Exposure to obinutuzumab does not affect outcomes of SARS-CoV-2 infection in vaccinated patients with newly diagnosed advanced-stage follicular lymphoma.

URBAN is a multicentric, ambispective study evaluating the effectiveness and safety of obinutuzumab-based immuno-chemotherapy and maintenance in patients with untreated advanced follicular lymphoma (FL). The study began before the COVID-19 emergency declaration in Italy. It is currently ongoing for follow-up, and the enrolment timeline encompassed different stages of the pandemic, various vaccination roll-out phases and prevalence of SARS-CoV-2 variants. Outcomes of interest of the present sub-analysis included SARS-CoV-2 infection rates and COVID-19-related hospitalizations/deaths. At data cut-off, 86 (28.8%) and 213 patients (71.2%) were treated before and during/after the COVID-19 outbreak respectively; 294 (98.3%) completed the induction, 31 (10.4%) completed maintenance and 170 (56.9%) were still on maintenance. Overall, 245 patients (81.9%) received at least one SARS-CoV-2 vaccine dose: 13.5%, 31.4% and 55.1% received one, two and three doses respectively. We observed a substantial decrease in COVID-19-related mortality rates in pre- versus post-vaccination phases, along with a reduction in COVID-19-related outcomes due to the shift from alpha/delta to omicron variant predominance. No differences emerged between patients given maintenance or not, although the schedule was modified in 65% of cases. To our knowledge, URBAN represents the largest dataset of COVID-19-related outcomes in FL patients extensively exposed to obinutuzumab. ClinicalTrials.gov identifier: NCT04034056.

Associations between clinical features and therapy with macrophage subpopulations and T cells in inflammatory lesions in the aorta from patients with Takayasu arteritis.

Takayasu arteritis (TAK) is a large-vessel granulomatous vasculitis; the inflammatory infiltration in arteries comprises macrophages, multi-nucleated giant cells, CD4+ and CD8+ T cells, γδ T cells, natural killer (NK) cells and neutrophils. However, it is unknown which subtype of macrophages predominates. This study aims to evaluate macrophages subpopulations in the aorta in TAK. Immunohistochemistry was performed in the aorta from TAK patients (n = 22), patients with atherosclerotic disease (n = 9) and heart transplant donors (n = 8) using the markers CD68, CD86, CD206, CD3, CD20 and CD56. Active disease was observed in 54·5% of patients and active histological lesions were found in 40·9%. TAK patients presented atherosclerotic lesions in 27·3% of cases. The frequency of macrophages, M1 macrophages, T, B and NK cells was higher in the aorta from TAK and atherosclerotic patients compared to heart transplant donors. In TAK, macrophages and T cells were the most abundant cells in the aorta, and the expression of CD206 was higher than CD86 (P = 0·0007). No associations were found between the expression of cell markers and active disease or with atherosclerotic lesions. In TAK patients, histological disease activity led to higher T cell counts than chronic fibrotic lesions (P = 0.030), whereas prednisone use was associated with lower T cell counts (P = 0·035). In conclusion, M1 macrophages were more frequent in TAK and atherosclerotic patients compared to heart transplant donors, while M2 macrophages dominated M1 macrophages in TAK. T cells were associated with histological disease activity and with prednisone use in TAK.

Bone metastases in biliary cancers: A multicenter retrospective survey.

•Natural history of biliary cancers metastatic to bone•The role of skeletal events in patients with biliary cancer•Biliary cancer and bone metastases: role of bisphosphonates.

Multivariate prognostic factors analysis for second-line chemotherapy in advanced biliary tract cancer.

BACKGROUND: The role of second-line chemotherapy (CT) is not established in advanced biliary tract cancer (aBTC). We investigated the outcome of aBTC patients treated with second-line CT and devised a prognostic model. METHODS: Baseline clinical and laboratory data of 300 consecutive aBTC patients were collected and association with overall survival (OS) was investigated by multivariable Cox models. RESULTS: The following parameters resulted independently associated with longer OS: Eastern Cooperative Oncology Group performance status of 0 (P<0.001; hazard ratio (HR), 0.348; 95% confidence interval (CI) 0.215-0.562), CA19.9 lower than median (P=0.013; HR, 0.574; 95% CI 0.370-0.891), progression-free survival after first-line CT ≥ 6 months (P=0.027; HR, 0.633; 95% CI 0.422-0.949) and previous surgery on primary tumour (P=0.027; HR, 0.609; 95% CI 0.392-0.945). We grouped the 249 patients with complete data available into three categories according to the number of fulfilled risk factors: median OS times for good-risk (zero to one factors), intermediate-risk (two factors) and poor-risk (three to four factors) groups were 13.1, 6.6 and 3.7 months, respectively (P<0.001). CONCLUSIONS: Easily available clinical and laboratory factors predict prognosis of aBTC patients undergoing second-line CT. This model allows individual patient-risk stratification and may help in treatment decision and trial design.

Intraobserver and interobserver variability in the calculation of apparent diffusion coefficient (ADC) from diffusion-weighted magnetic resonance imaging (DW-MRI) of breast tumours.

PURPOSE: This study evaluated intraobserver and interobserver variability in the measurement of apparent diffusion coefficient (ADC) values in breast carcinomas. MATERIALS AND METHODS: Twenty-eight patients with solid breast lesions >10 mm underwent conventional contrast-enhanced magnetic resonance imaging (MRI) and diffusion-weighted MRI (DW-MRI). Two observers (expert and trainee) segmented the lesion from the surrounding breast tissue on DW images with high b-value (1,000 s/mm(2)). This analysis was repeated by the expert reader after 6 months. Volumes were analysed to obtain mean, median and standard deviation (SD) of the ADC values. Interobserver and intraobserver variation was analysed using the Bland-Altman graph. RESULTS: All lesions were breast carcinomas, with a mean ADC value of 1.07 × 10(-3) mm(2)/s. The mean of the differences was 0.012 × 10(-3) mm(2)/s, corresponding to an intraobserver variability of 1.1% (limits of agreement: -5%/+8%). The mean interobserver difference was 0.022 × 10(-3) mm(2)/s, corresponding to an interobserver variability of 2% (limits of agreement: -9%/+14%). CONCLUSIONS: We found a low intraobserver and interobserver variability in calculating ADC in breast carcinomas, which supports its potential use in routine clinical practice.

CT perfusion in solid-body tumours. Part I: Technical issues.

Functional imaging is becoming increasingly important in both research and clinical diagnostic radiology. Perfusion computed tomography (CTP) is a readily available and widely used tool that allows an objective measurement of tissue perfusion through the mathematical analysis of data obtained from repeated scans performed after administration of contrast agent. Recently, CTP has been increasingly used in the oncological field, being studied as a potential marker of neoplastic angiogenesis, which is one of the main targets of new tumour therapies. The aim of this paper was to provide the theoretical background and practical guidance for accurately performing CTP and interpreting results of examinations in solid-body tumours. CTP could be a valid tool for functional imaging of tumours if the acquisition technique is robust, if image and data analysis is accurate and if interpretation of results is adequately inserted within a clinical context.

Endoscope-assisted removal of colloid cysts of the third ventricle.

Colloid cysts are benign space-occupying lesions, which arise from the velum interpositum or the choroid plexus of the third ventricle and are able to produce symptomatic obstruction of the foramina of Monro with resultant hydrocephalus. In our department, we have operated on colloid cysts routinely in an endoscope-assisted microsurgical manner via a key-hole approach. During a period of 10 years, 28 microsurgical resections of colloid cysts of the third ventricle were performed. Seven patients demonstrated colloid cysts inside the third ventricle with obstruction of the right foramen Monro, two patients demonstrated cysts with obstruction of the left foramen Monro. Twelve patients suffered from cysts inside the third ventricle with obstruction of both foramina Monro and five patients demonstrated cysts lying into the third ventricle without obstruction of the foramina. In 21 patients no preoperative therapy was performed outside. Three patients had received shunt systems before in other hospitals, two patients received aspiration of the cysts under stereotactic conditions and two patients received external ventricular drains. Total removal of the cyst was achieved in all patients (100%). No patient received a second operation, because none had a recurrent cyst. All cysts were removed with the cyst wall. Overall clinical improvement was achieved in a long-standing period between 6 and 83 months in 27 (96%) patients. In one patient (4%) the psychomotor disturbance was unchanged and no patient deteriorated. From the microsurgical point of view, the combination of keyhole surgery under endoscopic visual control using preexisting anatomical windows offers an effective minimally invasive approach.

Endoscopic and endoscope-assisted neurosurgical treatment of suprasellar arachnoidal cysts (Mickey Mouse cysts).

Suprasellar arachnoid cysts represent less than 10% of all intracranial arachnoid cysts. Some of them may be quiescent throughout life, some may become symptomatic as they become enlarged and some disappear spontaneously. In this study we discuss the surgical strategies for endoscopic and endoscope-assisted treatment of suprasellar (Mickey Mouse) cysts and analyze the clinical results and experience collected over some years in our department upon doing these operations routinely. Between December 1996 and December 2003, 13 patients (7 female and 6 male patients), mean age 29 years, underwent endoscopic or endoscope-assisted procedures for suprasellar cysts at our department. The indication for surgical treatment was based on the neurological and radiological examination. The goal of surgical treatment was to normalize the cerebrospinal fluid flow and to establish a communication, permanently, between the cyst cavity and the intraventricular or/and subarachnoid space. Intraoperatively we observed in all patients no complications. Seven of 13 patients, who had received shunt systems in other hospitals before admission in our clinic, remained shunt-free postoperatively. Overall clinical improvement was achieved for a long period of between 6 and 74 months in 11 patients, one developed a psychomotor disturbance and another one, who had epilepsy before treatment, was unchanged postoperatively. Our data suggest that suprasellar cysts are well treated by endoscopic or endoscope-assisted procedures with good clinical outcome and low surgical morbidity.

Gefitinib inhibits the ability of human bone marrow stromal cells to induce osteoclast differentiation: implications for the pathogenesis and treatment of bone metastasis.

Significant relief of bone pain in patients with bone metastases was observed in a clinical trial of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib in breast cancer. Osteoclast activation and differentiation are regulated by bone marrow stromal cells (BMSC), a heterogeneous cell compartment that comprehends undifferentiated mesenchymal stem cells (MSC) and their specialized progeny. In this regard, we found that human primary BMSCs express immunoreactive EGFR. Expression of EGFR mRNA and protein was also demonstrated in two human, continuous MSC-like cell lines, HDS-1 and HDS-2 cells. Treatment of HDS cells with EGF produced a significant increase in the levels of activated EGFR which was not observed in the presence of gefitinib. A significant reduction in the basal levels of activation of the EGFR and of Akt was observed in HDS cells following treatment with gefitinib. Treatment of HDS cells with gefitinib produced a significant reduction in the levels of secreted macrophage colony-stimulating factor (M-CSF) and cell-associated receptor activator of NF-kappaB ligand (RANKL) in both cell lines, as assessed by using specific ELISA and Western blotting techniques. Finally, the ability to sustain the differentiation of pre-osteoclasts of conditioned medium from gefitinib-treated HDS cells was reduced by approximately 45% as compared with untreated HDS cells. These data have demonstrated for the first time that the EGFR regulates the ability of BMSCs to induce osteoclast differentiation and strongly support clinical trials of gefitinib in breast cancer patients with bone disease.

Computer-aided navigation in neurosurgery.

The article comprises three main parts: a historical review on navigation, the mathematical basics for calculation and the clinical applications of navigation devices. Main historical steps are described from the first idea till the realisation of the frame-based and frameless navigation devices including robots. In particular the idea of robots can be traced back to the Iliad of Homer, the first testimony of European literature over 2500 years ago. In the second part the mathematical calculation of the mapping between the navigation and the image space is demonstrated, including different registration modalities and error estimations. The error of the navigation has to be divided into the technical error of the device calculating its own position in space, the registration error due to inaccuracies in the calculation of the transformation matrix between the navigation and the image space, and the application error caused additionally by anatomical shift of the brain structures during operation. In the third part the main clinical fields of application in modern neurosurgery are demonstrated, such as localisation of small intracranial lesions, skull-base surgery, intracerebral biopsies, intracranial endoscopy, functional neurosurgery and spinal navigation. At the end of the article some possible objections to navigation-aided surgery are discussed.

The role of third ventriculostomy in the management of obstructive hydrocephalus.

OBJECTIVE: Endoscopic third ventriculostomy (ETV) is an effective treatment for occlusive hydrocephalus caused by an obstruction of the CSF flow in the aqueduct or the posterior fossa. We evaluated the factors age, pathology and surgical technique on the results of the ETV. METHODS: Between November 1992 and October 2000 171 ETV have been performed in 159 patients. The follow-up was evaluated in 150 patients. The age ranged from 10 days to 77 years (mean age 35 years). The hydrocephalus was caused by benign aqueductal stenosis in 77 patients, space-occupying lesions in 59, by intraventricular hemorrhages in 11, and by other causes in 3 patients. The trajectory was planned in 31 patients by frame-based and in 4 patients by frameless stereotaxy. RESULTS: The overall success rate of a single ETV was 71.3 % and including successful re-ETV 76.7 %. Best results were observed in adults and children older than 1 year. Infants demonstrated significantly worser outcomes. Patients with benign aqueductal stenosis and tumor compressing the aqueduct had the greatest profit from the ETV. The stereotactic guidance had no influence on the outcome and the number of severe complications. Complications were one arterial bleeding, three venous bleedings, and one ICB, all without permanent deficit, except one permanent hemiparesis. No mortality was observed.

Frame-based and frameless stereotaxy in the localization of cavernous angiomas.

Cavernous angiomas are mostly small intracranial vascular lesions which can be intraoperatively localized by sonography or stereotactic methods. This paper compares the results of cavernous angioma surgery localized by frame-based vs frameless techniques. Thirty-nine patients with cortical or subcortical lobar cavernoma were operated on by a microsurgical trans-sulcal approach. The localization of the lesion was performed in 19 (49%) patients by frame-based technique and in 20 (51%) patients by frameless navigation. In 22 (56%) of the patients, the cavernomas were located in an eloquent cortical area. Ten of 22 of these lesions were localized by frame-based stereotaxy and 12/22 by frameless navigation. The patients demonstrated the following preoperative symptoms: seizures 20 (51%), hemorrhage 18 (46%), focal neurologic deficit 11 (28%), and headache three (7%), and three (7%) were asymptomatic. Thirteen of 19 patients localized with frame-based stereotaxy were postoperatively asymptomatic or their preoperative neurological symptoms improved. Four of 19 had a transitory neurologic deficit and 2/19 a permanent worsening. Seventeen of 20 patients localized by frameless navigation were asymptomatic or neurologically improved. Three out of 20 suffered from a transient neurologic deficit. Regarding the seizures, 14 (70%) patients were postoperatively free of seizures, three (15%) were improved, and three (15%) were unchanged. The frameless navigation was superior regarding the flexibility for approaches along the skull base and midline, and the frame-based method was superior regarding the accuracy for very small lesions (less than 7 mm). In other cases, both methods were equal. Frame-based and frameless stereotactic methods are useful in the localization of small cavernous angiomas. They make it possible to remove cavernous angiomas in eloquent cortical regions with low risk of a permanent neurologic deficit.

Cubital tunnel syndrome. Treatment by decompression without transposition of ulnar nerve.

Cubital tunnel syndrome is the second most common entrapment neuropathy in the upper limb; however, surgical treatment of the ulnar nerve entrapment at the elbow remains controversial. None of the presently advocated procedures (simple decompression of the ulnar nerve, medial epicondylectomy, subcutaneous, submuscular or intramuscular anterior transposition of the ulnar nerve) has proven optimal regarding long-term results. This paper presents the experience of treating cubital tunnel syndrome with simple decompression in 40 patients. Three months after surgery 23/36 patients did not feel any pain in their operated hands. In 11/36 cases we observed an improvement of preoperative pain. Sensory disturbances disappeared completely in 24/40 cases. 11/40 patients reported an improvement of preoperative dysesthesia or hypesthesia. In 12/22 patients we observed complete recovery of preoperative pareses of adductor muscle of thumb or hypothenar muscles weakness. 7/22 cases demonstrated an improvement of these pareses. In total 28 patients (70 %) had an excellent outcome without residual symptoms. For 5 patients treatment results were classified as good with slight residual pain and sensory disturbance (12.5 %). In 4 cases (10 %) we only observed a fair outcome with persistent severe sensory and motor deficits but slow improvement over the last three months. Three patients did not demonstrate any improvement (7.5 %). The mean duration of postoperative disablement in our working patients (18/40) was 28 days. In summary, simple decompression of the ulnar nerve seems to be an adequate and successful minimally invasive technique for the treatment of cubital tunnel syndrome.

Re-ventriculostomy for treatment of obstructive hydrocephalus in cases of stoma dysfunction.

In this article, 12 re-ventriculostomies in the treatment for obstructive hydrocephalus are described. The etiology of the hydrocephalus was a benign aqueductal stenosis in 9 patients, a tumor around the aqueduct in 2 patients and intraventricular bleeding in one patient. In all cases the initial ventriculostomy was successful, but after a time interval of 2 weeks to 6 years the patients developed similar clinical symptoms as preoperatively. In all except one case the radiological findings spoke in favour of stoma closure. Intraoperatively the stoma was completely closed in 9 patients and in 3 patients a subtotal closure was observed. In all cases a re-ventriculostomy was performed bluntly with a Fogarty catheter in loco typico at the floor of the third ventricle. Of the 12 patients 6 had an excellent outcome postoperatively, one patient improved and one had a benefit from the re-ventriculostomy although he died of cardiac problems. In the remaining 4 patients the re-ventriculostomy was not successful and the patients needed a shunt operation. In conclusion, after initially successful endoscopic third ventriculostomy, re-ventriculostomy should be considered as a sufficient treatment option in case of suspected stoma dysfunction.

Uniportal endoscopic surgery of carpal tunnel syndrome: technique and clinical results.

The endoscopic carpal tunnel release is a new minimally invasive method which has been used to decompress the median nerve in the carpal tunnel for the past decade. Advantages of this method should be a decreased postoperative morbidity and earlier return to work. Preoperative complaints, postoperative results and complications of the therapy for a total of 60 patients are presented. All endoscopic releases were performed using the Agee uniportal technique. The overall success rate in our study was 56/60 (93.3 %). 47/54 (87.0 %) patients were completely free of pain after endoscopic surgery. An improvement in preoperative pain was noted in 4/54 (7.4 %) patients. Hypesthesia and dysesthesia disappeared totally in 39/46 (84.8 %) patients. An improvement of the sensible disturbances was observed in 4/46 (8.7 %) cases. 10/13 (76.9 %) preoperative pareses recovered completely, 3/13 (23.1 %) remained unchanged. The complication rate in total in our series was 4/60 (6.7 %), thereof 3 cases of post-operative infection (5 %) and one serious median nerve injury (1.7 %). The mean time for return to work was 29 days. Summing up, it may be said that monoportal endoscopic carpal tunnel release appears to be an effective and safe minimally invasive method for the treatment of carpal tunnel syndrome.

Stereotactic biopsies guided by an optical navigation system: technique and clinical experience.

Frame-based stereotactic biopsies are time-consuming procedures making necessary head fixation in a ring, explicit coordinate calculation and setting of the parameters. Frameless systems make many of these intermediate steps unnecessary, impose less mechanical restrictions regarding access to the lesions, and with slight modifications can be used to perform stereotactic biopsies. A special adaptation designed to fix the holder and the biopsy instrument is described. The neuronavigation optical tracking system of Radionics was used. CT scans were performed with 6 skin markers. Calibration was performed after head fixation in the Mayfield clamp. Mean calibration error was 2.19 +/- 0.81 mm. The light-emitting diode holder of the pointer was fixed into 2 Leila arms and moved under visual control based on CT images. The target point was selected, Leila arms fixed and a burr hole performed. The cannula was introduced to the target, being fitted with a depth stop in a length identical to that of the pointer on the screen. If necessary a second trajectory was easily selected. 49 patients underwent a frameless stereotactic biopsy. All targets except seven were superficial or in the white matter. In selected cases the biopsies were taken from deep-seated lesions. A histological diagnosis was obtained in 100 % of the cases. Four cases deteriorated postoperatively, two of these related to intratumoral bleeding. Navigation is a simple and effective method to perform biopsies of superficial and relatively large lesions. Frame-based procedures are restricted to brainstem tumors and lesions less than 1.5 cm in diameter.

Bovine pericardium for duraplasty: clinical results in 32 patients.

Bovine pericardium has been widely used for grafts in cardiac surgery and seems to have suitable properties for use as a dural graft. We report on the use of solvent-preserved, gamma-sterilized Tutoplast bovine pericardium for dural grafts in 32 patients undergoing cranial and spinal operations with the objective of clinically assessing this material and technique by a retrospective analysis. All available records were reviewed and information regarding the indication for grafting, complications, and outcome were collected and analyzed for all patients. Indications for grafting included tethered cord myelolysis, closure of lumbosacral myeloceles, Chiari decompression, posterior fossa craniotomy, supratentorial craniotomy, and trauma. Outcomes were excellent in 31 patients; the one poor outcome was unrelated to surgical closure. The dural graft was not intended for outcome in any patient. Bovine pericardium was found to be a flexible and easily suturable, safe and cost-effective material for duraplasty. These results confirm the excellent suitability of Tutoplast bovine pericardium for dural substitution.

Recurrent cubital tunnel syndrome. Etiology and treatment.

Controversy surrounds the treatment of recurrent cubital tunnel syndrome after previous surgery. Irrespective of the surgical technique, namely pure decompression in the ulnar groove and the cubital tunnel distal of the medial epicondyle, and the different methods of volar transposition (subcutaneous, intramuscular, and submuscular), the results of surgical therapy of cubital tunnel syndrome are often not favorable, especially in cases of long-standing symptoms and severe deficits. Twenty-two patients who had previously undergone surgical treatment for ulnar nerve entrapment at the elbow were evaluated because of persistent or recurrent pain, paresthesia, numbness, and motor weakness. Ten patients had undergone a nerve transposition, 5 patients underwent a simple decompression of the ulnar nerve, and 7 patients experienced two previous operations with different surgical techniques. Two patients underwent surgery at our hospital, whereas 20 patients underwent their primary surgery at other institutions. Various surgical techniques were used during the subsequent surgery, such as external neurolysis, subcutaneous anterior transposition, and subsequent transfer of the nerve back into the sulcus. The causes of continued or recurrent symptoms after initial surgery included dense perineural fibrosis of the nerve after subcutaneous transposition, adhesions of the nerve to the medial epicondyle and retention of the medial intermuscular septum. The average follow-up after the last procedure was 7 months (2 - 20 months). All 7 patients with subsequent transfer of the ulnar nerve back into the sulcus became pain-free, whereas only 11 of 15 patients who had external neurolysis or subcutaneous transposition became free of pain or experienced reduced pain. The recovery of motor function and return of sensibility were variable and unpredictable. In summary, reoperation after primary surgery of cubital tunnel syndrome gave satisfactory results in 18 of 22 cases. Subsequent transfer of the ulnar nerve back into the sulcus promises to be useful in cases in which subcutaneous transposition had not been successful.

Tightness of duraplasty in rabbits: a comparative study.

OBJECTIVE: The purpose of this study was to test, in rabbits, the tightness of seven dural substitution materials commonly used in neurosurgery, i.e., Lyodura (B. Braun Melsungen AG, Melsungen, Germany), Tutoplast dura (Tutogen Medical, Inc., Parsippany, NJ), Tutoplast fascia lata (Tutogen Medical, Inc.), autologous periosteum, Neuropatch (B. Braun Melsungen AG), Dacron (E.I. du Pont de Nemours and Co., Wilmington, DE), and Ethisorb (Ethicon, Inc., Somerville, NJ). METHODS: Duraplasties were performed with sutures alone or were additionally fixed with fibrin glue. Leakage pressures were assessed by infusion of artificial cerebrospinal fluid, containing sodium fluorescein, into the cisterna magna and detection of fluorescence using a charge-coupled display camera with background substraction, 3 days, 3 weeks, or 3 months after surgery. RESULTS: Three days after implantation, the mean tightness values of duraplasties with Lyodura or Neuropatch were significantly higher (P = 0.007) than the values for the other substitutes. A significant improvement of tightness with increasing implantation time could be demonstrated for autologous periosteum (P = 0.0063). Improvement of tightness with the use of fibrin glue could be proven only for the heterologous grafts (P = 0.0071). The tightness values for Neuropatch fixed only with sutures were similar to those for the best heterologous substitutes implanted with additional fibrin glue. Lyodura, Tutoplast dura, and Neuropatch demonstrated favorable implantation characteristics; they were thin, flexible, and easily suturable. Neither adhesions to the brain nor space-occupying scars were noted. CONCLUSION: These results confirm the excellent suitability of Lyodura and Neuropatch for dural substitution.