methods show the ability to resolve blood vessels with diameters of 250 µm at depths of up to 2 cm. The vessel diameters derived on MSOT showed an excellent correlation (R2-score of 0.9426) with the vessel diameters on histopathology. Subsequently, we identify features of malignancy observable in MSOT, such as intranodular microvascularity and extrathyroidal extension verified by histopathology. Despite these promising features in selected patients, we could not determine statistically relevant differences between benign and malignant thyroid nodules based on mean oxygen saturation in thyroid nodules. Thus, we illustrate general imaging artifacts of the whole field of optoacoustic imaging that reduce image fidelity and distort spectral contrast, which impedes quantification of chromophore presence based on mean concentrations. CONCLUSION: We recommend examining optoacoustic features in addition to chromophore quantification to rank malignancy risk. We present optoacoustic images of thyroid nodules with the highest spatial resolution and spectral contrast to date, directly correlated to histopathology, pushing the clinical translation of MSOT.

An aggressive lactotroph pituitary tumor in a young male: A pituitary carcinoma without metastasis.

This case report concerns a 31-year-old male with an aggressive pituitary tumor who presented initially with bitemporal hemianopsia and slightly elevated prolactin. On magnetic resonance imaging of the brain, there was a sellar mass with parasellar invasion to the lateral aspects of the internal carotid arteries, compressing the optic chiasm. On histopathological analysis, the diagnosis was made of a densely granulated lactotroph pituitary tumor with a Ki67 proliferation rate of 15%, a mitotic count of 6/10 high-power fields, and p53 positivity. Based on these features, the tumor was classified as a grade 2b tumor according to the Trouillas classification, and a more aggressive behavior of the tumor could be expected. In order to anticipate a future need for alternative drug treatments, the following analyses were undertaken: MGMT methylation (present) as well as the expression of estrogen receptor (negative), programmed-death ligand 1 (60 - 70% positive tumor cells), vascular endothelial growth factor-A and somatostatin receptor 2 (both positive). There was regrowth of residual tumor tissue, and the treatment consisted thus far of repeat surgery, cabergoline, pasireotide, and radiotherapy. Chemotherapy with temozolomide could not yet be initiated due to a concurrent infertility treatment. This case is unique because the tumor displays atypical characteristics, both in terms of morphology and behavior. It also illustrates how pathologists can play an important role in determining the diagnosis, prognosis, and possibilities for targeted therapy.

An aggressive poorly differentiated plurihormonal Pit-1-positive adenoma.

SUMMARY: In July 2017, a 35-year-old woman was referred to our care for treatment of a large pituitary mass with an unusually high growth rate. She presented with right-sided ptosis and diplopia (n. III palsy), increasing retrobulbar pain and vertigo. Although laboratory investigations were consistent with acromegaly, she exhibited no clear phenotypic traits. During transsphenoidal surgery aimed at biopsy, typical adenomatous tissue was encountered, upon which it was decided to proceed to debulking. Histopathological analysis demonstrated a poorly differentiated plurihormonal Pit-1-positive adenoma with focal growth hormone (GH) and prolactin positivity, positive SSTR2 staining and a Ki-67 of 20-30%. Postoperative magnetic resonance imaging (MRI) examination revealed a large tumour remnant within the sella invading the right cavernous sinus with total encasement of the internal carotid artery and displacement of the right temporal lobe. As a consequence, she was treated additionally with radiotherapy, and a long-acting first-generation somatostatin analogue was prescribed. Subsequently, the patient developed secondary hypocortisolism and diabetes mellitus despite adequate suppression of GH levels. In September 2019, her symptoms recurred. Laboratory evaluations indicated a notable loss of biochemical control, and MRI revealed tumour progression. Lanreotide was switched to pasireotide, and successful removal of the tumour remnant and decompression of the right optic nerve was performed. She received adjuvant treatment with temozolomide resulting in excellent biochemical and radiological response after three and six courses. Symptoms of right-sided ptosis and diplopia remained. Evidence for systemic therapy in case of tumour progression after temozolomide is currently limited, although various potential targets can be identified in tumour tissue. LEARNING POINTS: Poorly differentiated plurihormonal Pit-1-positive adenoma is a potentially aggressive subtype of pituitary tumours. This subtype can express somatostatin receptors, allowing treatment with somatostatin analogues. A multidisciplinary approach involving an endocrinologist, neurosurgeon, pituitary pathologist, neuroradiologist, radiation oncologist and medical oncologist is key for the management of patients with aggressive pituitary tumours, allowing the successful application of multimodality treatment. Temozolomide is first-line chemotherapy for aggressive pituitary tumours and carcinomas. Further development of novel targeted therapies, such as peptide receptor radionuclide therapy (PRRT), vascular endothelial growth factor (VEGF) receptor-targeted therapy, tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors and immune checkpoint inhibitors, is needed.

Diagnostic reliability of low dose multidetector CT and cone beam CT in maxillofacial trauma-an experimental blinded and randomized study.

OBJECTIVES: To assess the diagnostic reliability of low dose multidetector CT (MDCT) and cone beam CT (CBCT) for zygomaticomaxillary fracture diagnosis. METHODS: Unilateral zygomaticomaxillary fractures were inflicted on four out of six fresh frozen human cadaver head specimens. All specimens were scanned using four MDCT and two CBCT imaging protocols of which the radiation exposure was systematically reduced. A blinded diagnostic routine was simulated at which 16 radiologists and 8 oral and maxillofacial (OMF) surgeons performed randomized image assessments. We considered the findings during an open operative approach of the zygomatic region as the gold standard. RESULTS: Zygomaticomaxillary fractures were correctly diagnosed in 90.3% (n = 130) of the image assessments. The zygomatic arch was most often correctly diagnosed (91.0%). The zygomatic alveolar crest showed the lowest degree of correct diagnosis (65.3%). Dose reduction did not significantly affect the objective visualization of fractures of the zygomaticomaxillary complex. The sensitivity and specificity also remained consistent among the low dose scan protocols. Dose reduction did not decrease the ability to assess dislocation, comminution, orbital volume, volume rendering and soft tissues. OMF surgeons considered the low dose protocols sufficient for treatment planning. CONCLUSIONS: Dose reduction did not decrease the diagnostic reliability of MDCT and CBCT for the diagnosis of zygomaticomaxillary fractures.

Incidence of Tumour Progression and Pseudoprogression in High-Grade Gliomas: a Systematic Review and Meta-Analysis.

BACKGROUND: High-grade gliomas are the most common primary brain tumours. Pseudoprogression describes the false appearance of radiation-induced progression on MRI. A distinction should be made from true tumour progression to correctly plan treatment. However, there is wide variation of reported pseudoprogression. We thus aimed to establish the incidence of pseudoprogression and tumour progression in high-grade glioma patients with a systematic review and meta-analysis. METHODS: We searched PubMed, Embase and Web of Science on the incidence of pseudoprogression and tumour progression in adult high-grade glioma patients from 2005, the latest on 8 October 2014. Histology or imaging follow-up was used as reference standard. Extracted data included number of patients with worsening of imaging findings on T1 postcontrast or T2/FLAIR, pseudoprogression and tumour progression. Study quality was assessed. Heterogeneity was tested with I 2 . Pooling of the results was done with random models using Metaprop in STATA (StataCorp. Stata Statistical Software. College Station, TX: StataCorp LP). RESULTS: We identified 73 studies. MRI progression occurred in 2603 patients. Of these, 36% (95% confidence interval [CI] 33-40%) demonstrated pseudoprogression, 60% (95%CI 56-64%) tumour progression and unknown outcome was present in the remaining 4% of the patients (range 1-37%). CONCLUSION: This meta-analysis demonstrated for the first time a notably high pooled incidence of pseudoprogression in patients with a form of progression across the available literature. This highlighted the full extent of the problem of the currently conventional MRI-based Response Assessment in Neuro-Oncology (RANO) criteria for treatment evaluation in high-grade gliomas. This underscores the need for more accurate treatment evaluation using advanced imaging to improve diagnostic accuracy and therapeutic approach.

Diagnostic accuracy of magnetic resonance imaging techniques for treatment response evaluation in patients with head and neck tumors, a systematic review and meta-analysis.

BACKGROUND: Novel advanced MRI techniques are investigated in patients treated for head and neck tumors as conventional anatomical MRI is unreliable to differentiate tumor from treatment related imaging changes. PURPOSE: As the diagnostic accuracy of MRI techniques to detect tumor residual or recurrence during or after treatment is variable reported in the literature, we performed a systematic meta-analysis. DATA SOURCES: Pubmed, EMBASE and Web of Science were searched from their first record to September 23th 2014. STUDY SELECTION: Studies reporting diagnostic accuracy of anatomical, ADC, perfusion or spectroscopy to identify tumor response confirmed by histology or follow-up in treated patients for head and neck tumors were selected by two authors independently. DATA ANALYSIS: Two authors independently performed data extraction including true positives, false positives, true negatives, false negatives and general study characteristics. Meta-analysis was performed using bivariate random effect models when ≥5 studies per test were included. DATA SYNTHESIS: We identified 16 relevant studies with anatomical MRI and ADC. No perfusion or spectroscopy studies were identified. Pooled analysis of anatomical MRI of the primary site (11 studies, N = 854) displayed a sensitivity of 84% (95%CI 72-92) and specificity of 82% (71-89). ADC of the primary site (6 studies, N = 287) showed a pooled sensitivity of 89% (74-96) and specificity of 86% (69-94). LIMITATIONS: Main limitation are the low, but comparable quality of the included studies and the variability between the studies. CONCLUSIONS: The higher diagnostic accuracy of ADC values over anatomical MRI for the primary tumor location emphases the relevance to include DWI with ADC for response evaluation of treated head and neck tumor patients.

Delineation of organs at risk involved in swallowing for radiotherapy treatment planning.

BACKGROUND AND PURPOSE: Radiotherapy, alone or combined with chemotherapy, is a treatment modality used frequently in head and neck cancer. In order to report, compare and interpret the sequelae of radiation treatment adequately, it is important to delineate organs at risk (OARs) according to well-defined and uniform guidelines. The aim of this paper was to present our institutional Computed Tomography (CT)-based delineation guidelines for organs in the head and neck at risk for radiation-induced swallowing dysfunction (SWOARs). MATERIAL AND METHODS: After analyses of the human anatomy of the head and neck area and literature review, CT-based guidelines for delineation of the most relevant SWOARs were described by a panel of experts. RESULTS AND CONCLUSIONS: This paper described institutional guidelines for the delineation of potential SWOARs, accompanied by CT-based illustrations presenting examples of the delineated structures and their corresponding anatomic borders. This paper is essential to ensure adequate interpretation of future reports on the relationship between dose distribution in these SWOARs and different aspects of post-treatment swallowing dysfunction.

Intracranial aneurysms in patients with subarachnoid hemorrhage: CT angiography as a primary examination tool for diagnosis--systematic review and meta-analysis.

PURPOSE: To calculate the sensitivity and specificity of computed tomographic (CT) angiography in the diagnosis of cerebral aneurysms in patients with acute subarachnoid hemorrhage (SAH) at presentation. MATERIALS AND METHODS: A systematic search for relevant studies was performed of the PubMed/MEDLINE and EMBASE databases. Two reviewers independently assessed the methodologic quality of each study by using the Quality Assessment of Diagnostic Accuracy Studies tool. The inclusion criteria were met by 50 studies. Heterogeneity was tested, and the presence of publication bias was visually assessed (by using a funnel plot). A meta-analysis of the reported sensitivity and specificity of each study with 95% confidence intervals (CIs) was performed on a per-patient level. RESULTS: Concerning sensitivity, the selected studies showed moderate heterogeneity. For specificity, low heterogeneity was observed. Moderate-heterogeneity studies that investigated only sensitivity or specificity were excluded from the pooled analyses by using a bivariate random effects model. The majority of the studies (n = 30) used a four-detector row CT scanner. The studies had good methodologic quality. Pooled sensitivity was 98% (95% CI: 97%, 99%), and pooled specificity was 100% (95% CI: 97%, 100%). Potential sources of variability among the studies were variations in the methodologic features (quality score), CT examination procedure (number of rows on the multidetector CT scanner), the standard of reference used, and the prevalence of ruptured intracranial aneurysms. There was evidence for publication bias, which may have led to overestimation of the diagnostic accuracy of CT angiography. CONCLUSION: Multidetector CT angiography can be used as a primary examination tool in the diagnostic work-up of patients with SAH.

Feasibility of magnetic resonance angiography (MRA) follow-up as the primary imaging modality after coiling of intracranial aneurysms.

BACKGROUND: Digital subtraction angiography (DSA) is still regarded as the gold standard for detecting residual flow in treated aneurysms. Recent reports have also shown excellent results from magnetic resonance angiography (MRA) imaging. This is an important observation, since DSA is associated with a risk of medical complications, is time consuming, and is more expensive. PURPOSE: To determine whether MRA could replace conventional DSA and serve as the primary postinterventional imaging modality in patients with coiled intracranial aneurysms. MATERIAL AND METHODS: We studied a prospectively enrolled cohort of 190 patients treated endovascularly for a first-ruptured and/or unruptured intracranial aneurysm between January 2004 and December 2008. The imaging protocol included a 1.5T time-of-flight (TOF) MRA and a DSA at 3 months (on the same day) and, depending on comparability, a 1.5T TOF-MRA or DSA 1 year after treatment. All images were evaluated by a multidisciplinary panel. RESULTS: In 141/190 patients, both an MRA and DSA were performed after 3-month follow-up. In 2/141 patients (1.4%), (small) neck remnants gave false-negative MRA results. In one patient (0.7%), this led to additional neurosurgical clipping of the aneurysm. In 25/141 patients, future follow-up (>3 months) consisted of DSA because of various reasons. In 24/25 of these patients, primary MRA images alone would invariably have led to additional DSA imaging. CONCLUSION: The present study shows that 1.5T TOF-MRA is a feasible primary follow-up modality after coiling of intracranial aneurysms. Given our data, we now suggest that, in every patient with a coiled intracranial aneurysm, the first follow-up, 3 months after coiling, should be an MRA study. Only when this MRA is inconclusive (e.g., because of coil artifacts), or in the case of suspicion of recanalization, should DSA be performed additionally.

Delineation guidelines for organs at risk involved in radiation-induced salivary dysfunction and xerostomia.

BACKGROUND AND PURPOSE: It is believed that minimizing inconsistencies in OAR-volume definition will help to improve adequate reporting and interpreting of radiation treatment results. The aim of this paper is to introduce computed tomography (CT)-based delineation guidelines for organs at risk (OARs) in the head and neck area, associated with radiation-induced salivary dysfunction and xerostomia. MATERIAL AND METHODS: After analyses of the human anatomy of the head and neck area, computed tomography (CT)-based guidelines for delineation of the most relevant OARs were described by a panel of experts. RESULTS AND CONCLUSIONS: The provided OAR guidelines are accompanied by CT-based illustrations presenting examples of the delineated structures and their corresponding anatomic boundaries. The parts of the tongue bearing minor salivary glands could not be outlined. Difficulties and uncertainties in defining these minor salivary glands on CT remain to be resolved. Implementation of these guidelines in practice should lead to a reduction in inter- and intra-observer variability and therefore unambiguous reporting of possible dose-volume effect relationships.

Magnetic resonance angiography in the selection of patients suitable for neurosurgical intervention of ruptured intracranial aneurysms.

This study was aimed at establishing whether magnetic resonance angiography (MRA) can be applied to planning and performing surgery on ruptured intracranial aneurysms, especially in the early phase, without recourse to intra-arterial digital subtraction angiography (IA-DSA). From February 1998 to August 2001, in all patients presenting with a subarachnoid hemorrhage, MRA was performed first. A three-dimensional time-of-flight MRA protocol with T2-weighted coronal and axial images was used. If MRA demonstrated an aneurysm, surgery was undertaken. IA-DSA was limited to patients with negative or inconclusive MRA findings. We compared MRA images with operative findings in positive patients and with IA-DSA in negatives. IA-DSA was considered the gold standard when MRA findings were inconclusive. In this study, 205 consecutive patients (mean age 52.7 years, 69% women) were included. In 133 patients (64.9%) MRA demonstrated an aneurysm, directly followed by neurosurgical intervention. In 33 patients (16.1%) MRA findings were categorized as inconclusive. In 39 patients (19.0%) MRA results were negative. No false-negative ruptured aneurysms were selected by MRA. In only one patient surgical intervention was performed based on false-positive MRA findings. MRA can replace IA-DSA as a first diagnostic modality in the selection of patients suitable for surgical treatment of ruptured intracranial aneurysms.