Expanding the clinicopathological spectrum of TGFBR3-PLAG1 rearranged salivary gland neoplasms with myoepithelial differentiation including evidence of high-grade transformation.

PLAG1 rearrangements have been described as a molecular hallmark of salivary gland pleomorphic adenoma (PA), carcinoma ex pleomorphic adenoma (CEPA), and myoepithelial carcinoma (MECA). Several fusion partners have been described, however, commonly no further assignment to the aforementioned entities or a morphological prediction can be made based on the knowledge of the fusion partner alone. In contrast, TGFBR3-PLAG1 fusion has been specifically described and characterized as an oncogenic driver in MECA, and less common in MECA ex PA. Here, we describe the clinicopathological features of three TGFBR3-PLAG1 fusion-positive salivary gland neoplasms, all of which arose in the deep lobe of the parotid gland. Histopathology showed high morphological similarities, encompassing encapsulation, a polylobular growth pattern, bland basaloid and oncocytoid cells with myoepithelial differentiation, and a distinct sclerotic background. All cases showed at least limited, unusual foci of minimal invasion into adjacent salivary gland tissue, including one case with ERBB2 (Her2/neu) amplified, TP53 mutated high-grade transformation, and lymph node metastases. Of note, all cases illustrated focal ductal differentiation. Classification remains difficult, as morphological overlaps between myoepithelial-rich cellular PA, myoepithelioma, and MECA were observed. However, evidence of minimal invasion advocates classification as low-grade MECA. This case series further characterizes the spectrum of uncommon cellular myoepithelial neoplasms harboring TGFBR3-PLAG1 fusion, which show recurrent minimal invasion of the adjacent salivary gland tissue, a predilection to the deep lobe of the parotid gland, and potential high-grade transformation.

Infiltrative growth pattern of prostate cancer is associated with lower uptake on PSMA PET and reduced diffusion restriction on mpMRI.

PURPOSE: Recently, a significant association was shown between novel growth patterns on histopathology of prostate cancer (PCa) and prostate-specific membrane antigen (PSMA) uptake on [68Ga]PSMA-PET. It is the aim of this study to evaluate the association between these growth patterns and ADC (mm2/1000 s) values in comparison to [68Ga]PSMA uptake on PET/MRI. METHODS: We retrospectively evaluated patients who underwent [68Ga]PSMA PET/MRI for staging or biopsy guidance, followed by radical prostatectomy at our institution between 07/2016 and 01/2020. The dominant lesion per patient was selected based on histopathology and correlated to PET/MRI in a multidisciplinary meeting, and quantified using SUVmax for PSMA uptake and ADCmean for diffusion restriction. PCa growth pattern was classified as expansive (EXP) or infiltrative (INF) according to its properties of forming a tumoral mass or infiltrating diffusely between benign glands by two independent pathologists. Furthermore, the corresponding WHO2016 ISUP tumor grade was evaluated. The t test was used to compare means, Pearson's test for categorical correlation, Cohen's kappa test for interrater agreement, and ROC curve to determine the best cutoff. RESULTS: Sixty-two patients were included (mean PSA 11.7 ± 12.5). The interrater agreement between both pathologists was almost perfect with κ = 0.81. While 25 lesions had an EXP-growth with an ADCmean of 0.777 ± 0.109, 37 showed an INF-growth with a significantly higher ADCmean of 1.079 ± 0.262 (p < 0.001). We also observed a significant difference regarding PSMA SUVmax for the EXP-growth (19.2 ± 10.9) versus the INF-growth (9.4 ± 6.2, p < 0.001). Within the lesions encompassing the EXP- or the INF-growth, no significant correlation between the ISUP groups and ADCmean could be observed (p = 0.982 and p = 0.861, respectively). CONCLUSION: PCa with INF-growth showed significantly lower SUVmax and higher ADCmean values compared to PCa with EXP-growth. Within the growth groups, ADCmean values were independent from ISUP grading.

Hand or foot train-of-four tests and surgical site muscle relaxation assessed with multiple motor evoked potentials: A prospective observational study.

BACKGROUND: Intra-operative muscle relaxation is often required in orthopaedic surgery and the hand train-of-four (TOF) test is usually used for its quantification. However, even though full muscle relaxation is claimed by anaesthesiologists based on a TOF count of zero, surgeons observe residual muscle activity. OBJECTIVE: The aim of the study was to assess if hand or foot TOF adequately represents intra-operative muscle relaxation compared with multiple motor evoked potentials. DESIGN: Prospective observational study. SETTING: A single-centre study performed between February 2016 and December 2018 at the Balgrist University Hospital, Zurich, Switzerland. PATIENTS: Twenty patients scheduled for elective lumbar spinal fusion were prospectively enrolled in this study after giving written informed consent. INTERVENTIONS: To assess neuromuscular blockade (NMB) with the intermediate duration nondepolarising neuromuscular blocking agent rocuronium, hand TOF (adductor pollicis) and foot TOF (flexor hallucis brevis) monitoring, and muscle motor evoked potentials (MMEPs) from the upper and lower extremities were assessed prior to surgery under general anaesthesia. Following baseline measurements, muscle relaxation was performed with rocuronium until the spinal surgeon observed sufficient relaxation for surgical intervention. At this timepoint, NMB was assessed by TOF and MMEP. MAIN OUTCOME MEASURES: The primary outcome was to determine the different effect of rocuronium on muscle relaxation comparing hand and foot TOF with the paraspinal musculature assessed by MMEP. RESULTS: Hand TOF was more resistant to NMB and had a shorter recovery time than foot TOF. When comparing MMEPs, muscle relaxation occurred first in the hip abductors, and the paraspinal and deltoid muscles. The most resistant muscle to NMB was the abductor digiti minimi. Direct comparison showed that repetitive MMEPs simultaneously recorded from various muscles at the upper and lower extremities and from paraspinal muscles reflect muscle relaxation similar to TOF testing. CONCLUSION: Hand TOF is superior to foot TOF in assessing muscle relaxation during spinal surgery. Hand TOF adequately represents the degree of muscle relaxation not only for the paraspinal muscles but also for all orthopaedic surgical sites where NMB is crucial for good surgical conditions. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03318718).

Reappraisal of Grading in Intestinal-Type Sinonasal Adenocarcinoma: Tumor Budding as an Independent Prognostic Parameter.

Since sinonasal intestinal-type adenocarcinomas (ITAC) show resemblance to colorectal adenocarcinomas, we aimed to investigate novel prognostic factors of outcome, with particular focus on the role of tumor budding (TB). Retrospective clinico-pathological single-institution study on consecutive ITAC patients between 1996 and 2020. Histopathological parameters including conventional subtypes and TB features (low, intermediate, high) were evaluated with the aid of pancytokeratin (AE1/AE3) immunohistochemical staining. Parameters were correlated to clinical data and outcome. A total of 31 ITAC patients were included. Overall, 19/31 patients (61.3%) presented with stage III/IV disease. Presence of lymph node or distant metastases was rare (1/31 patient, 3.2%). Treatment protocols consisted of tumor resection in 30/31 patients (96.8%) and primary radiochemotherapy in 1/31 patient (3.2%). Adjuvant radiation therapy was conducted in 20/30 surgically treated patients (66.7%). The 3- and 5-year overall survival (OS) was 83.9% and 78.3% and the 3- and 5-years disease-specific survival (DSS) 83.7% % and 78.5%, respectively. The presence of intermediate/high TB (defined as ≥ 5 buds) was associated with both, worse DSS (log rank p = 0.03) and OS (log rank p = 0.006). No patient with low TB revealed progressive disease or died of the disease. No association between TB and tumor stage or conventional tumor subtype was found. Tumor budding seems to be an independent prognostic factor of worse outcome in ITAC.

Association of perinatal sentinel events, placental pathology and cerebral MRI in neonates with hypoxic-ischemic encephalopathy receiving therapeutic hypothermia.

OBJECTIVE: Placental pathology might provide information on the etiology of hypoxic-ischemic encephalopathy (HIE). To evaluate the association of perinatal sentinel events (PSE), placental pathology and cerebral MRI in cooled neonates with moderate/severe HIE. STUDY DESIGN: Retrospective analysis of 52 neonates with HIE registered in the Swiss National Asphyxia and Cooling Register 2011-2019. PSE and Non-PSE groups were tested for association with placental pathology. Placental pathology categories were correlated with MRI scores. RESULTS: In total, 14/52 neonates (27%) had a PSE, 38 neonates (73%) did not have a PSE. There was no evidence for an association of occurrence of PSE and placental pathologies (p = 0.364). Neonates with high MRI scores tended to have more often chronic pathologies in their placentas than acute pathologies or normal placentas (p = 0.067). CONCLUSION: Independent of the occurrence of PSE, chronic placental pathologies might be associated with more severe brain injury and needs further study.

Immunohistochemical Expression Pattern of Theragnostic Targets SSTR2 and PSMA in Endolymphatic Sac Tumors: A Single Institution Case Series.

BACKGROUND: Endolymphatic sac tumors are rare neoplasia characterized by slow growth. However, their clinical impact should not be underestimated, considering their potential for local aggressive behavior and strong association with von Hippel-Lindau syndrome. Therefore, early detection with emerging theragnostic examinations such as 68Ga-DOTATATE-PET/CT might improve patient management and reduce morbidity. METHODS: We report the clinicopathological features of seven endolymphatic sac tumors. In this cohort, we performed immunohistochemical analysis of somatostatin receptor 2A (SSTR2A) and prostate specific membrane antigen (PSMA) protein expression patterns; two targets providing rationale for novel imaging modalities such as PSMA- or SSTR-targeted PET. RESULTS: The tumor cells of all cases were negative for prostate specific membrane antigen and somatostatin receptor 2A, however immunolabeling was consistently detected in intratumoral endothelial cells of endolymphatic sac tumors for PSMA (7/7 cases, 100%), and for SSTR2A (5/7 cases, 71%). CONCLUSIONS: Our results show a high rate of PSMA and SSTR2A expression in the tumor vasculature of endolymphatic sac tumors. PSMA and SSTR2A can be targeted with appropriate radioligands for diagnostic and therapeutic purposes. This finding provides a rationale for prospective clinical studies to test this approach as a sensitive screening tool for patients with suspected endolymphatic sac tumors including an improved management of von Hippel-Lindau syndrome.

Identification of Urine Biomarkers to Improve Eligibility for Prostate Biopsy and Detect High-Grade Prostate Cancer.

PCa screening is based on the measurements of the serum prostate specific antigen (PSA) to select men with higher risks for tumors and, thus, eligible for prostate biopsy. However, PSA testing has a low specificity, leading to unnecessary biopsies in 50-75% of cases. Therefore, more specific screening opportunities are needed to reduce the number of biopsies performed on healthy men and patients with indolent tumors. Urine samples from 45 patients with elevated PSA were collected prior to prostate biopsy, a mass spectrometry (MS) screening was performed to identify novel biomarkers and the best candidates were validated by ELISA. The urine quantification of PEDF, HPX, CD99, CANX, FCER2, HRNR, and KRT13 showed superior performance compared to PSA. Additionally, the combination of two biomarkers and patient age resulted in an AUC of 0.8196 (PSA = 0.6020) and 0.7801 (PSA = 0.5690) in detecting healthy men and high-grade PCa, respectively. In this study, we identified and validated novel urine biomarkers for the screening of PCa, showing that an upfront urine test, based on quantitative biomarkers and patient age, is a feasible method to reduce the number of unnecessary prostate biopsies and detect both healthy men and clinically significant PCa.

SalvGlandDx - a comprehensive salivary gland neoplasm specific next generation sequencing panel to facilitate diagnosis and identify therapeutic targets.

Diagnosis of salivary gland neoplasms is often challenging due to their high morphological diversity and overlaps. Several recurrent molecular alterations have been described recently, which can serve as powerful diagnostic tools and potential therapeutic targets (e.g. NTRK or RET fusions). However, current sequential molecular testing can be expensive and time consuming. In order to facilitate the diagnosis of salivary gland neoplasms, we designed an all-in-one RNA-based next generation sequencing panel suitable for the detection of mutations, fusions and gene expression levels (including NR4A3) of 27 genes involved in salivary gland neoplasms. Here we present the validation of the "SalvGlandDx" panel on FFPE histological specimen including fine needle aspiration (FNA) cell block material, against the standard methods currently used at our institution. In a second part we describe selected unique cases in which the SalvGlandDx panel allowed proper diagnosis and new insights into special molecular characteristics of selected salivary gland tumors. We characterize a unique salivary gland adenocarcinoma harboring a ZCCHC7-NTRK2 fusion, a highly uncommon spindle cell and pseudoangiomatoid adenoid-cystic carcinoma with MYBL1-NFIB fusion, and a purely oncocytic mucoepidermoid carcinoma, whereas diagnosis could be made by detection of a CRTC3-MAML2 rearrangement on the cell block specimen of the FNA. Further, a rare case of a SS18-ZBTB7A rearranged low-grade adenocarcinoma previously described as potential spectrum of microsecretory adenocarcinoma, is reported. In addition, features of six cases within the spectrum of polymorphous adenocarcinoma / cribriform adenocarcinoma of salivary gland including PRKD1 p.E710D mutations and novel fusions involving PRKAR2A-PRKD1, SNX9-PRKD1 and ATL2-PRKD3, are described.

New Insights into Tumor Heterogeneity: A Case of Solid-Oncocytic Epithelial-Myoepithelial Carcinoma of the Parotid Gland Harboring a HRAS and Heterogeneous Terminating ARID1A Mutation.

Epithelial-myoepithelial carcinoma (EMC) can be a challenging diagnosis due to a lack of obvious invasion and bland cytology. We report an unusual case of a low-grade EMC with prominent fibrous stroma, an extensive solid-oncocytic differentiation and limited areas of morphological clearly identifiable characteristic biphasic (tubular) differentiation, clear cells and PAS-positive secretions/calcifications. Both areas were investigated by next generation sequencing (Oncomine comprehensive assay) and revealed a typical concordant HRAS p.Q61R mutation. An additional heterogeneous ARID1A (p.E672*) terminating mutation with loss of heterozygosity, which could be visualized predominantly in the solid-oncocytic differentiation by immunohistochemical loss of ARID1A protein expression, was found. This is the first case of an EMC of the salivary gland to be described with two separate tumor clones involving concordant HRAS and heterogeneous ARID1A mutations. The latter seem to be a "second hit" and was predominantly found in the solid-oncocytic differentiation, suggesting a potential morpho-molecular association.

Early Recognition of a Transient Ischemic Attack Utilizing Cerebral Oxygenation Monitoring During Shoulder Surgery in the Beach Chair Position: A Case Report.

Shoulder surgery in the beach chair position is routinely performed, and central neurological events are rare but potentially devastating. We present a patient with transient neurological deficits after a sudden blood pressure drop with a simultaneous decrease of regional cerebral saturation values registered by cerebral oximetry. We reviewed published cases and proposed possible strategies to prevent the occurrence of similar complications in this context.

The beach chair position for shoulder surgery in intravenous general anesthesia and controlled hypotension: Impact on cerebral oxygenation, cerebral blood flow and neurobehavioral outcome.

STUDY OBJECTIVES: The aim of this study was to assess the impact of intravenous general anesthesia and controlled hypotension on cerebral saturation (rScO2), cerebral blood flow measured as middle cerebral artery blood flow velocity (Vmax MCA) and neurobehavioral outcome in patients scheduled for shoulder surgery in beach chair position. DESIGN: Prospective, assessor-blinded observational study. SETTING: University hospital, shoulder surgery operating room. PATIENTS: Forty ASA I-II patients scheduled for shoulder surgery in beach chair position and controlled hypotension. INTERVENTIONS: Neurological and neurobehavioral tests were performed prior and the day after surgery. The baseline data for near-infrared spectroscopy, bispectral index, cerebral blood flow, PaCO2 and invasive blood pressure (radial artery) were taken prior anesthesia and after anesthesia induction, after beach chair positioning and all 20 min after surgery start until discharge of the patient. MEASUREMENTS: Neurological and neurobehavioral tests, cerebral saturation (rScO2) using near-infrared spectroscopy, BIS, cerebral blood flow using Doppler of the middle cerebral artery (Vmax MCA), PaCO2 and invasive blood pressure assessed at heart and at the external acoustic meatus level. MAIN RESULTS: The incidence of cerebral desaturation events (CDEs) was 25%. The blood pressure drop 5 min after beach chair position measured at the acoustic meatus level in the CDE group was higher compared to patients without CDEs (p = 0.009) as was the rScO2 (p = 0.039) and the Vmax MCA (p = 0.002). There were no neurological deficits but patients with CDEs showed a greater negative impact on neurobehavioral tests 24 h after surgery compared to patients without CDEs (p = 0.001). CONCLUSIONS: In ASA I-II patients intravenous general anesthesia and controlled hypotension in the beach chair position affects cerebral blood flow and cerebral oxygenation with impact on the neurobehavioral outcome.

Spinal versus general anesthesia for lumbar spine surgery in high risk patients: Perioperative hemodynamic stability, complications and costs.

OBJECTIVE: More stable perioperative hemodynamic conditions, lower costs and a lower perioperative complication rate were reported in young healthy patients undergoing lumbar spine surgery in spinal anesthesia (SA) compared to general anesthesia (GA). However, the benefits of SA in high risk patients (ASA≥II suffering from cardiovascular and/or pulmonary pathologies) undergoing this surgery are unclear. Our objective was to analyze whether SA leads to an improved perioperative hemodynamic stability and to a more cost-effective management compared to GA in high risk patients undergoing this surgery. METHODS: In a retrospective analysis 146 ASA II-III patients who underwent lumbar spine surgery in SA were compared with 292 ASA I-III patients who were operated in GA between 2000 and 2014. Hemodynamic effects, hospitalization times, complications, and costs according to the Swiss billing system were assessed. The data extraction was conducted according to Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) initiative for cohort studies. RESULTS: The patients in the SA group were older (75years (±9.6) vs 69 (±11.5), p<0.001), had a lower BMI (25.8kg/m2 (±4.8) vs 27.2 (±4.7), p=0.003) and showed a higher ASA score (3 vs 2, p<0.001). However, SA was associated with significantly better perioperative hemodynamic stability with less need for intraoperative vasopressors (15% vs 57%, p<0.001), volume supplementation (1113ml ±458 vs 1589±644, p<0.001) and transfusions (0% vs 4%, p<0.001). Additionally, the number of hypotension episodes was lower in the SA group (15% vs 47%, p<0.001). Furthermore, the SA group showed a significantly shorter duration of surgery (70min (±1.2) vs 91 (±41), p<0.001), lower postoperative nausea and vomiting (PONV) (4% vs 28%, p<0.001) and pain in the post anesthesia care unit (PACU) (visual analogue scale (VAS) 2.3 (±1.1) vs 0.8 (±0.8), p<0.001), whereas pain after 24h did not differ (VAS 0.9 (±1) vs 0.8 (±1.1), p=ns). The postoperative complication (7% vs 5%, p=0.286) and revision rates (4% vs 5%, p=0.626) were similar in both groups. Total costs (United States Dollars (USD) 6377 (±2332) vs 7018 (±4056), p=0.003) and PACU time were significantly lower in the SA group (35min (±12) vs 109 (±173), p<0.001). CONCLUSIONS: Lumbar spine surgery in cardiovascular high risk patients with SA is safe, allows good perioperative hemodynamic stability and might lead to lower health care costs. Further prospective studies are needed to confirm these findings.

Cerebral oxygenation in the beach chair position for shoulder surgery in regional anesthesia: impact on cerebral blood flow and neurobehavioral outcome.

STUDY OBJECTIVE: Beach chair position is considered a potential risk factor for central neurological events particularly if combined with low blood pressure. The aim of this study was to assess the impact of regional anesthesia on cerebral blood flow and neurobehavioral outcome. DESIGN: This is a prospective, assessor-blinded observational study evaluating patients in the beach chair position undergoing shoulder surgery under regional anesthesia. SETTING: University hospital operating room. PATIENTS: Forty patients with American Society of Anesthesiologists classes I-II physical status scheduled for elective shoulder surgery. INTERVENTIONS: Cerebral saturation and blood flow of the middle cerebral artery were measured prior to anesthesia and continued after beach chair positioning until discharge to the postanesthesia care unit. The anesthesiologist was blinded for these values. Controlled hypotension with systolic blood pressure≤100mm Hg was maintained during surgery. MEASUREMENTS: Neurobehavioral tests and values of regional cerebral saturation, bispectral index, the mean maximal blood flow of the middle cerebral artery, and invasive blood pressure were measured prior to regional anesthesia, and measurements were repeated after placement of the patient on the beach chair position and every 20 minutes thereafter until discharge to postanesthesia care unit. The neurobehavioral tests were repeated the day after surgery. MAIN RESULTS: The incidence of cerebral desaturation events was 5%. All patients had a significant blood pressure drop 5 minutes after beach chair positioning, measured at the heart as well as the acoustic meatus levels, when compared with baseline values (P<.05). There was no decrease in either the regional cerebral saturation (P=.136) or the maximal blood flow of the middle cerebral artery (P=.212) at the same time points. Some neurocognitive tests showed an impairment 24 hours after surgery (P<.001 for 2 of 3 tests). CONCLUSIONS: Beach chair position in patients undergoing regional anesthesia for shoulder surgery had no major impact on cerebral blood flow and cerebral oxygenation. However, some impact on neurobehavioral outcome 24 hours after surgery was observed.