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Using a novel three-dimensional (3D) approach, we tracked histological changes to elucidate the earliest stages of renal clear cell neoplasia in normal kidney tissue of patients with von Hippel-Lindau (VHL) disease. Tissue blocks of interest were procured, serially sectioned, and 3D reconstruction of the entirety of pathologic events was performed. The results reveal an abundance of foci with aberrant clear cell proliferation that initially develop along the tubular lining, but have the potential to aggregate within individual tubules. This stage is followed by the extension of clear cell aggregates beyond the tubular basement membrane, which allows for the recruitment of angiogenesis derived from interstitial vasculature. The results suggest that the most frequent pathologic event in VHL kidneys is the presence of isolated or aggregated clear cells within the tubular epithelium, potentially developing further into a protracted process of neoplasia. The abundance of independent pathologic events in VHL kidneys confirms developmental mechanisms to precede tumor initiation. To our knowledge, this is the first report demonstrating that tracking of histologic changes in the 3rd dimension enables the confirmation of the sequence of events from the earliest pathologic change in the VHL kidney to the neoplastic stage. This approach is not only useful for visualization and quantification of pathologic changes but also for targeted sampling allowing selective analysis of the earliest stages of clear cell carcinogenesis., (Copyright: Mubarak M, et al.)

Objective: The optimal treatment paradigm for large arteriovenous malformations (AVMs) is controversial. One approach is volume-staged stereotactic radiosurgery (VS-SRS). The authors previously reported efficacy of VS-SRS for large AVMs in a multiinstitutional cohort; here they focus on risk of symptomatic adverse radiation effects (AREs)., Methods: This is a multicentered retrospective review of patients treated with a planned prospective volume staging approach to stereotactically treat the entire nidus of an AVM, with volume stages separated by intervals of 3-6 months. A total of 9 radiosurgical centers treated 257 patients with VS-SRS between 1991 and 2016. The authors evaluated permanent, transient, and total ARE events that were symptomatic., Results: Patients received 2-4 total volume stages. The median age was 33 years at the time of the first SRS volume stage, and the median follow-up was 5.7 years after VS-SRS. The median total AVM nidus volume was 23.25 cm3 (range 7.7-94.4 cm3), with a median margin dose per stage of 17 Gy (range 12-20 Gy). A total of 64 patients (25%) experienced an ARE, of which 19 were permanent. Rather than volume, maximal linear dimension in the Z (craniocaudal) dimension was associated with toxicity; a threshold length of 3.28 cm was associated with an ARE, with a 72.5% sensitivity and a 58.3% specificity. In addition, parietal lobe involvement for superficial lesions and temporal lobe involvement for deep lesions were associated with an ARE., Conclusions: Size remains the dominant predictor of toxicity following SRS, but overall rates of AREs were lower than anticipated based on baseline features, suggesting that dose and size were relatively dissociated through volume staging. Further techniques need to be assessed to optimize outcomes.

Stand-alone (SA) zero-profile implants are an alternative to cervical plating (CP) in anterior cervical discectomy and fusion (ACDF). In this study, we investigate differences in surgical outcomes between SA and CP in ACDF. We conducted a retrospective analysis of 166 patients with myelopathy and/or radiculopathy who had ACDF with SA or CP from Jan 2013-Dec 2016. We measured surgical outcomes including Bazaz dysphagia score at 3 months, Nurick grade at last follow-up, and length of hospital stay. 166 patients (92F/74M) were reviewed. 92 presented with radiculopathy (55%), 37 with myelopathy (22%), and 37 with myeloradiculopathy (22%). The average operative time with CP was longer than SA (194 ± 69 vs. 126 ± 46 min) ( p < 0.001), as was the average length of hospital stay (2.1 ± 2 vs. 1.5 ± 1 days) ( p = 0.006). At 3 months, 82 patients (49.4%) had a follow-up for dysphagia, with 3 patients reporting mild dysphagia and none reporting moderate or severe dysphagia. Nurick grade at last follow-up for the myelopathy and myeloradiculopathy cohorts improved in 63 patients (85%). Prolonged length of stay was associated with reduced odds of having an optimal outcome by 0.50 (CI = 0.35-0.85, p = 0.003). Overall, we demonstrate that there is no significant difference in neurological outcome or rates of dysphagia between SA and CP, and that both lead to overall improvement of symptoms based on Nurick grading. However, we also show that the SA group has shorter length of hospital stay and operative time compared to CP.

Background: Optimal treatment paradigm for large arteriovenous malformations (AVMs) is controversial. Volume-staged stereotactic radiosurgery (VS-SRS) provides an effective option for these high-risk lesions, but optimizing treatment for these recalcitrant and rare lesions has proven difficult., Methods: This is a multi-centered retrospective review of patients treated with a planned prospective volume staging approach to stereotactically treat the entire nidus of an AVM with volume stages separated by intervals of 3-6 months. A total of 9 radiosurgical centers treated 257 patients with VS-SRS between 1991 and 2016. We evaluated near complete response (nCR), obliteration, cure, and overall survival., Results: With a median age of 33 years old at the time of first SRS volume stage, patients received 2-4 total volume stages and a median follow up of 5.7 years after VS-SRS. The median total AVM nidus volume was 23.25 cc (range: 7.7-94.4 cc) with a median margin dose per stage of 17 Gy (range: 12-20 Gy). Total AVM volume, margin dose per stage, compact nidus, lack of prior embolization, and lack of thalamic location involvement were all associated with improved outcomes. Dose >/= 17.5 Gy was strongly associated with improved rates of nCR, obliteration, and cure. With dose >/= 17.5 Gy, 5- and 10-year cure rates were 33.7% and 76.8% in evaluable patients compared to 23.7% and 34.7% of patients with 17 Gy and 6.4% and 20.6% with <17 Gy per volume-stage (p = 0.004). Obliteration rates in diffuse nidus architecture with <17 Gy were particularly poor with none achieving obliteration compared to 32.3% with doses >/= 17 Gy at 5 years (p = 0.007). Comparatively, lesions with a compact nidus architecture exhibited obliteration rates at 5 years were 10.7% vs 9.3% vs 26.6% for dose >17 Gy vs 17 Gy vs >/=17.5 Gy., Conclusion: VS-SRS is an option for upfront treatment of large AVMs. Higher dose was associated with improved rates of nCR, obliteration, and cure suggesting that larger volumetric responses may facilitate salvage therapy and optimize the chance for cure., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Case Report: A 64-year-old woman presented to our emergency department during the outbreak of the covid-19 emergency in Italy with syncope, anosmia, mild dyspnoea and atypical chest and dorsal pain. A chest CT scan showed an acute type B aortic dissection (ATBAD) and bilateral lung involvement with ground-glass opacity, compatible with interstitial pneumonia. Nasopharyngeal swabs resulted positive for SARS-CoV-2. For the persistence of chest pain, despite the analgesic therapy, we decided to treat her with a TEVAR. Patient's chest and back pain resolved during the first few days after the procedure. No surgical or respiratory complications occurred and the patient was discharged 14 days after surgery., Discussion: By performing the operation under local anesthesia, it was possible to limit both the staff inside the operatory room and droplet/aerosol release. Since we had to perform the operation in a hemodynamics room, thanks to the limited extension of the endoprosthesis and the good caliber of the right vertebral artery we were able to reduce the risk of spinal cord ischemia despite the lack of a revascularization of the left subclavian artery., Conclusions: A minimally invasive total endovascular approach allows, through local anesthesia and percutaneous access, to avoid surgical cut down and orotracheal intubation. This, combined with a defined management protocol for infected patients, seems to be a reasonable way to perform endovascular aortic procedures in urgent setting, even in a SARSCoV- 2 positive patient., Key Words: COVID-19, Dissection, TEVAR.

Objective: Klippel-Feil syndrome (KFS) is characterized by congenital fusion of the cervical vertebrae. Due to its rarity, minimal research has been done to assess the quality and management of pain associated with this disorder. Using a large global database, the authors report a detailed analysis of the type, location, and treatment of pain in patients with KFS., Methods: Data were obtained from the Coordination of Rare Diseases at Stanford registry and Klippel-Feil Syndrome Freedom registry. The cervical fusions were categorized into Samartzis type I, II, or III. The independent-sample t-test, Wilcoxon rank-sum test, and Friedman test were conducted, with significance set at p < 0.05., Results: Seventy-five patients (60 female, 14 male, and 1 unknown) were identified and classified as having the following types of Samartzis fusion: type I, n = 21 (28%); type II, n = 15 (20%); type III, n = 39 (52%). Seventy participants (93.3%) experienced pain associated with their KFS. The median age of patients at pain onset was 16.0 years (IQR 6.75-24.0 years), and the median age when pain worsened was 28.0 years (IQR 15.25-41.5 years). Muscle, joint, and nerve pain was primarily located in the shoulders/upper back (76%), neck (72%), and back of head (50.7%) and was characterized as tightness (73%), dull/aching (67%), and tingling/pins and needles (49%). Type III fusions were significantly associated with greater nerve pain (p = 0.02), headache/migraine pain (p = 0.02), and joint pain (p = 0.03) compared to other types of fusion. Patients with cervical fusions in the middle region (C2-6) tended to report greater muscle, joint, and nerve pain (p = 0.06). Participants rated the effectiveness of oral over-the-counter medications as 3 of 5 (IQR 1-3), oral prescribed medications as 3 of 5 (IQR 2-4), injections as 2 of 5 (IQR 1-4), and surgery as 3 of 5 (IQR 1-4), with 0 indicating the least pain relief and 5 the most pain relief. Participants who pursued surgical treatment reported significantly more comorbidities (p = 0.02) and neurological symptoms (p = 0.01) than nonsurgically treated participants and were significantly older when pain worsened (p = 0.03), but there was no difference in levels of muscle, joint, or nerve pain (p = 0.32); headache/migraine pain (p = 0.35); total number of cervical fusions (p = 0.77); location of fusions; or age at pain onset (p = 0.16)., Conclusions: More than 90% of participants experienced pain. Participants with an increased number of overall cervical fusions or multilevel, contiguous fusions reported greater levels of muscle, joint, and nerve pain. Participants who pursued surgery had more comorbidities and neurological symptoms, such as balance and gait disturbances, but did not report more significant pain than nonsurgically treated participants.

Spinal disorders and associated interventions are costly in the United States, putting them in the limelight of economic analyses. The Patient-Reported Outcomes Measurement Information System Global Health Survey (PROMIS-GHS) requires mapping to other surveys for economic investigation. Previous studies have proposed transformations of PROMIS-GHS to EuroQol 5-Dimension (EQ-5D) health index scores. These models require validation in adult spine patients. In our study, PROMIS-GHS and EQ-5D were randomly administered to 121 adult spine patients. The actual health index scores were calculated from the EQ-5D instrument and estimated scores were calculated from the PROMIS-GHS responses with six models. Goodness-of-fit for each model was determined using the coefficient of determination ( R 2 ), mean squared error (MSE), and mean absolute error (MAE). Among the models, the model treating the eight PROMIS-GHS items as categorical variables (CAT Reg ) was the optimal model with the highest R 2 (0.59) and lowest MSE (0.02) and MAE (0.11) in our spine sample population. Subgroup analysis showed good predictions of the mean EQ-5D by gender, age groups, education levels, etc. The transformation from PROMIS-GHS to EQ-5D had a high accuracy of mean estimate on a group level, but not at the individual level., Competing Interests: The authors declare no conflict of interest.

Background: Data from the literature suggest that in patients with acute, complicated type B aortic dissection (cTBAD), initial successful treatment with thoracic endovascular aneurysm repair (TEVAR) is not necessarily associated with favorable remodeling of the dissected aorta during follow-up, and long-term results indicate that TEVAR failed to completely suppress false lumen patency. Sealing of all relevant distal reentries, infrarenal and/or iliac, seems to be the key issue to induce total false lumen thrombosis in abdominal aorta as well as the iliac arteries, especially in complicated patients presenting with malperfusion or complete true lumen collapse., Materials and Methods: Of the 34 consecutive patients diagnosed with cTBAD at our hospital from January 2015 to April 2018, 30 had complicated dissections receiving endovascular treatment according to the standard Provisional ExTension To Induce COmplete ATtachment (PETTICOAT) technique and were excluded from this study, whereas 4 patients with radiologic evidence of multiple reentry tears at detached lumbar arteries and iliac bifurcation with complete true lumen collapse and clinical evidence of malperfusion were treated with a modified PETTICOAT technique with distal extension of the aortic stent, balloon expansion of the stented true lumen, and use of the AFX bifurcated endograft system to preserve the natural aortic bifurcation and provide complete distal sealing of reentry tears., Results: Primary technical success was achieved in all patients. No postoperative deaths were observed, but 1 patient experienced an hemorrhagic shock on the second postoperative day. No patient suffered postoperative stroke, paraplegia, paraparesis, or acute renal failure., Conclusions: Using an abdominal aortic bifurcated endograft with PETTICOAT to treat acute cTBAD seems to be a feasible approach in high-risk patients to improve aortic remodeling. The AFX bifurcated endograft system meets the requirements of anatomical fixation and sealing of distal tears., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: The counseling of patients with idiopathic normal pressure hydrocephalus (iNPH) is difficult; there is variability in the diagnostic criteria, and a definitive diagnosis can be made only postoperatively. A patient's clinical response to shunting is also difficult to predict. This study examines the subjective experience of patients treated for iNPH, to identify the challenges patients face and to improve patient outcomes and satisfaction., Methods: We reviewed a consecutive series of patients diagnosed with iNPH who underwent ventriculoperitoneal shunt surgery between January 2012 and March 2016 at our institution. Semistructured telephone interviews were conducted with 31 patients. Interviews were analyzed using the principles of grounded theory., Results: Thirty-one patients who underwent shunt surgery for iNPH were interviewed to reach saturation of themes. Seven themes were identified: 1) long preoperative course causes morbidity; 2) the decision to have shunt surgery is easy to make; 3) patients primarily desire to gain independence; 4) patients show variable levels of anxiety; 5) comorbid conditions interfere with postoperative assessment; 6) patients stand by their decision to have shunt surgery; and 7) outside information is used before surgery., Conclusions: Patients often present to the neurosurgeon frustrated and desperate after a long preoperative course. It is important to acknowledge the uncertainty regarding diagnosis and response to shunting when counseling patients. Comorbid conditions interfere with the ability to assess progression of iNPH and the effectiveness of the shunt. Patient caregivers play a large role in decision making and clinical course and should be included when counseling patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Spontaneous intracerebral hemorrhage (ICH) is a morbid disease with a high case fatality rate. Prognosis, rehemorrhage rates, and acute, clinical decision making are greatly affected by the underlying etiology of hemorrhage. This review focuses on the evaluation, diagnosis, and management of structural, macrovascular lesions presenting with ICH, including ruptured aneurysms, brain arteriovenous malformations, cranial dural arteriovenous fistulas, and cerebral cavernous malformations., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Introduction: Syndrome of the trephined (ST) is a post-craniectomy complication. It is characterized by the appearance of new neurological symptoms following the craniectomy, which are relieved after cranioplasty. The purpose of our work was to identify radiological signs and imaging biomarkers of the ST., Methods: CT images of 32 patients were retrospectively analyzed (ST = 13, controls = 19). While the shapes of craniectomy flap were qualitatively assessed, deviation of the midline structures, relative intracranial cerebrospinal fluid (CSF) volume, and the 3rd ventricle's volume were quantitatively measured., Results: We did not find between-group differences in the mean age or number of post-craniectomy days. ST was diagnosed during the second post-craniectomy month. The occurrence of a sunken skin flap sign was similar in both groups (69.23 % in ST group, 57.89 % in control group). Occurrence of paradoxical herniation and deviation of the midline structures were not significantly different between groups. Mean relative intracranial CSF volume was significantly smaller in ST patients (ST = 5.59 %, controls = 8.12 %, p = 0.01). ST patients, compared to controls, had also significantly smaller mean 3rd ventricle volumes (ST = 1748 mm(3), controls = 2772.97 mm(3), p = 0.03)., Conclusions: ST is an infrequent and delayed post-craniectomy complication. The most common radiological findings (paradoxical herniation, deviation of the midline structures, and sunken skin flap sign) might not be specific for ST. Significantly lower 3rd ventricle, and relative intracranial CSF volumes, suggest that altered biophysical CSF properties underlie ST pathophysiology. Therefore, volume measurements of 3rd ventricle could be useful for identification of patients who have higher probability of developing the ST.

A genetically engineered apoferritin variant consisting of 24 heavy-chain subunits (HFn) was produced to achieve a cumulative delivery of an antitumor drug, which exerts its cytotoxic action by targeting the DNA at the nucleus of human cancer cells with subcellular precision. The rationale of our approach is based on exploiting the natural arsenal of defense of cancer cells to stimulate them to recruit large amounts of HFn nanoparticles loaded with doxorubicin inside their nucleus in response to a DNA damage, which leads to a programmed cell death. After demonstrating the selectivity of HFn for representative cancer cells compared to healthy fibroblasts, doxorubicin-loaded HFn was used to treat the cancer cells. The results from confocal microscopy and DNA damage assays proved that loading of doxorubicin in HFn nanoparticles increased the nuclear delivery of the drug, thus enhancing doxorubicin efficacy. Doxorubicin-loaded HFn acts as a "Trojan Horse": HFn was internalized in cancer cells faster and more efficiently compared to free doxorubicin, then promptly translocated into the nucleus following the DNA damage caused by the partial release in the cytoplasm of encapsulated doxorubicin. This self-triggered translocation mechanism allowed the drug to be directly released in the nuclear compartment, where it exerted its toxic action. This approach was reliable and straightforward providing an antiproliferative effect with high reproducibility. The particular self-assembling nature of HFn nanocage makes it a versatile and tunable nanovector for a broad range of molecules suitable both for detection and treatment of cancer cells., (Copyright © 2014 Elsevier B.V. All rights reserved.)