Motion-robust, blood-suppressed, reduced-distortion diffusion MRI of the liver.

PURPOSE: To evaluate feasibility and reproducibility of liver diffusion-weighted (DW) MRI using cardiac-motion-robust, blood-suppressed, reduced-distortion techniques. METHODS: DW-MRI data were acquired at 3T in an anatomically accurate liver phantom including controlled pulsatile motion, in eight healthy volunteers and four patients with known or suspected liver metastases. Standard monopolar and motion-robust (M1-nulled, and M1-optimized) DW gradient waveforms were each acquired with single-shot echo-planar imaging (ssEPI) and multishot EPI (msEPI). In the motion phantom, apparent diffusion coefficient (ADC) was measured in the motion-affected volume. In healthy volunteers, ADC was measured in the left and right liver lobes separately to evaluate ADC reproducibility between the two lobes. Image distortions were quantified using the normalized cross-correlation coefficient, with an undistorted T2-weighted reference. RESULTS: In the motion phantom, ADC mean and SD in motion-affected volumes substantially increased with increasing motion for monopolar waveforms. ADC remained stable in the presence of increasing motion when using motion-robust waveforms. M1-optimized waveforms suppressed slow flow signal present with M1-nulled waveforms. In healthy volunteers, monopolar waveforms generated significantly different ADC measurements between left and right liver lobes ( p = 0 . 0078 $$ p=0.0078 $$ , reproducibility coefficients (RPC) =  470 × 1 0 - 6 $$ 470\times 1{0}^{-6} $$ mm 2 $$ {}^2 $$ /s for monopolar-msEPI), while M1-optimized waveforms showed more reproducible ADC values ( p = 0 . 29 $$ p=0.29 $$ , RPC = 220 × 1 0 - 6 $$ \mathrm{RPC}=220\times 1{0}^{-6} $$ mm 2 $$ {}^2 $$ /s for M1-optimized-msEPI). In phantom and healthy volunteer studies, motion-robust acquisitions with msEPI showed significantly reduced image distortion ( p < 0 . 001 $$ p<0.001 $$ ) compared to ssEPI. Patient scans showed reduction of wormhole artifacts when combining M1-optimized waveforms with msEPI. CONCLUSION: Synergistic effects of combined M1-optimized diffusion waveforms and msEPI acquisitions enable reproducible liver DWI with motion robustness, blood signal suppression, and reduced distortion.

Nivolumab-Induced Lichen Planopilaris: Case Report and Literature Review of Hair Disorders Associated with Targeted Oncological Therapies.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapies. Their mechanism promotes a cytotoxic T-cell activation against the tumor cells, but as a consequence, immune-mediated toxicities are increasingly being identified. Cutaneous immune-mediated adverse events (AE) occur in 32% of patients, with possible higher grade AEs seen with anti-programmed cell death protein 1, such as nivolumab. A 67-year-old woman with metastatic melanoma, previously treated for 2 years on dual ICI (ipilimumab and nivolumab), had her treatment interrupted due to grade-3 hepatitis. She was subsequently recommenced on single-agent nivolumab with good response, before discontinuation due to remission. She reported worsening scalp pruritus with associated erythema, scaling, and global hair thinning. On examination, she had significant erythema throughout the scalp with perifollicular scaling and evidence of scarring. She reported severe distress from her symptoms. Her scalp biopsy demonstrated features of scarring alopecia with infundibular and isthmic inflammation and interface change in keeping with lichen planopilaris. Follicular toxicities are rarely reported, possibly due to imprecise AE phenotyping or underreporting. However, growing evidence suggests that patients can develop follicular pigmentary changes and nonscarring alopecia. To our knowledge, this is the first case of scarring alopecia reported with nivolumab. Current treatments for ICI-induced toxicities are limited.

Prevalence of wound complications following Mohs micrographic surgery (MMS): a cross-sectional study of 1000 patients undergoing MMS and wound repair in a UK teaching hospital.

BACKGROUND: Mohs micrographic surgery (MMS) for nonmelanoma skin cancer is often quoted as having an excellent safety profile. AIM: To determine the complication rate of patients undergoing MMS in a large UK Mohs unit and subdivide complication rates into mild/intermediate and major, and to identify potential risk factors necessitating a clinical intervention. METHODS: This was a single-centre, cross-sectional study of 1000 consecutive cases of MMS performed with in-house repair. Notes from the postsurgical dressing clinics were reviewed at Visit 1 (Days 7-14) and Visit 2 (approximately Week 6). Based upon the intervention required and effect on cosmetic/functional outcome, complications were classified as minor, intermediate or major. Logistic regression modelling was used to identify risk factors associated with a complication that needed a clinical intervention (i.e. intermediate or major). RESULTS: In total, 1000 Mohs surgeries were performed on 803 patients, resulting in 1067 excisions. Complication rates in our cohort were low (minor 3.6%, intermediate 3.1% and major 0.8%) Potential risk factors for developing a complication included skin graft (unadjusted OR = 4.89, 95% CI 1.93-12.39; fully adjusted OR = 7.13, 95% CI 2.26-22.45) and patients undergoing surgery on the forehead (unadjusted OR = 3.32, 95% CI 0.95-11.58; fully adjusted OR = 5.34, 95% CI 1.40-20.42). Patients whose wounds were allowed to heal by secondary intention healing (6.8%) exhibited no complications. CONCLUSION: We advocate that patients should be informed during the consent procedure that less than 1 in every 100 patients (0.75%) undergoing MMS will have a serious adverse event (major complication) affecting their cosmetic or functional outcome.

Inhibition of Shh Signaling through MAPK Activation Controls Chemotherapy-Induced Alopecia.

Chemotherapy-induced hair loss (alopecia) (CIA) remains a major unsolved problem in clinical oncology. CIA is often considered to be a consequence of the antimitotic and apoptosis-promoting properties of chemotherapy drugs acting on rapidly proliferating hair matrix keratinocytes. Here, we show that in a mouse model of CIA, the downregulation of Shh signaling in the hair matrix is a critical early event. Inhibition of Shh signaling recapitulated key morphological and functional features of CIA, whereas recombinant Shh protein partially rescued hair loss. Phosphoproteomics analysis revealed that activation of the MAPK pathway is a key upstream event, which can be further manipulated to rescue CIA. Finally, in organ-cultured human scalp hair follicles as well as in patients undergoing chemotherapy, reduced expression of SHH gene correlates with chemotherapy-induced hair follicle damage or the degree of CIA, respectively. Our work revealed that Shh signaling is an evolutionarily conserved key target in CIA pathobiology. Specifically targeting the intrafollicular MAPK-Shh axis may provide a promising strategy to manage CIA.

A pilot study of bladder voiding with real-time MRI and computational fluid dynamics.

Lower urinary track symptoms (LUTS) affect many older adults. Multi-channel urodynamic studies provide information about bladder pressure and urinary flow but offer little insight into changes in bladder anatomy and detrusor muscle function. Here we present a novel method for real time MRI during bladder voiding. This was performed in a small cohort of healthy men and men with benign prostatic hyperplasia and lower urinary tract symptoms (BPH/LUTS) to demonstrate proof of principle; The MRI urodynamic protocol was successfully implemented, and bladder wall displacement and urine flow dynamics were calculated. Displacement analysis on healthy controls showed the greatest bladder wall displacement in the dome of the bladder while men with BPH/LUTS exhibited decreased and asymmetric bladder wall motion. Computational fluid dynamics of voiding showed men with BPH/LUTS had larger recirculation regions in the bladder. This study demonstrates the feasibility of performing MRI voiding studies and their potential to provide new insight into lower urinary tract function in health and disease.

Vascular Endothelial Growth Factor Blockade Induces Dermal Endothelial Cell Apoptosis in a Clinically Relevant Skin Organ Culture Model.

BACKGROUND/AIMS: Vascular endothelial growth factor (VEGF), a key mediator of angiogenesis, plays a key role in physiological processes and is a major contributor to several diseases including cancer and psoriasis. Anti-VEGF therapies are widely used as cancer and ophthalmological treatments. There is some evidence that VEGF blockade may have utility in the management of psoriasis, although their potential has been largely unexplored. We hypothesized that a human skin organ culture could provide a stable ex vivo model in which the cutaneous microvascular network could be studied and experimentally manipulated. METHODS: Punch biopsies (3 mm) of skin, donated by healthy individuals (39-72 years old, n = 5), were incubated with monoclonal antibody (mAb) to human VEGF (bevacizumab) at doses based on data from animal and clinical studies. After 3-day culture, cell death and proliferation as well as vascular endothelial cell changes were assessed using quantitative immunohistomorphometry. RESULTS: Anti-VEGF mAb at 0.8 mg/mL induced a significant increase in cleaved caspase-3 expression in CD31+ cells (p < 0.05). None of the doses tested increased TUNEL or decreased Ki-67 expression in the basal layer of the epidermis, confirming the model's viability. In addition, the lactate dehydrogenase (LDH) assay showed no increase in LDH activity in treated samples compared to untreated control. The highest anti-VEGF mAb dose (0.8 mg/mL) induced an increase in TUNEL expression in the upper epidermis, which did not correlate with caspase-3 immunoreactivity. Further investigation revealed that anti-VEGF mAb did not change the expression of markers of terminal differentiation such as keratin 10, filaggrin, and involucrin, suggesting that VEGF depletion does not affect keratinocyte terminal differentiation. In contrast to the control group, levels of VEGF protein were undetectable in the culture supernatant of samples treated with 0.8 mg/mL of anti-VEGF mAb, suggesting sufficient dose. CONCLUSION: Our pilot study provides the first evidence that anti-VEGF therapy promotes endothelial cell apoptosis in human skin ex vivo. Our pragmatic human skin organ culture assay offers a valuable tool for future preclinical endothelial cell and translational microvascular network/anti-angiogenesis research in human skin.

Mri-based cancer lesion analysis with 3d printed patient specific prostate cutting guides.

Purpose: MRI methods have improved diagnosis and treatment planning for prostate cancer. However, validation and standardization is needed to encourage widespread adoption of these methods. The purpose of this study was to improve validation methods by creating a prostate cutting guide and to develop a method for 3D comparison between MRI data and post-prostatectomy histological tissue slices. Methods: Prostate Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET)/MRI was performed on 10 patients with prostate cancer before and after chemohormonal treatment. Post-treatment images were used to design patient-specific prostate cutting guides that were used to create uniform thickness sections of surgically removed prostates. The thickness of the prostate tissue slices matched the imaging slice thickness so that comparisons could be made between MRI results and histopathological study results. A method was also developed to compare post-slicing prostate bulk geometry with the predicted MRI prostate geometry. Results: The prostate cutting guides were used to successfully section the prostate for histopathogical evaluation and slice-by-slice MRI comparison. Surface comparison results displayed an average dimensional difference of 1.99 ± 3.19 mm between MRI and post-prostatectomy slice reconstruction prostate geometries. Conclusion: MRI-based prostate cutting guides were designed, fabricated, and implemented in a study examining the utility and accuracy of MRI for the detection of prostate cancer. Furthermore, a three-dimensional part comparison method was developed, which can be used for validation of MRI with pathological and histological data. Future work will analyze more subjects to examine the effectiveness of these guides for histopathological prostate analysis with MRI and PET/MRI.

The Potential Benefits of Certolizumab Pegol in Patients with Concurrent Psoriatic Arthritis and Chronic Plaque Psoriasis: A Case Series and Review of the Literature.

INTRODUCTION: We review the literature evaluating certolizumab in psoriasis and report our experience of treatment outcomes in a joint dermatology and rheumatology clinic. METHODS: Patients with concomitant psoriatic arthritis (PsA) and psoriasis who had been commenced on certolizumab were included within our retrospective review. Data was collected for patient demographics, Patient Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI) and previous treatments. The literature was systematically searched using Pubmed and Scopus. RESULTS: Very recent results from the CIMPASI-1 and CIMPASI-2 studies have demonstrated the high efficacy of certolizumab in the treatment of psoriasis at both week 16 and 48. Pooled results from these studies showed a PASI75 at week 16 and week 48 of 82% and 83.6% respectively, in the certolizumab 400 mg group. In our cohort of eight patients (two female; six male; median age 49 and mean PASI of 20.8) all had failed at least two systemic non-biologic agents. Objective improvements were observed in seven patients, with five achieving PASI90 and two demonstrating either PASI75 or PASI50. CONCLUSION: Certolizumab is efficacious in both psoriasis and PsA, including in patients who are biologic failures, and could be considered as an alternative treatment modality.

Surgical planning for living donor liver transplant using 4D flow MRI, computational fluid dynamics and in vitro experiments.

This study used magnetic resonance imaging (MRI), computational fluid dynamics (CFD) modeling, and in vitro experiments to predict patient-specific alterations in hepatic hemodynamics in response to partial hepatectomy in living liver donors. 4D Flow MRI was performed on three donors before and after hepatectomy and models of the portal venous system were created. Virtual surgery was performed to simulate (1) surgical resection and (2) post-surgery vessel dilation. CFD simulations were conducted using in vivo flow data for boundary conditions. CFD results showed good agreement with in vivo data, and in vitro experimental values agreed well with imaging and simulation results. The post-surgery models predicted an increase in all measured hemodynamic parameters, and the dilated virtual surgery model predicted post-surgery conditions better than the model that only simulated resection. The methods used in this study have potential significant value for the surgical planning process for the liver and other vascular territories.

Impact of image reconstruction parameters when using 3D DSA reconstructions to measure intracranial aneurysms.

BACKGROUND AND PURPOSE: Safe and effective use of newly developed devices for aneurysm treatment requires the ability to make accurate measurements in the angiographic suite. Our purpose was to determine the parameters that optimize the geometric accuracy of three-dimensional (3D) vascular reconstructions. METHODS: An in vitro flow model consisting of a peristaltic pump, plastic tubing, and 3D printed patient-specific aneurysm models was used to simulate blood flow in an intracranial aneurysm. Flow rates were adjusted to match values reported in the literature for the internal carotid artery. 3D digital subtraction angiography acquisitions were obtained using a commercially available biplane angiographic system. Reconstructions were done using Edge Enhancement (EE) or Hounsfield Unit (HU) kernels and a Normal or Smooth image characteristic. Reconstructed images were analyzed using the vendor's aneurysm analysis tool. Ground truth measurements were derived from metrological scans of the models with a microCT. Aneurysm volume, surface area, dome height, minimum and maximum ostium diameter were determined for the five models. RESULTS: In all cases, measurements made with the EE kernel most closely matched ground truth values. Differences in values derived from reconstructions displayed with Smooth or Normal image characteristics were small and had only little impact on the geometric parameters considered. CONCLUSIONS: Reconstruction parameters impact the accuracy of measurements made using the aneurysm analysis tool of a commercially available angiographic system. Absolute differences between measurements made using reconstruction parameters determined as optimal in this study were, overall, very small. The significance of these differences, if any, will depend on the details of each individual case.

First evidence of genotype-phenotype correlations in Gorlin syndrome.

BACKGROUND: Gorlin syndrome (GS) is an autosomal dominant syndrome characterised by multiple basal cell carcinomas (BCCs) and an increased risk of jaw cysts and early childhood medulloblastoma. Heterozygous germline variants in PTCH1 and SUFU encoding components of the Sonic hedgehog pathway explain the majority of cases. Here, we aimed to delineate genotype-phenotype correlations in GS. METHODS: We assessed genetic and phenotypic data for 182 individuals meeting the diagnostic criteria for GS (median age: 47.1; IQR: 31.1-61.1). A total of 126 patients had a heterozygous pathogenic variant, 9 had SUFU pathogenic variants and 46 had no identified mutation. RESULTS: Patients with variants were more likely to be diagnosed earlier (p=0.02), have jaw cysts (p=0.002) and have bifid ribs (p=0.003) or any skeletal abnormality (p=0.003) than patients with no identified mutation. Patients with a missense variant in PTCH1 were diagnosed later (p=0.03) and were less likely to develop at least 10 BCCs and jaw cysts than those with other pathogenic PTCH1 variants (p=0.03). Patients with SUFU pathogenic variants were significantly more likely than those with PTCH1 pathogenic variants to develop a medulloblastoma (p=0.009), a meningioma (p=0.02) or an ovarian fibroma (p=0.015), but were less likely to develop a jaw cyst (p=0.0004). CONCLUSION: We propose that the clinical heterogeneity of GS can in part be explained by the underlying or SUFU variant.

A qualitative study of the knowledge, behaviour and attitudes of patients with skin cancer regarding sunlight exposure and vitamin D.

BACKGROUND: Solar UVR is a major cause of skin cancer but also an important source of vitamin D (VitD), essential for musculoskeletal health. Conflicting public health messages may confuse patients with skin cancer prone to further skin cancer. OBJECTIVE: To explore the knowledge, behaviour and attitudes of patients with skin cancer to sunlight exposure and VitD sources. METHODS: Patients (n = 10) previously treated for multiple basal cell cancer in a hospital setting participated in focus group sessions with semi-structured discussions to explore: knowledge of VitD, sun-avoidance behaviour and attitude towards sunlight exposure messages. Thematic data analysis was performed using software programme MAXQDA11. RESULTS: Pre-existing knowledge of VitD was low. Most patients practised sun avoidance and were not inclined to increase exposure. Patients did not perceive VitD deficiency as a substantial risk to their own health, or a need to take VitD supplements. They aimed to increase VitD status through dietary intake, but knowledge of food VitD content was lacking. CONCLUSIONS: The patients with skin cancer, appropriate to their heightened skin cancer risk, appeared unlikely to increase their sun exposure to gain VitD. However, education is required regarding the generally low levels of VitD in foodstuffs, and the requirement for supplements/fortified foods if strict sun avoidance is employed.