Expanding the spectrum of low-grade sinonasal adenocarcinoma with biphasic seromucinous differentiation and activating HRAS/AKT1 mutations.

AIMS: Low-grade non-intestinal-type sinonasal adenocarcinoma (LGSNAC) is a rare heterogeneous and poorly characterised group of tumours, distinct from intestinal- and salivary-type neoplasms. Therefore, further characterisation is needed for clearer biological understanding and classification. METHODS AND RESULTS: Clinical, histological and molecular characterisation of four cases of biphasic, low-grade adenocarcinomas of the sinonasal tract was performed. All patients were male, aged between 48 and 78 years, who presented with polypoid masses in the nasal cavity. Microscopically, virtually all tumours were dominated by tubulo-glandular biphasic patterns, microcystic, focal (micro)papillary, oncocytic or basaloid features. Immunohistochemical staining confirmed biphasic differentiation with an outer layer of myoepithelial cells. Molecular profiling revealed HRAS (p.G13R, p.Q61R) mutations, and concomitant AKT1 (p.E17K, p.Q79R) mutations in two cases. Two cases showed potential in-situ/precursor lesions adjacent to the tumour. Follow-up periods ranged from 1 to 30 months, with one case relapsing locally after 12 and > 20 years. CONCLUSION: This study further corroborates a distinct biphasic low-grade neoplasm of the sinonasal tract with seromucinous differentiation. Although morphological and molecular features overlap with salivary gland epithelial-myoepithelial carcinoma, several arguments favour categorising these tumours within the spectrum of LGSNAC.

Clinical predictors of negative/equivocal SPECT imaging outcomes in primary hyperparathyroidism: Factors calling for 18F-choline-PET.

PURPOSE: For minimally invasive surgery of parathyroid adenomas, exact localization diagnostics are essential. Main imaging modalities used for diagnostics are sonography, SPECT with/without CT (traditional imaging) and 18F-choline-PET. The aim of our study was to identify predictors for inconclusive SPECT imaging and subsequently determine in which cases 18F-choline-PET is needed. METHODS: Retrospective analysis of 138 patients with histologically confirmed primary hyperparathyroidism (pHPT). After sonography, patients underwent SPECT or SPECT/CT imaging, with subsequent 18F-choline-PET in cases of disconcordant results. Logistic regression analysis was used to identify clinical and laboratory factors predictive for negative SPECT results. RESULTS: Sensitivity rates for sonography, SPECT, SPECT/CT, and choline-PET were 47 %, 49 %, 71.7 %, and 97 %, respectively. Logistic regression revealed lower PTH levels (p < 0.001), presence of structural thyroid disease (p = 0.018), and negative sonography (p < 0.001) as predictive of negative/equivocal SPECT outcome. An additional traditional imaging CT scan to a SPECT enhanced detection odds, as did greater adenoma weight. Urolithiasis, osteoporosis, and calcium values as measurement of activity and duration of disease showed no significant association with the detection rate. Furthermore, our study demonstrated that 18F-choline-PET exhibited remarkable sensitivity in detecting adenomas among patients with negative/equivocal SPECT results. CONCLUSION: Our study reveals potential predictive factors for a negative/equivocal SPECT outcome in pHPT. Identifying these factors might allow minimizing futile SPECT examinations and perhaps encourage timely utilization of 18F-choline-PET imaging. Our study reinforces the clinical significance of 18F-choline-PET, especially in complex cases with disconcordant results by conventional parathyroid imaging methods.

Prediction of extranodal extension in oropharyngeal cancer patients and carcinoma of unknown primary: value of metabolic tumor imaging with hybrid PET compared with MRI and CT.

OBJECTIVES: The aim of this study was to investigate the value of metabolic tumor imaging using hybrid PET for the preoperative detection of extranodal extension (ENE) in lymph node metastases of oropharyngeal squamous cell carcinoma (OPSCC). METHODS: We performed a retrospective analysis of a consecutive cohort of patients with OPSCC treated with primary surgery with or without adjuvant (chemo-) radiotherapy at the Kantonsspital Sankt-Gallen and the University Hospital Zurich, Switzerland, from 2010 until 2019. Hybrid PET was compared to conventional cross-sectional imaging with MRI and CT. Histopathological presence of ENE of neck dissection specimen served as gold standard. RESULTS: A total number of 234 patients were included in the study, 95 (40.6%) of which had pathological ENE (pENE). CT has a good specificity with 93.7%; meanwhile, MRI was the most sensitive diagnostic method (72.0%). The nodal metabolic tumor parameters (SUVmax, TLG, MTV) were significantly higher in patients with positive ENE (p < 0.001 for all three parameters) than in patients with negative ENE (p < 0.001, for all three parameters). CONCLUSIONS: CT achieved the best specificity, while MRI had the best sensitivity to detect ENE. Nodal metabolic tumor parameters differed significantly between ENE-positive/negative and p16-positive/negative patients. Hence, quantitative data obtained by metabolic imaging might predict presence of ENE and, therefore, could be helpful in customizing therapy management.

SUVmax for predicting regional control in oropharyngeal cancer.

PURPOSE: To investigate the predictive value of pretherapeutic metabolic tumor imaging using 18-fluorodeoxyglucose positron emission tomography (FDG-PET) for regional response in oropharyngeal cancer patients undergoing primary (chemo)radiation. METHODS: Retrospective analysis of oropharyngeal cancer patients treated with primary (chemo)radiation at the University Hospital Zurich from 2010 to 2019 with available FDG-PET. The SUVmax of the largest lymph node metastases was recorded. Regional response was assessed using posttherapeutic FDG-PET at 12 weeks and regional recurrence-free survival. RESULTS: 95 patients with a mean age of 68.5 years (SD 10.3) were included. The median pretherapeutic nodal SUVmax was 8.3 (interquartile range 4.4-13.3). A pretherapeutic nodal SUVmax above 6 significantly predicted poorer regional recurrence-free survival (log-rank test, P = 0.009) in univariate analysis. However, in multivariate analysis SUVmax above 6 was not significant in predicting regional recurrence-free survival (Cox regression P = 0.189). Clinical N category showed a trend in which a more severe stage had a poorer regional survival (Cox regression P = 0.073). CONCLUSION: The SUVmax of the largest lymph node metastasis seems to play a role in predicting regional response in oropharyngeal cancer patients, after stratifying for N category. More research is needed to investigate whether highly metabolically active disease is less likely to respond to chemoradiation.

FDG-PET/CT for oral focus assessment in head and neck cancer patients.

OBJECTIVES: To compare oral and maxillo-mandibular inflammatory foci on standard oral radiographs (OPT, periapical radiograph) with available fluorine-18-labelled fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) data and to discuss whether additional metabolic information derived from FDG-PET/CT can support oral care specialists when performing oral focus examinations. MATERIALS AND METHODS: Data from 23 patients with head and neck cancer who underwent FDG-PET/CT and panoramic and periapical radiography in close succession before first-line radiotherapy and/or chemotherapy were included in this exploratory retrospective study. Periapical lesions and marginal periodontal inflammation on FDG-PET/CT scans and standard oral radiographs were analysed and compared with regard to metabolic activity on FDG-PET/CT in comparison to recorded clinical symptoms and radiological scores. Additionally, inflammatory maxillo-mandibular pathologies were analysed using FDG-PET/CT. RESULTS: The maximum standardised uptake value (SUVmax) in FDG-avid marginal periodontal sites could not be conclusively associated with the radiologically recorded severity of marginal bone loss, but a potential positive correlation was identified. No association was found either between the metabolic activity of periapical lesions and their extent, as recorded on standard oral radiographs, or regarding clinical symptoms (percussion test). Most maxillo-mandibular pathologies did not show increased FDG uptake. CONCLUSIONS: FDG-PET/CT provided additional metabolic information that can help clinicians identify lesions with increased inflammatory activity. The incorporation of available oral FDG-PET/CT findings into the primary oral focus assessment may allow for more accurate oral focus treatment. CLINICAL RELEVANCE: FDG-PET/CT provides valuable metabolic information for oral care specialists. The detection of inflammatory oral processes using FDG-PET/CT facilitates treatment.

Current concepts in advanced sinonasal mucosal melanoma: a single institution experience.

PURPOSE: To present outcome measures of sinonasal mucosal melanoma (SMM) patients with particular focus on current radiological and therapeutic options, especially in the non-curative setting (immunotherapy). METHODS: Retrospective study on SMM patients treated at our institution between January 1992 and December 2018. RESULTS: FDG-PET/MRI has emerged as the new hybrid imaging modality, addressing the need for high local tissue contrast in the paranasal sinuses and the skull base, while allowing for whole-body staging in search for distant metastases, including the brain. Primary treatment protocols consisted of tumor resection in 30/34 patients (88%), palliative radiation therapy (RT) in 3/34 patients (9%) and best supportive care therapy in 1/34 patient (3%). Of all the initially operated patients, 25/30 patients (83%) received adjuvant RT. A total of 9/34 patients (26%) was treated with immunotherapy after the previous combined therapy. For patients treated in curative intention, we observed a 1-year overall survival (OS) of 60% (18/30 patients) and a 3-year OS of 40% (12/30 patients). For patients treated with immunotherapy, median progression-free survival (PFS) was 5 months (IQR 0-13.75), with a maximum PFS of 16 months (combination of nivolumab and ipilimumab). However, there was no difference in OS in patients treated with immunotherapy vs. no immunotherapy (log rank 0.99). CONCLUSIONS: Sinonasal mucosal melanoma is a highly aggressive tumor, requiring multimodal therapy and developing a substantial incidence of distant metastases. The introduction of FDG-PET/MRI offers new possibilities in the radiological assessment of the tumor and immunotherapy has altered the management in the non-curative setting, resulting in a substantial progression-free survival in selected cases.

WITHDRAWN: Evaluation of multifunctional imaging parameters in gastro-oesophageal cancer using F-18-FDG-PET/CT with integrated perfusion CT.

Ahead of Print article withdrawn by publisher.

Oral manifestation of Langerhans cell histiocytosis: a case report.

BACKGROUND: Bone necrosis of the jaw is a serious condition with a broad differential diagnosis of pathologies such as cutaneous histiocytosis, bone metastases or malignant tumours. In addition to the most common cause, medication related osteonecrosis of the jaw (MRONJ), one must consider a number of other causes, such as histiocytosis. Langerhans cell histiocytosis (LCH) is a histiocytic disorder with a large spectrum of clinical manifestations and with possible involvement of a variety of organs. This case shows the importance of an early detection of this rare disease in order to prevent further spreading. Even if an initial diagnosis in the oral cavity is rare, dentists should be aware of this disease. CASE PRESENTATION: The presented case describes a patient who was referred for evaluation and treatment due to exposed bone and extensive osteolysis in the region of the upper and lower jaw. After biopsy and diagnosis of LCH, the patient was treated with systemic therapy, achieved remission and is disease free after a 2 year of follow up. CONCLUSIONS: This case report illustrates that when dealing with unclear osteolytic changes of the jawbone, Langerhans cell histiocytosis must be taken into consideration in the differential diagnosis and biopsy must be performed in case of suspicion.

Effect of Time-of-Flight Information on PET/MR Reconstruction Artifacts: Comparison of Free-breathing versus Breath-hold MR-based Attenuation Correction.

Purpose To evaluate the magnitude and anatomic extent of the artifacts introduced on positron emission tomographic (PET)/magnetic resonance (MR) images by respiratory state mismatch in the attenuation map. Materials and Methods The method was tested on 14 patients referred for an oncologic examination who underwent PET/MR imaging. The acquisition included standard PET and MR series for each patient, and an additional attenuation correction series was acquired by using breath hold. PET data were reconstructed with and without time-of-flight (TOF) information, first by using the standard free-breathing attenuation map and then again by using the additional breath-hold map. Two-tailed paired t testing and linear regression with 0 intercept was performed on TOF versus non-TOF and free-breathing versus breath-hold data for all detected lesions. Results Fluorodeoxyglucose-avid lesions were found in eight of the 14 patients included in the study. The uptake differences (maximum standardized uptake values) between PET reconstructions with free-breathing versus breath-hold attenuation ranged, for non-TOF reconstructions, from -18% to 26%. The corresponding TOF reconstructions yielded differences from -15% to 18%. Conclusion TOF information was shown to reduce the artifacts caused at PET/MR by respiratory mismatch between emission and attenuation data. © RSNA, 2016 Online supplemental material is available for this article.

Combined PET/CT-perfusion in patients with head and neck cancers might predict failure after radio-chemotherapy: a proof of concept study.

BACKGROUND: [18F]FDG-PET/CT imaging is broadly used in head and neck cancer (HNSCC) patients. CT perfusion (CTP) is known to provide information about angiogenesis and blood-flow characteristics in tumors. The aim of this study was to evaluate the potential relationship of FDG-parameters and CTP-parameters in HNSCC preand post-therapy and the potential prognostic value of a combined PET/CT with CTP. METHODS: Thirteen patients with histologic proven HNSCC were prospectively included. All patients underwent a combined PET/CT with integrated CTP before and after therapy. Pre- and post-therapeutic data of CTP and PET of the tumors were compared. Differences were tested using Spearman's rho test and Pearson's correlation. A p-value of p <0.05 was considered statistically significant. Correlations were calculated using Pearson's correlation. Bootstrap confidence intervals were calculated to test for additive confidence intervals. RESULTS: Three patients died due to malignancy recurrence, ten patients were free of recurrence until the end of the follow-up period. Patients with recurrent disease had significantly higher initial CTP-values compared to the recurrence-free patients: BFpre 267.4 (171.2)ml/100 mg/min, BVpre 40.9 (8.4)ml/100 mg and MTTpre 8.2 (6.1)sec. No higher SUVs initially but significantly higher TLG compared to patients without recurrence were found. Post-therapeutic PET-values differed significantly between the two groups: SUVmaxpost 6.0 (3.2), SUVmeanpost 3.6 (2.0) and TLG 21751.7 (29794.0). CONCLUSION: In our proof of concept study, combined PET/CT with integrated CTP might show complementary prognostic data pre- and post chemo-radiotherapy. CTP may be used to predict local tumor recurrence, while FDGPET/CT is still needed for whole-body staging.

Evaluation of pelvic ring injuries using SPECT/CT.

OBJECTIVE: The incidence of pelvic fractures is relatively low compared with other fracture locations. The low incidence is in great contrast to the high morbidity and mortality. Particularly in the elderly, with apparently isolated fractures of the pubic rami, these observations are believed to be due to additional occult lesions of the posterior pelvic ring. In these cases diagnosis cannot be established by conventional imaging alone and SPECT/CT is considered as a diagnostic adjunct. The aim of this study was to assess concomitant bony or soft tissue lesions within the pelvic ring in a population of patients with fractures of the anterior elements. MATERIALS AND METHODS: In all patients with no obvious lesions of the posterior pelvic ring on X-rays and CT or with suspicious but inconclusive findings on CT an additional SPECT/CT was carried out in a non-acute setting within 3 days of the trauma. RESULTS: In all cases additional lesions within the pelvic ring were found. Most lesions were vertical sacral fractures, followed by transverse fractures, one non-dislocated fracture of the acetabulum on the side of the pubic rami fracture, and one post-traumatic dilatation of the sacroiliac joint with increased tracer uptake. CONCLUSION: According to our results after SPECT/CT all patients with pubic rami fracture suffered additional lesions, none detectable previously by X-ray or CT, within the pelvic ring. In this context SPECT/CT has proved to be very helpful in the clinical routine to visualize occult fractures and instability within the sacroiliac joint.

Use of diffusion-weighted imaging (DWI) in PET/MRI for head and neck cancer evaluation.

OBJECTIVE: The purpose of this study was to analyze whether diffusion-weighted imaging (DWI) adds significant information to positron emission tomography/magnetic resonance imaging (PET/MRI) on lesion detection and characterization in head and neck cancers. METHODS: Seventy patients with different head and neck cancers were enrolled in this prospective study. All patients underwent sequential contrast-enhanced (ce) PET/computed tomography (CT) and cePET/MRI using a tri-modality PET/CT-MR setup either for staging or re-staging. First, the DWI alone was evaluated, followed by the PET/MRI with conventional sequences, and in a third step, the PET/MRI with DWI was evaluated. McNemar's test was used to evaluate differences in the accuracy of PET/MRI with and without DWI compared to the standard of reference. RESULTS: One hundred eighty-eight (188) lesions were found, and of those, 118 (62.8%) were malignant and 70 (37.2%) were benign. PET/MRI without DWI had a higher accuracy in detecting malignant lesions than DWI alone (86.8% vs. 60.6%, p < 0.001). PET/MRI combined with DWI detected 120 concurrent lesions (89 malignant and 31 benign), PET/MRI alone identified 48 additional lesions (20 malignant and 28 benign), and DWI alone detected 20 different lesions (nine malignant and 11 benign). However, lesions detected on DWI did not change overall staging. SUV maximum and mean were significantly higher in malignant lesions than in benign lesions. DWI parameters between malignant and benign lesions were not statistically different. CONCLUSION: The use of DWI as part of PET/MRI to evaluate head and neck cancers does not provide remarkable information. Thus, the use of DWI might not be needed in clinical PET/MRI protocols for the staging or restaging of head and neck cancers.

PET/MRI and PET/CT in follow-up of head and neck cancer patients.

PURPOSE: Positron emission tomography (PET)/MRI combines the functional ability of PET and the high soft tissue contrast of MRI. The aim of this study was to assess contrast-enhanced (ce)PET/MRI compared to cePET/CT in patients with suspected recurrence of head and neck cancer (HNC). METHODS: Eighty-seven patients underwent sequential cePET/CT and cePET/MRI using a trimodality PET/CT-MRI set-up. Diagnostic accuracy for the detection of recurrent HNC was evaluated using cePET/CT and cePET/MRI. Furthermore, image quality, presence of unclear (18)F-fluorodeoxy-D-glucose (FDG) findings of uncertain significance and the diagnostic advantages of use of gadolinium contrast enhancement were analysed. RESULTS: cePET/MRI showed no statistically significant difference in diagnostic accuracy compared to cePET/CT (91.5 vs 90.6%). Artefacts' grade was similar in both methods, but their location was different. cePET/CT artefacts were primarily located in the suprahyoid area, while on cePET/MRI, artefacts were more equally distributed among the supra and infrahyoid neck regions. cePET/MRI and cePET/CT showed 34 unclear FDG findings; of those 11 could be solved by cePET/MRI and 5 by cePET/CT. The use of gadolinium in PET/MRI did not yield higher diagnostic accuracy, but helped to better define tumour margins in 6.9% of patients. CONCLUSION: Our data suggest that cePET/MRI may be superior compared to cePET/CT to specify unclear FDG uptake related to possible tumour recurrence in follow-up of patients after HNC. It seems to be the modality of choice for the evaluation of the oropharynx and the oral cavity because of a higher incidence of artefacts in cePET/CT in this area mainly due to dental implants. However, overall there is no statistically significant difference.

Protocol requirements and diagnostic value of PET/MR imaging for liver metastasis detection.

PURPOSE: To compare the accuracy of PET/MR imaging with that of FDG PET/CT and to determine the MR sequences necessary for the detection of liver metastasis using a trimodality PET/CT/MR set-up. METHODS: Included in this single-centre IRB-approved study were 55 patients (22 women, age 61 ± 11 years) with suspected liver metastases from gastrointestinal cancer. Imaging using a trimodality PET/CT/MR set-up (time-of-flight PET/CT and 3-T whole-body MR imager) comprised PET, low-dose CT, contrast-enhanced (CE) CT of the abdomen, and MR with T1-W/T2-W, diffusion-weighted (DWI), and dynamic CE imaging. Two readers evaluated the following image sets for liver metastasis: PET/CT (set A), PET/CECT (B), PET/MR including T1-W/T2-W (C), T1-W/T2-W with either DWI (D) or CE imaging (E), and a combination (F). The accuracy of each image set was determined by receiver-operating characteristic analysis using image set B as the standard of reference. RESULTS: Of 120 liver lesions in 21/55 patients (38%), 79 (66%) were considered malignant, and 63/79 (80%) showed abnormal FDG uptake. Accuracies were 0.937 (95% CI 89.5 - 97.9%) for image set A, 1.00 (95% CI 99.9 - 100.0%) for set C, 0.998 (95% CI 99.4 - 100.0%) for set D, 0.997 (95% CI 99.3 - 100.0%) for set E, and 0.995 (95% CI 99.0 - 100.0%) for set F. Differences were significant for image sets D - F (P < 0.05) when including lesions without abnormal FDG uptake. As shown by follow-up imaging after 50 - 177 days, the use of image sets D and both sets E and F led to the detection of metastases in one and three patients, respectively, and further metastases in the contralateral lobe in two patients negative on PET/CECT (P = 0.06). CONCLUSION: PET/MR imaging with T1-W/T2-W sequences results in similar diagnostic accuracy for the detection of liver metastases to PET/CECT. To significantly improve the characterization of liver lesions, we recommend the use of dynamic CE imaging sequences. PET/MR imaging has a diagnostic impact on clinical decision making.

Characterization of the impact to PET quantification and image quality of an anterior array surface coil for PET/MR imaging.

OBJECT: The aim of this study was to determine the impact to PET quantification, image quality and possible diagnostic impact of an anterior surface array used in a combined PET/MR imaging system. MATERIALS AND METHODS: An extended oval phantom and 15 whole-body FDG PET/CT subjects were re-imaged for one bed position following placement of an anterior array coil at a clinically realistic position. The CT scan, used for PET attenuation correction, did not include the coil. Comparison, including liver SUV(mean), was performed between the coil present and absent images using two methods of PET reconstruction. Due to the time delay between PET scans, a model was used to account for average physiologic time change of SUV. RESULTS: On phantom data, neglecting the coil caused a mean bias of -8.2% for non-TOF/PSF reconstruction, and -7.3% with TOF/PSF. On clinical data, the liver SUV neglecting the coil presence fell by -6.1% (± 6.5%) for non-TOF/PSF reconstruction; respectively -5.2% (± 5.3%) with TOF/PSF. All FDG-avid features seen with TOF/PSF were also seen with non-TOF/PSF reconstruction. CONCLUSION: Neglecting coil attenuation for this anterior array coil results in a small but significant reduction in liver SUV(mean) but was not found to change the clinical interpretation of the PET images.

White matter hyperintensity patterns: associations with comorbidities, amyloid, and cognition.

BACKGROUND: White matter hyperintensities (WMHs) are often measured globally, but spatial patterns of WMHs could underlie different risk factors and neuropathological and clinical correlates. We investigated the spatial heterogeneity of WMHs and their association with comorbidities, Alzheimer's disease (AD) risk factors, and cognition. METHODS: In this cross-sectional study, we studied 171 cognitively unimpaired (CU; median age: 65 years, range: 50 to 89) and 51 mildly cognitively impaired (MCI; median age: 72, range: 53 to 89) individuals with available amyloid (18F-flutementamol) PET and FLAIR-weighted images. Comorbidities were assessed using the Cumulative Illness Rating Scale (CIRS). Each participant's white matter was segmented into 38 parcels, and WMH volume was calculated in each parcel. Correlated principal component analysis was applied to the parceled WMH data to determine patterns of WMH covariation. Adjusted and unadjusted linear regression models were used to investigate associations of component scores with comorbidities and AD-related factors. Using multiple linear regression, we tested whether WMH component scores predicted cognitive performance. RESULTS: Principal component analysis identified four WMH components that broadly describe FLAIR signal hyperintensities in posterior, periventricular, and deep white matter regions, as well as basal ganglia and thalamic structures. In CU individuals, hypertension was associated with all patterns except the periventricular component. MCI individuals showed more diverse associations. The posterior and deep components were associated with renal disorders, the periventricular component was associated with increased amyloid, and the subcortical gray matter structures was associated with sleep disorders, endocrine/metabolic disorders, and increased amyloid. In the combined sample (CU + MCI), the main effects of WMH components were not associated with cognition but predicted poorer episodic memory performance in the presence of increased amyloid. No interaction between hypertension and the number of comorbidities on component scores was observed. CONCLUSION: Our study underscores the significance of understanding the regional distribution patterns of WMHs and the valuable insights that risk factors can offer regarding their underlying causes. Moreover, patterns of hyperintensities in periventricular regions and deep gray matter structures may have more pronounced cognitive implications, especially when amyloid pathology is also present.

Combinational expression of tumor testis antigens NY-ESO-1, MAGE-A3, and MAGE-A4 predicts response to immunotherapy in mucosal melanoma patients.

PURPOSE: Immunotherapy using immune checkpoint inhibitors (ICI) has revolutionized cancer treatment in recent years, particularly in melanoma. While response to immunotherapy is associated with high tumor mutational burden (TMB), PD-L1 expression, and microsatellite instability in several cancers, tumors lacking these biomarkers can still respond to this treatment. Especially, mucosal melanoma, commonly exhibiting low TMB compared to cutaneous melanoma, may respond to immunotherapy with immune checkpoint inhibitors. Therefore, the aim of our study was to investigate novel biomarkers in mucosal melanoma that predict response to combined ipilimumab and nivolumab. METHODS: We investigated 10 tumor samples from 10 patients (three responders, seven non-responders) before treatment and six tumor samples from five patients after progression using a targeted Next Generation Sequencing (NGS) gene expression panel. The findings were corroborated with an independent method (i.e., immunohistochemical staining) on the same 10 tumor samples before treatment and, to increase the cohort, in addition on three tumor samples before treatment of more recent patients (one responder, two non-responders). RESULTS: With the targeted gene expression panel, we found the three tumor testis antigens CTAG1B (NY-ESO-1), MAGE-A3, and MAGE-A4 to be predominantly expressed in responding tumors. This marker panel was either not or not completely expressed in non-responders (p < 0.01). Using immunohistochemistry for all three markers, we could confirm the elevated expression in tumors responding to the ipilimumab/nivolumab combination therapy. CONCLUSION: In conclusion, these three biomarkers await validation in a larger patient cohort and could be easily used in future routine diagnostics to predict the outcome of ipilimumab/nivolumab combination therapy in mucosal melanoma patients.

Comparison of clinically available dynamic susceptibility contrast post processing software to differentiate progression from pseudoprogression in post-treatment high grade glioma.

INTRODUCTION: The purpose of this retrospective study was to compare two, widely available software packages for calculation of Dynamic Susceptibility Contrast (DSC) perfusion MRI normalized relative Cerebral Blood Volume (rCBV) values to differentiate tumor progression from pseudoprogression in treated high-grade glioma patients. MATERIAL AND METHODS: rCBV maps processed by Siemens Syngo.via (Siemens Healthineers) and Olea Sphere (Olea Medical) software packages were co-registered to contrast-enhanced T1 (T1-CE). Regions of interest based on T1-CE were transferred to the rCBV maps. rCBV was calculated using mean values and normalized using contralateral normal- appearing white matter. The Wilcoxon test was performed to assess for significant differences, and software-specific optimal rCBV cutoff values were determined using the Youden index. Interrater reliability was evaluated for two raters using the intraclass correlation coefficient. RESULTS: 41 patients (18 females; median age = 59 years; range 21-77 years) with 49 new or size-increasing post-treatment contrast-enhancing lesions were included (tumor progression = 40 lesions; pseudoprogression = 9 lesions). Optimal rCBV cutoffs of 1.31 (Syngo.via) and 2.40 (Olea) were significantly different, with an AUC of 0.74 and 0.78, respectively. Interrater reliability was 0.85. DISCUSSION: We demonstrate that different clinically available MRI DSC-perfusion software packages generate significantly different rCBV cutoff values for the differentiation of tumor progression from pseudoprogression in standard-of-care treated high grade gliomas. Physicians may want to determine the unique value of their perfusion software packages on an institutional level in order to maximize diagnostic accuracy when faced with this clinical challenge. Furthermore, combined with implementation of current DSC-perfusion recommendations, multi-center comparability will be improved.

Hemodynamic Failure Staging With Blood Oxygenation Level-Dependent Cerebrovascular Reactivity and Acetazolamide-Challenged (15O-)H2O-Positron Emission Tomography Across Individual Cerebrovascular Territories.

BACKGROUND: Staging of hemodynamic failure (HF) in symptomatic patients with cerebrovascular steno-occlusive disease is required to assess the risk of ischemic stroke. Since the gold standard positron emission tomography-based perfusion reserve is unsuitable as a routine clinical imaging tool, blood oxygenation level-dependent cerebrovascular reactivity (BOLD-CVR) with CO2 is a promising surrogate imaging approach. We investigated the accuracy of standardized BOLD-CVR to classify the extent of HF. METHODS AND RESULTS: Patients with symptomatic unilateral cerebrovascular steno-occlusive disease, who underwent both an acetazolamide challenge (15O-)H2O-positron emission tomography and BOLD-CVR examination, were included. HF staging of vascular territories was assessed using qualitative inspection of the positron emission tomography perfusion reserve images. The optimum BOLD-CVR cutoff points between HF stages 0-1-2 were determined by comparing the quantitative BOLD-CVR data to the qualitative (15O-)H2O-positron emission tomography classification using the 3-dimensional accuracy index to the randomly assigned training and test data sets with the following determination of a single cutoff for clinical application. In the 2-case scenario, classifying data points as HF 0 or 1-2 and HF 0-1 or 2, BOLD-CVR showed an accuracy of >0.7 for all vascular territories for HF 1 and HF 2 cutoff points. In particular, the middle cerebral artery territory had an accuracy of 0.79 for HF 1 and 0.83 for HF 2, whereas the anterior cerebral artery had an accuracy of 0.78 for HF 1 and 0.82 for HF 2. CONCLUSIONS: Standardized and clinically accessible BOLD-CVR examinations harbor sufficient data to provide specific cerebrovascular reactivity cutoff points for HF staging across individual vascular territories in symptomatic patients with unilateral cerebrovascular steno-occlusive disease.