Evidence for inflammation in normal-appearing brain regions in patients with growing sporadic vestibular schwannoma: A PET study.

Background: Nonauditory symptoms can be a prominent feature in patients with sporadic vestibular schwannoma (VS), but the cause of these symptoms is unknown. Inflammation is hypothesized to play a key role in the growth and symptomatic presentation of sporadic VS, and in this study, we investigated through translocator protein (TSPO) positron emission tomography (PET) whether inflammation occurred within the "normal appearing" brain of such patients and its association with tumor growth. Methods: Dynamic PET datasets from 15 patients with sporadic VS (8 static and 7 growing) who had been previously imaged using the TSPO tracer [11C](R)-PK11195 were included. Parametric images of [11C](R)-PK11195 binding potential (BPND) and the distribution volume ratio (DVR) were derived and compared across VS growth groups within both contralateral and ipsilateral gray (GM) and white matter (WM) regions. Voxel-wise cluster analysis was additionally performed to identify anatomical regions of increased [11C](R)-PK11195 binding. Results: Compared with static tumors, growing VS demonstrated significantly higher cortical (GM, 1.070 vs. 1.031, P = .03) and whole brain (GM & WM, 1.045 vs. 1.006, P = .03) [11C](R)-PK11195 DVR values. The voxel-wise analysis supported the region-based analysis and revealed clusters of high TSPO binding within the precentral, postcentral, and prefrontal cortex in patients with growing VS. Conclusions: We present the first in vivo evidence of increased TSPO expression and inflammation within the brains of patients with growing sporadic VS. These results provide a potential mechanistic insight into the development of nonauditory symptoms in these patients and highlight the need for further studies interrogating the role of neuroinflammation in driving VS symptomatology.

Efficacy of virtual surgical planning and a three-dimensional-printed, patient-specific reduction system to facilitate alignment of diaphyseal tibial fractures stabilized by minimally invasive plate osteosynthesis in dogs: A prospective clinical study.

OBJECTIVE: To evaluate the efficacy of a three-dimensional (3D)-printed, patient-specific reduction system for aligning diaphyseal tibial fractures stabilized using minimally invasive plate osteosynthesis (MIPO). STUDY DESIGN: Prospective clinical trial. SAMPLE POPULATION: Fifteen client owned dogs. METHODS: Virtual 3D models of both pelvic limbs were created. Pin guides were designed to conform to the proximal and distal tibia. A reduction bridge was designed to align the pin guides based on the guides' spatial location. Guides were 3D printed, sterilized, and applied, in conjunction with transient application of a circular fixator, to facilitate indirect fracture realignment before plate application. Alignment of the stabilized tibiae was assessed using postoperative computed tomography scans. RESULTS: Mean duration required for virtual planning was 2.5 h and a mean of 50.7 h elapsed between presentation and surgery. Guide placement was accurate with minor median discrepancies in translation and frontal, sagittal, and axial plane positioning of 2.9 mm, 3.6°, 2.7°, and 6.8°, respectively. Application of the reduction system restored mean tibial length and frontal, sagittal, and axial alignment within 1.7 mm, 1.9°, 1.7°, and 4.5°, respectively, of the contralateral tibia. CONCLUSION: Design and fabrication of a 3D-printed, patient-specific fracture reduction system is feasible in a relevant clinical timeline. Intraoperative pin-guide placement was reasonably accurate with minor discrepancies compared to the virtual plan. Custom 3D-printed reduction system application facilitated near-anatomic or acceptable fracture reduction in all dogs. CLINICAL SIGNIFICANCE: Virtual planning and fabrication of a 3D-printing patient-specific fracture reduction system is practical and facilitated acceptable, if not near-anatomic, fracture alignment during MIPO.

Evidence for Behavioral Autorepression in Covid-19 Epidemiological Dynamics.

It has long been hypothesized that behavioral reactions to epidemic severity autoregulate infection dynamics, for example when susceptible individuals self-sequester based on perceived levels of circulating disease. However, evidence for such 'behavioral autorepression' has remained elusive, and its presence could significantly affect epidemic forecasting and interventions. Here, we analyzed early COVID-19 dynamics at 708 locations over three epidemiological scales (96 countries, 50 US states, and 562 US counties). Signatures of behavioral autorepression were identified through: (i) a counterintuitive mobility-death correlation, (ii) fluctuation-magnitude analysis, and (iii) dynamics of SARS-CoV-2 infection waves. These data enabled calculation of the average behavioral-autorepression strength (i.e., negative feedback 'gain') across different populations. Surprisingly, incorporating behavioral autorepression into conventional models was required to accurately forecast COVID-19 mortality. Models also predicted that the strength of behavioral autorepression has the potential to alter the efficacy of non-pharmaceutical interventions. Overall, these results provide evidence for the long-hypothesized existence of behavioral autorepression, which could improve epidemic forecasting and enable more effective application of non-pharmaceutical interventions during future epidemics. Significance: Challenges with epidemiological forecasting during the COVID-19 pandemic suggested gaps in underlying model architecture. One long-held hypothesis, typically omitted from conventional models due to lack of empirical evidence, is that human behaviors lead to intrinsic negative autoregulation of epidemics (termed 'behavioral autorepression'). This omission substantially alters model forecasts. Here, we provide independent lines of evidence for behavioral autorepression during the COVID-19 pandemic, demonstrate that it is sufficient to explain counterintuitive data on 'shutdowns', and provides a mechanistic explanation of why early shutdowns were more effective than delayed, high-intensity shutdowns. We empirically measure autorepression strength, and show that incorporating autorepression dramatically improves epidemiological forecasting. The autorepression phenomenon suggests that tailoring interventions to specific populations may be warranted.

Dysplastic Hips Have Decreased Iliofemoral Ligament Thickness on Coronal Sequences in Magnetic Resonance Imaging: A Matched Cohort Analysis.

PURPOSE: To characterize hip capsule thickness on advanced imaging in patients with and without hip dysplasia and to also evaluate differences in capsular thickness between borderline and true dysplastic patients. METHODS: Patients evaluated by the senior author for concerns of hip pathology from June 2020 to June 2021 were queried and images reviewed to determine dysplasia status by lateral center edge angle (LCEA) ≤ 25 degrees. A group of non-dysplastic patients was identified and matched for age, sex, and body mass index (BMI). Hip capsular thickness was quantified using MRI. A sub-analysis was conducted to compare true dysplastic patients (LCEA < 20°) to borderline dysplastic patients (LCEAs between 20 - 25°). Analysis included independent samples t-tests, Chi-square tests, and multivariable regression. RESULTS: Eighty total patients were included, with a mean age of 31.8 ± 11.7 years, a mean BMI of 26.6 ± 6.5 points, and 70% (56) female patients. Dysplastic patients had a mean LCEA of 19.8 ± 4.3 degrees. Dysplastic individuals had decreased capsular thickness compared to their non-dysplastic controls (2.75 ± 0.96 vs 3.52 ± 1.22 mm, p = 0.003). Multivariable regression showed decreased capsular thickness associated with decreased LCEAs (ß = 2.804, R = 0.432, p<0.001) and dysplasia (ß = -0.709, R2 = 0.056, p = 0.004). Results of a sub-analysis of the dysplastic group examining differences between accepted definitions of borderline dysplasia and true dysplasia showed no significant differences in capsular thickness between the two groups (p = 0.379). CONCLUSIONS: Patients with hip dysplasia were found to have thinner iliofemoral ligaments in the coronal plane on magnetic resonance imaging on magnetic resonance imaging. Further investigation is needed to evaluate any potential implications with hip instability given the thinner hip capsule demonstrated in this study.

An open-label feasibility trial of transdermal cannabidiol for hand osteoarthritis.

Hand osteoarthritis (OA) is an irreversible degenerative condition causing chronic pain and impaired functionality. Existing treatment options are often inadequate. Cannabidiol (CBD) has demonstrated analgesic and anti-inflammatory effects in preclinical models of arthritis. In this open-label feasibility trial, participants with symptomatically active hand OA applied a novel transdermal CBD gel (4% w/w) three times a day for four weeks to their most painful hand. Changes in daily self-reported pain scores were measured on a 0-10 Numeric Pain Rating Scale (NPRS). Hand functionality was determined via daily grip strength measures using a Bluetooth equipped squeeze ball and self-report questionnaire. Quality of life (QoL) ratings around sleep, anxiety, stiffness and fatigue were also measured. All self-report measures and grip strength data were gathered via smartphone application. Urinalysis was conducted at trial end to determine systemic absorption of CBD. Eighteen participants were consented and 15 completed the trial. Pain ratings were significantly reduced over time from pre-treatment baseline including current pain (- 1.91 ± 0.35, p < 0.0001), average pain (- 1.92 ± 0.35, p < 0.0001) and maximum pain (- 1.97 ± 0.34, p < 0.0001) (data represent mean reduction on a 0-10 NPRS scale ± standard error of the mean (SEM)). A significant increase in grip strength in the treated hand (p < 0.0001) was observed although self-reported functionality did not improve. There were significant (p < 0.005) improvements in three QoL measures: fatigue, stiffness and anxiety. CBD and its metabolites were detected at low concentrations in all urine samples. Measured reductions in pain and increases in grip strength seen during treatment reverted back towards baseline during the washout phase. In summary, pain, grip strength and QoL measures, using smartphone technology, was shown to improve over time following transdermal CBD application suggesting feasibility of this intervention in relieving osteoarthritic hand pain. Proof of efficacy, however, requires further confirmation in a placebo-controlled randomised trial.Trial registration: ANZCTR public trials registry (ACTRN12621001512819, 05/11/2021).

Pantarsal arthrodesis stabilized with circular external skeletal fixators in 8 dogs (2010-2022).

OBJECTIVE: To report the surgical technique, complications, and outcomes of 8 dogs that underwent a unilateral pantarsal arthrodesis stabilized using a circular external skeletal fixator (CESF) construct for the treatment of uni- or multilevel tarsal instability. ANIMALS: 8 dogs. CLINICAL PRESENTATION: Medical records from 2010 to 2023 from 2 small animal hospitals were retrospectively reviewed for dogs undergoing pantarsal arthrodeses stabilized with CESF. Data collected for each dog included signalment, injury etiology, construct configuration, radiographic imaging, antimicrobial use, complications, length of time until construct removal, and outcome based on clinical evaluation by the owner and veterinary surgeon. RESULTS: 8 dogs met the requirements of inclusion for the study. Dogs had a mean age of 5.5 years (range, 0.42 to 13 years) and weight of 15.1 kg (range, 2.5 to 26.4 kg). Angulated 3- and 4-ring constructs were used in 5 and 3 dogs, respectively, with or without hybridization. Tarsi were stabilized with a mean angle of extension of 124.8° (range, 111.5° to 136.5°). Fixator removal was performed at a mean time of 11.3 weeks (range, 6 to 16 weeks). Complications developed in 4 dogs, 2 of which had poor clinical outcomes despite additional interventions, including recurrent digit trauma and poor limb use postoperatively. Six dogs had excellent outcomes. CLINICAL RELEVANCE: A CESF may be considered as an alternative to plate stabilization when performing a pantarsal arthrodesis. This fixation requires rigorous postoperative care but obviates the need for supplemental postoperative coaptation.

Hydrogen Peroxide May Reduce the Risk for Revision Surgery and Infection in Primary Shoulder Arthroplasty: Two-year Follow-up From a Prospective, Blinded, Controlled Trial.

BACKGROUND: The purpose of this study was to determine whether the addition of hydrogen peroxide to the preoperative skin preparation for primary total shoulder arthroplasty is associated with a difference in patient-reported outcomes, risk for postoperative infection, and risk for revision surgery at a minimum of 2-year follow-up. METHODS: This was a prospective, blinded, and controlled trial, which included a consecutive series of patients undergoing primary shoulder arthroplasty. The control group underwent standard sterile skin preparation using ethyl alcohol and ChloraPrep applicators, and the peroxide group had the same preparation with the addition of hydrogen peroxide between the alcohol and ChloraPrep applications. We then compared patient-reported outcome scores (American Shoulder and Elbow Surgeons Shoulder Score [ASES], simple shoulder test [SST], visual analog scale [VAS]), infections, and revision surgeries between the two groups at 2-year follow-up. RESULTS: Of the 61 patients included in the original study, 52 of 58 (85%) living patients agreed to participate in this study. No preoperative differences were observed between groups. No difference was observed in ASES, SST, or VAS scores at 2 years. More revision surgeries were done in the control group (7 versus 2, P = 0.268) and Cutibacterium acnes infections (2 versus 0, P = 0.168). CONCLUSION: The addition of hydrogen peroxide to the preoperative skin preparation before primary shoulder arthroplasty is safe, and additional research is warranted to investigate whether it may decrease the risk for revision surgery and postoperative C acnes infection. LEVEL OF EVIDENCE: III.

Post-streptococcal small-vessel vasculitis in a 16-month-old with associated intussusception and hypertension: Henoch Schönlein purpura?

Henoch Schönlein purpura (HSP), also known as IgA vasculitis, is a systemic small-vessel vasculitis typically occurring in children 3-15 years of age, with peak incidence at 4-6 years. It is characterized by a constellation of symptoms including palpable purpura, arthralgias or arthritis, abdominal pain including intussusception, and renal involvement. We report a patient with these clinical findings whose IgA immunofluorescence was negative but with a presumptive diagnosis of HSP at 16 months of age, significantly younger than the classic population. This condition rarely affects this age group, and we highlight the importance of considering vasculitis in children of all ages, as a failure to diagnose could lead to insufficient long-term monitoring, particularly regarding renal function.

A rare case of multifocal craniospinal leptomeningeal melanocytoma: A case report and scoping review.

Introduction: Leptomeningeal melanocytomas are rare tumours originating from neural crest derived melanocytes. They are usually solitary and presentation with multifocal meningeal melanocytoma is very rare and indicative of potentially more aggressive behaviour. This case report and scoping review sought to evaluate the presentation, and key radiological features that can help differentiate multifocal meningeal melanocytoma from other differentials and provide a discussion of the key management and prognostic points once these tumours are diagnosed. Case presentation: A 26 year old male presented with neck pain radiating to both shoulders and subjective weakness in left shoulder movement. MRI demonstrated a large enhancing C2-C3 intradural-extramedullary lesion with further lesions at the T7/T8 level, left cerebellopontine angle and midline suprachiasmatic region. Whilst the imaging appearances were initially thought be indicative of a phacomatosis such as NF2-related schwannomatosis, surgical excision of the cervical tumour confirmed a melanocytic tumour of leptomeningeal origin, consistent with multifocal meningeal melanocytoma. Patient made a good post-operative recovery and remains under half yearly radiological surveillance, with repeat MRI 6 months after surgery demonstrating subtle growth of the untreated intracranial and spinal lesions. Literature review and conclusions: This is the first description, to our knowledge, of a multifocal meningeal melanocytoma associated with both cerebellopontine angle and suprasellar lesions. This case and included scoping review highlight the need to consider this rare diagnosis whenever multifocal craniospinal lesions are encountered, and the need to consider aggressive management through surgical resection and adjuvant craniospinal radiotherapy once these tumours are diagnosed.

Similar Efficacy and Lower Cost Associated With Ceftazidime Compared to Tobramycin Coupled With Vancomycin in Antibiotic Spacers in the Treatment of Periprosthetic Joint Infection.

BACKGROUND: Vancomycin and tobramycin have traditionally been used in antibiotic spacers. In 2020, our institution replaced tobramycin with ceftazidime. We hypothesized that the use of ceftazidime/vancomycin (CV) in antibiotic spacers would not lead to an increase in treatment failure compared to tobramycin/vancomycin (TV). METHODS: From 2014 to 2022, we identified 243 patients who underwent a stage I revision for periprosthetic joint infection. The primary outcome was a recurrent infection requiring antibiotic spacer exchange. We were adequately powered to detect a 10% difference in recurrent infection. Patients who had a prior failed stage I or two-stage revision for infection, acute kidney injury prior to surgery, or end-stage renal disease were excluded. Given no other changes to our spacer constructs, we estimated cost differences attributable to the antibiotic change. Chi-square and t-tests were used to compare the two groups. Multivariable logistic regressions were utilized for the outcomes. RESULTS: The combination of TV was used in 127 patients; CV was used in 116 patients. Within one year of stage I, 9.8% of the TV group had a recurrence of infection versus 7.8% of the CV group (P = .60). By final follow-up, results were similar (12.6 versus 8.6%, respectively, P = .32). Adjusting for potential risk factors did not alter the results. Cost savings for ceftazidime versus tobramycin are estimated to be $68,550 per one hundred patients treated. CONCLUSIONS: Replacing tobramycin with ceftazidime in antibiotic spacers yielded similar periprosthetic joint infection eradication success at a lower cost. While larger studies are warranted to confirm these efficacy and cost-saving results, our data justifies the continued investigation and use of ceftazidime as an alternative to tobramycin in antibiotic spacers.

Small Extracellular Vesicles Promote Stiffness-mediated Metastasis.

Tissue stiffness is a critical prognostic factor in breast cancer and is associated with metastatic progression. Here we show an alternative and complementary hypothesis of tumor progression whereby physiologic matrix stiffness affects the quantity and protein cargo of small extracellular vesicles (EV) produced by cancer cells, which in turn aid cancer cell dissemination. Primary patient breast tissue released by cancer cells on matrices that model human breast tumors (25 kPa; stiff EVs) feature increased adhesion molecule presentation (ITGα2ß1, ITGα6ß4, ITGα6ß1, CD44) compared with EVs from softer normal tissue (0.5 kPa; soft EVs), which facilitates their binding to extracellular matrix proteins including collagen IV, and a 3-fold increase in homing ability to distant organs in mice. In a zebrafish xenograft model, stiff EVs aid cancer cell dissemination. Moreover, normal, resident lung fibroblasts treated with stiff and soft EVs change their gene expression profiles to adopt a cancer-associated fibroblast phenotype. These findings show that EV quantity, cargo, and function depend heavily on the mechanical properties of the extracellular microenvironment. SIGNIFICANCE: Here we show that the quantity, cargo, and function of breast cancer-derived EVs vary with mechanical properties of the extracellular microenvironment.

Modifiability of surgical timing in postinjury multiple organ failure patients.

BACKGROUND: Postinjury multiple organ failure (MOF) is the leading cause of late trauma deaths, with primarily non-modifiable risk factors. Timing of surgery as a potentially modifiable risk factor is frequently proposed, but has not been quantified. We aimed to compare mortality, hospital length of stay (LOS), and ICU LOS between MOF patients who had surgery that preceded MOF with modifiable timings versus those with non-modifiable timings. METHODS: Retrospective analysis of an ongoing 17-year prospective cohort study of ICU polytrauma patients at-risk of MOF. Among MOF patients (Denver score>3), we identified patients who had surgery that preceded MOF, determined whether the timing of these operation(s) were modifiable(M) or non-modifiable (non-M), and evaluated the change in physiological parameters as a result of surgery. RESULTS: Of 716 polytrauma patients at-risk of MOF, 205/716 (29%) developed MOF, and 161/205 (79%) had surgery during their ICU admission. Of the surgical MOF patients, 147/161 (91%) had one or more operation(s) that preceded MOF, and 65/161 (40%) of them had operation(s) with modifiable timings. There were no differences in age (mean (SD) 52 (19) vs 53 (21)years), injury severity score (median (IQR) 34 (26-41)vs34 (25-44)), admission physiological and resuscitation parameters, between M and non-M-patients. M patients had longer ICU LOS (median (IQR) 18 (12-28)versus 11 (8-16)days, p < 0.0001) than non-M-patients, without difference in mortality (14%vs16%, p = 0.7347), or hospital LOS (median (IQR) 32 (18-52)vs27 (17-47)days, p = 0.3418). M-patients had less fluids and transfusions intraoperatively. Surgery did not compromise patient physiology. CONCLUSION: Operations preceding MOF are common in polytrauma and seem to be safe in maintaining physiology. The margin for improvement from optimizing surgical timing is modest, contrary to historical assumptions.

A retrospective study of hydrocortisone continuous rate infusion compared with administration of dexamethasone boluses in dogs with adrenal crisis.

BACKGROUND: Evidence indicating the optimal treatment protocol for dogs in adrenal crisis is lacking. OBJECTIVES: Compare outcomes of dogs presented in adrenal crisis treated with either hydrocortisone (HC) continuous rate infusion (CRI) or intermittent dexamethasone (DEX) administration. ANIMALS: Thirty-nine client-owned dogs. METHODS: Multi-institutional retrospective observational study (July 2016-May 2022) including dogs diagnosed with adrenal crisis and with available sequential blood work during hospitalization. Dogs were excluded if already on treatment with exogenous corticosteroids. Outcomes assessed included duration of hospitalization, survival, number of repeat measurements of electrolyte concentrations, and time to normalization of electrolyte and acid-base status. RESULTS: No significant difference was found between the groups for hospitalization time (P = .41; HC median [range] 48 h [19-105 h]; DEX 57 h [17-167 h]) nor case fatality rate 2/28 in the DEX group and 0/11 in the HC group (P = 1), nor in number of measurements of electrolyte concentrations (P = .90; HC 4 [2-10]; DEX 4.5 [2-15]). No significant differences were found between the 2 treatment groups in time to normalization of serum Na (P = .30; HC 33 h [7-66 h]; DEX 16 h [1.5-48 h]), K (P = .92; HC 17 h [4-48 h]; DEX 16 h [1.25-60 h]) or Na/K ratio (P = .08; HC 17 h [8-48 h]; DEX 26 h [1.5-60 h]). CONCLUSIONS: This study detected no difference in outcomes for dogs in adrenal crisis treated with either DEX boluses or HC CRIs.

Low-dose GBCA administration for brain tumour dynamic contrast enhanced MRI: a feasibility study.

A key limitation of current dynamic contrast enhanced (DCE) MRI techniques is the requirement for full-dose gadolinium-based contrast agent (GBCA) administration. The purpose of this feasibility study was to develop and assess a new low GBCA dose protocol for deriving high-spatial resolution kinetic parameters from brain DCE-MRI. Nineteen patients with intracranial skull base tumours were prospectively imaged at 1.5 T using a single-injection, fixed-volume low GBCA dose, dual temporal resolution interleaved DCE-MRI acquisition. The accuracy of kinetic parameters (ve, Ktrans, vp) derived using this new low GBCA dose technique was evaluated through both Monte-Carlo simulations (mean percent deviation, PD, of measured from true values) and an in vivo study incorporating comparison with a conventional full-dose GBCA protocol and correlation with histopathological data. The mean PD of data from the interleaved high-temporal-high-spatial resolution approach outperformed use of high-spatial, low temporal resolution datasets alone (p < 0.0001, t-test). Kinetic parameters derived using the low-dose interleaved protocol correlated significantly with parameters derived from a full-dose acquisition (p < 0.001) and demonstrated a significant association with tissue markers of microvessel density (p < 0.05). Our results suggest accurate high-spatial resolution kinetic parameter mapping is feasible with significantly reduced GBCA dose.

Association of travel time, patient characteristics, and hospital quality with patient mobility for breast cancer surgery: A national population-based study.

BACKGROUND: This national study investigated hospital quality and patient factors associated with treatment location for breast cancer surgery. METHODS: By using linked administrative data sets from the English National Health Service, the authors identified all women diagnosed between January 2, 2016, and December 31, 2018, who underwent breast-conserving surgery (BCS) or a mastectomy with or without immediate breast reconstruction. The extent to which patients bypassed their nearest hospital was investigated using a geographic information system (ArcGIS). Conditional logistic regressions were used to estimate the impact of travel time, hospital quality, and patient characteristics. RESULTS: 22,622 Of 69,153 patients undergoing BCS, 22,622 (32.7%) bypassed their nearest hospital; and, of 23,536 patients undergoing mastectomy, 7179 (30.5%) bypassed their nearest hospital. Women who were younger, without comorbidities, or from rural areas were more likely to travel to more distant hospitals (p < .05). Patients undergoing BCS (odds ratio [OR], 1.85; 95% confidence interval [CI], 1.36-2.50) or mastectomy (OR, 1.52; 95% CI, 1.14-2.02) were more likely to be treated at specialist breast reconstruction centers despite not undergoing the procedure. Patients receiving mastectomy and immediate breast reconstruction were more likely to travel to hospitals employing surgeons who had a media reputation (OR, 2.41; 95% CI, 1.28-4.52). Patients undergoing BCS were less likely to travel to hospitals with shorter surgical waiting times (OR, 0.65; 95% CI, 0.46-0.92). The authors did not observe a significant impact for research activity, hospital quality rating, breast re-excision rates, or the status as a multidisciplinary cancer center. CONCLUSIONS: Patient choice policies may drive inequalities in the health care system without improving patient outcomes.

The impact of transportation mode, socioeconomic deprivation and rurality on travel times to radiotherapy and surgical services for patients with prostate cancer: A national population-based evaluation.

BACKGROUND: The distances that patients have to travel can influence their access to cancer treatment. We investigated the determinants of travel time, separately for journeys by car and public transport, to centres providing radical surgery or radiotherapy for prostate cancer. METHODS: Using national cancer registry records linked to administrative hospital data, we identified patients who had radical surgery or radiotherapy for prostate cancer between January 2017 and December 2018 in the English National Health Service. Estimated travel times from the patients' residential area to the nearest specialist surgical or radiotherapy centre were estimated for journeys by car and by public transport. RESULTS: We included 13,186 men who had surgery and 26,581 who had radiotherapy. Estimated travel times by public transport (74.4 mins for surgery and 69.4 mins for radiotherapy) were more than twice as long as by car (33.4 mins and 29.1mins, respectively). Patients living in more socially deprived neighbourhoods in rural areas had the longest travel times to the nearest cancer treatment centres by car (62.0 mins for surgery and 52.1 mins for radiotherapy). Conversely patients living in more affluent neighbourhoods in urban conurbations had the shortest (18.7 mins for surgery and 17.9 mins for radiotherapy). CONCLUSION: Travel times to cancer centres vary widely according to mode of transport, socioeconomic deprivation, and rurality. Policies changing the geographical configuration of cancer services should consider the impact on the expected travel times both by car and by public transport to avoid enhancing existing inequalities in access to treatment and patient outcomes.

Small extracellular vesicles promote stiffness-mediated metastasis.

Tissue stiffness is a critical prognostic factor in breast cancer and is associated with metastatic progression. Here we show an alternative and complementary hypothesis of tumor progression whereby physiological matrix stiffness affects the quantity and protein cargo of small EVs produced by cancer cells, which in turn drive their metastasis. Primary patient breast tissue produces significantly more EVs from stiff tumor tissue than soft tumor adjacent tissue. EVs released by cancer cells on matrices that model human breast tumors (25 kPa; stiff EVs) feature increased adhesion molecule presentation (ITGα 2 ß 1 , ITGα 6 ß 4 , ITGα 6 ß 1 , CD44) compared to EVs from softer normal tissue (0.5 kPa; soft EVs), which facilitates their binding to extracellular matrix (ECM) protein collagen IV, and a 3-fold increase in homing ability to distant organs in mice. In a zebrafish xenograft model, stiff EVs aid cancer cell dissemination through enhanced chemotaxis. Moreover, normal, resident lung fibroblasts treated with stiff and soft EVs change their gene expression profiles to adopt a cancer associated fibroblast (CAF) phenotype. These findings show that EV quantity, cargo, and function depend heavily on the mechanical properties of the extracellular microenvironment.