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BackgroundPeripheral blood leucocyte telomere length (PBL-TL) is associated with outcomes in patients with idiopathic pulmonary fibrosis. Whether PBL-TL is associated with progression of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is unknown.MethodsA retrospective observational cohort study was performed using prospectively collected data from 213 patients with SSc followed at the University of California San Francisco (UCSF) Scleroderma Center. PBL-TL was measured by quantitative PCR of DNA isolated from peripheral blood. Associations between PBL-TL and pulmonary function test trends in patients with SSc-ILD were assessed by longitudinal analysis using Generalised Linear Mixed Models. Findings were validated in a cohort of 61 patients with SSc-ILD enrolled in the Stanford University Scleroderma Center database.ResultsPatients with UCSF SSc with ILD were found to have shorter PBL-TL compared with those without ILD (6554±671 base pairs (bp) vs 6782±698 bp, p=0.01). Shorter PBL-TL was associated with the presence of ILD (adjusted OR 2.1 per 1000 bp TL decrease, 95% CI [1.25 to 3.70], p=0.006). PBL-TL was shorter in patients with SSc-ILD lacking SSc-specific autoantibodies compared with seropositive subjects (6237±647 bp vs 6651±653 bp, p=0.004). Shorter PBL-TL was associated with increased risk for lung function deterioration with an average of 67 mL greater loss in per year for every 1000 bp decrease in PBL-TL in the combined SSc-ILD cohorts (longitudinal analysis, adjusted model: 95% CI -104 mL to -33 mL, p

Purpose: 4-dimensional computed tomography (4D-CT)-based pulmonary ventilation imaging is an emerging functional imaging modality. The purpose of this study was to investigate the physiological significance of 4D-CT ventilation imaging by comparison with pulmonary function test (PFT) measurements and single-photon emission CT (SPECT) ventilation images, which are the clinical references for global and regional lung function, respectively. Methods and Materials: In an institutional review board-approved prospective clinical trial, 4D-CT imaging and PFT and/or SPECT ventilation imaging were performed in thoracic cancer patients. Regional ventilation (V 4DCT) was calculated by deformable image registration of 4D-CT images and quantitative analysis for regional volume change. V 4DCT defect parameters were compared with the PFT measurements (forced expiratory volume in 1second (FEV1; % predicted) and FEV1/forced vital capacity (FVC; %). V 4DCT was also compared with SPECT ventilation (V SPECT) to (1) test whether V 4DCT in V SPECT defect regions is significantly lower than in nondefect regions by using the 2-tailed t test; (2) to quantify the spatial overlap between V 4DCT and V SPECT defect regions with Dice similarity coefficient (DSC); and (3) to test ventral-to-dorsal gradients by using the 2-tailed t test. Results: Of 21 patients enrolled in the study, 18 patients for whom 4D-CT and either PFT or SPECT were acquired were included in the analysis. V 4DCT defect parameters were found to have significant, moderate correlations with PFT measurements. For example, V4DCTHU defect volume increased significantly with decreasing FEV1/FVC (R=-0.65, P

PurposeTo study the dosimetric differences of various channel combinations of the Capri vaginal applicator.Methods and materialsThe Capri consists of a single central channel (R1), an inner array of 6 channels (R2), and an outer array of 6 channels (R3). Three-dimensional plans were simulated for 6 channel arrangements (R1, R2, R12, R13, R23, and R123). Treatment plans were optimized to the applicator surface or 5-mm depth while minimizing dose to organs at risk (OARs: bladder, rectum, sigmoid, and urethra). The clinical target volume (CTV) was defined as a 5-mm circumferential shell extending 4 cm in length around the applicator. Clinical target volume coverage (Dmean, D90, V100, and V150) and OAR doses (D0.1 cm3, D1 cm3, D2 cm3, and Dmean) were compared. A comparison between the Capri (R123) and a conventional single-channel applicator was also done. Statistical significance (P value

PurposeTo determine the utility of focal high-dose-rate brachytherapy for localized prostate cancer, we investigated the impact on target coverage and dose to organs at risk (OARs) with hemigland (HG) compared with whole-gland (WG) treatment.Methods and materialsA total of 10 WG implants were used to generate 10 WG and 20 HG (left and right) treatment plans optimized with the inverse planning simulation annealing algorithm using Oncentra MasterPlan (Nucletron B.V., Veenendaal, The Netherlands). The standard distribution of 17-18 catheters designed for WG was used to generate HG plans. The same OARs namely bladder, rectum, and urethra contours and dose constraints were applied for HG and WG plans. The HG contour was a modification of the WG contour whereby the urethra divided the prostate into HGs. The prescription dose was 7.25 Gy×6. Evaluated dose parameters were target dose D90, V100, and V150 and D0.1 cc, D1 cc, and D2 cc to OARs.ResultsThe HG plans had a D90, V100, and V150 to the HG target of 112%, 97.6%, and 33.8%, respectively. The WG plans had a D90, V100, and V150 to the WG target of 108%, 98.8%, and 26.5%, respectively. The OAR D2 cc doses were significantly lower in HG vs. WG plans: rectum (53.1% vs. 64.1%, p

PurposeTo determine predictors of distant metastases (DM) in prostate cancer patients treated with high dose rate brachytherapy boost (HDR-B) and external beam radiation therapy (EBRT).Material and methodsFrom 1991 to 2002, 768 men with localized prostate cancer were treated with HDR-B and EBRT. The mean EBRT dose was 37.5 Gy (range: 30.6-45 Gy), and the HDR-B was 22 or 24 Gy delivered in 4 fractions. Univariate and multivariate analyses using a Cox proportional hazards model including age at diagnosis, T stage, Gleason score (GS), pretreatment PSA, biologically equivalent dose (BED), and use of androgen deprivation therapy (ADT) was used to determine predictors of developing distant metastases.ResultsThe median follow-up time for the entire patient population was 4.2 years (range: 1-11.2 years). Distant metastases were identified in 22/768 (3%) of patients at a median of 4.1 years. PSA failure according to the Phoenix definition developed in 3%, 5%, and 14% of men with low, intermediate, and high risk disease with a median time to failure of 3.8 years. Prostate cancer specific mortality was observed in 2% of cases. T stage, GS, and use of ADT were significantly associated with developing DM on univariate analysis. GS, and use of ADT were the only factors significantly associated with developing DM on multivariate analysis (p < 0.01). Patients who received ADT had significantly higher risk features suggesting patient selection bias for higher DM in this group of patients rather than a negative interaction between HDR-B and EBRT.ConclusionsIn men treated with HDR-B and EBRT, GS is a significant factor on multivariate analysis for developing distant metastasis.

Rationale and objectivesA novel ventilation imaging method based on four-dimensional (4D) computed tomography (CT) has been applied to the field of radiation oncology. Understanding its reproducibility is a prerequisite for clinical applications. The purpose of this study was to quantify the reproducibility of 4D CT ventilation imaging over different days and the same session.Materials and methodsTwo ventilation images were created from repeat 4D CT scans acquired over the average time frames of 15 days for 6 lung cancer patients and 5 minutes for another 6 patients. The reproducibility was quantified using the voxel-based Spearman rank correlation coefficients for all lung voxels and Dice similarity coefficients (DSC) for the spatial overlap of segmented high-, moderate-, and low-functional lung volumes. Furthermore, the relationship between the variation in abdominal motion range as a measure of the depth of breathing and variation in ventilation was evaluated using linear regression.ResultsThe voxel-based correlation between the two ventilation images was moderate on average (0.50 ± 0.15). The DSCs were also moderate for the high- (0.60 ± 0.08), moderate- (0.46 ± 0.06), and low-functional lung (0.58 ± 0.09). No patients demonstrated strong correlations. The relationship between the motion range variation and ventilation variation was found to be moderate and significant.ConclusionsWe investigated the reproducibility of 4D CT ventilation imaging over the time frames of 15 days and 5 minutes and found that it was only moderately reproducible. Respiratory variation during 4D CT scans was found to deteriorate the reproducibility. Improvement of 4D CT imaging is necessary to increase the reproducibility of 4D CT ventilation imaging.

Objectives We evaluated the safety and efficacy of oral treprostinil in preventing progression of SSc-associated calcinosis. Methods This prospective open-label study enrolled 12 SSc patients meeting 2013 ACR/EULAR classification criteria with confirmed clinical and radiographic evidence of one or more calcinosis deposit in the hands. Patients received oral treprostinil for 1 year. Primary endpoints were safety/tolerability and percentage of patients without radiographic progression of calcinosis at 1 year (<25% increase in Scleroderma Clinical Trials Consortium radiographic score). Secondary endpoints included 1-year changes in Scleroderma HAQ (SHAQ), Cochin Hand Functional Scale, Medical Outcomes Survey Short Form 36 (SF-36), Raynaud Condition Score and patient/physician assessment of calcinosis severity. Results Twelve female patients were enrolled, half with diffuse cutaneous disease; median age was 55 years (range 35–68 years). Five patients completed the study. Seven patients withdrew due to intolerable adverse effects (n  = 3), intercurrent unrelated illness (n  = 2, cirrhosis, cancer), progressive SSc (n  = 1) and personal reasons (n  = 1). Most patients developed headaches and gastrointestinal adverse effects. Four of 11 (36%) patients with 1-year follow-up hand radiographs experienced progression of calcinosis. Of five who completed treatment, calcinosis was stable in four (80%) with progression in one. Based on SF-36 Physical and Mental Component and Domain scores, transition question and SF-6D utility score, all patients who finished the trial reported overall improvement or no change compared with baseline. Conclusion Oral treprostinil was poorly tolerated in SSc patients with calcinosis. Of five patients who completed treatment, most (80%) had documented stability of calcinosis on hand radiographs at 1 year. ClinicalTrials.gov identifier NCT02663895. [ABSTRACT FROM AUTHOR]

Background: Peripheral blood leucocyte telomere length (PBL-TL) is associated with outcomes in patients with idiopathic pulmonary fibrosis. Whether PBL-TL is associated with progression of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is unknown.Methods: A retrospective observational cohort study was performed using prospectively collected data from 213 patients with SSc followed at the University of California San Francisco (UCSF) Scleroderma Center. PBL-TL was measured by quantitative PCR of DNA isolated from peripheral blood. Associations between PBL-TL and pulmonary function test trends in patients with SSc-ILD were assessed by longitudinal analysis using Generalised Linear Mixed Models. Findings were validated in a cohort of 61 patients with SSc-ILD enrolled in the Stanford University Scleroderma Center database.Results: Patients with UCSF SSc with ILD were found to have shorter PBL-TL compared with those without ILD (6554±671 base pairs (bp) vs 6782±698 bp, p=0.01). Shorter PBL-TL was associated with the presence of ILD (adjusted OR 2.1 per 1000 bp TL decrease, 95% CI [1.25 to 3.70], p=0.006). PBL-TL was shorter in patients with SSc-ILD lacking SSc-specific autoantibodies compared with seropositive subjects (6237±647 bp vs 6651±653 bp, p=0.004). Shorter PBL-TL was associated with increased risk for lung function deterioration with an average of 67 mL greater loss in per year for every 1000 bp decrease in PBL-TL in the combined SSc-ILD cohorts (longitudinal analysis, adjusted model: 95% CI -104 mL to -33 mL, p<0.001).Conclusions: These findings suggest that telomere dysfunction may be associated with SSc-ILD progression and that PBL-TL measurement may be useful for stratifying risk for SSc-ILD progression. [ABSTRACT FROM AUTHOR]

To evaluate the prevalence and clinical associations of ultrasound (US) findings of inflammatory arthritis and joint and soft tissue pathology in patients with systemic sclerosis (SSc). The hands and wrists of 43 SSc patients and 35 age-balanced controls were evaluated by clinical exam and musculoskeletal US. Synovial and tenosynovial pathology were assessed using semi-quantitative Gray Scale (GS) and Power Doppler (PD) scoring. US evaluation for osteophytes, erosions, ulnar artery occlusion, and median nerve cross-sectional areas was performed. Tender joints (TJ), swollen joints (SJ), modified Rodnan skin score (mRSS), digital ulcers, contractures, and calcinosis were evaluated. Concordance between US and physical exam findings at each joint region were assessed, and associations between their severity were analyzed. TJs and SJs were present in 44.2% and 62.8% of SSc patients, respectively. Inflammatory arthritis, defined as having both GS>0 and PD>0, was observed in 18.6% of SSc patients and no controls. There was a high concordance by joint region between GS synovial hypertrophy and osteophytes (κ=0.88) as well as TJs (κ=0.72). SSc patients had more osteophytes compared to controls (48.8% vs 22.9%, p = 0.018) as well as higher osteophyte severity (p = 0.033). Despite a high percentage of tender and swollen joints, less than 20% of SSc patients met criteria for inflammatory arthritis on US. The high concordance of osteophytes with GS synovial hypertrophy and tender joints suggest that osteophytosis may be a significant contributor to joint pain in SSc patients. [ABSTRACT FROM AUTHOR]

Objective: Interstitial lung disease (ILD) is a major cause of morbidity and mortality in connective tissue diseases (CTDs). We aimed to assess the effect of rituximab ± mycophenolate mofetil (MMF) compared with MMF on pulmonary function and prednisone dosage in patients with CTD‐related ILD (CTD‐ILD). Methods: This retrospective study included 83 patients from Stanford and Centre Hospitalier de l'Universite de Montreal. Fifteen patients received rituximab ± MMF (rituximab group), and 68 patients received MMF only (control group). Results: Median ILD duration at the start of treatment was longer in the rituximab group at 47 months (range: 4‐170) versus 6.5 months (range: 0‐164) in controls. Forced vital capacity (FVC) decreased by 3.0% (range: 11%‐21%) after treatment in the rituximab group, whereas it increased by 2.0% (range: 14%‐25%) in the control group (p = 0.025). Diffusing capacity of carbon monoxide (DLCO) decreased by 3.0% (range: 10%‐12%) after treatment in the rituximab group, whereas it increased by 4.5% (range: 30%‐36%) in the control group (p = 0.046). Mixed model analysis controlling for ILD duration, baseline DLCO, systemic sclerosis, pulmonary hypertension, and prednisone use showed no significant difference in FVC or DLCO between groups at 6 months or 1 year. The average daily prednisone dose score decreased after treatment in the rituximab group, whereas it remained unchanged in the control group (p = 0.017). Conclusion: Rituximab ± MMF did not significantly change pulmonary function compared with MMF alone, but it did result in a relative decrease in average daily prednisone dose in a population with recalcitrant CTD‐ILD. [ABSTRACT FROM AUTHOR]

Objective. Gastric antral vascular ectasia (GAVE) is a vascular manifestation of systemic sclerosis (SSc) that can lead to iron deficiency anemia or acute gastrointestinal (GI) bleeding. We aimed to identify clinical features associated with GAVE. Methods. We performed a cohort study of SSc patients who were seen at Stanford between 2004 and 2018 and had undergone esophagogastroduodenoscopy (EGD). We compared the clinical features of those with and without GAVE, and multivariable logistic regression was performed to identify clinical correlates with GAVE. Results. A total of 225 patients with SSc who underwent EGD were included in this study and 19 (8.4%) had GAVE. Those with GAVE were more likely to have scleroderma renal crisis (SRC) (21% vs 3%; p < 0.01), positive anti-RNA polymerase III antibody (71% vs 19%; p < 0.01), nucleolar pattern of anti-nuclear antibody (ANA) (33% vs 11%; p =0.04), and negative ANA (<1:80 by immunofluorescence) (33% vs 11%; p =0.02). On multivariate analysis with multiple imputation, anti-RNA polymerase III positivity (OR 4.57; 95% CI (1.57 – 13.23), p < 0.01) and ANA negativity (OR 3.75; 95% CI (1.21 – 11.62), p =0.02) remained significantly associated with GAVE. Conclusion. Positive anti-RNA polymerase III antibody and ANA negativity were significantly associated with GAVE. Further studies are necessary to determine whether patients with these autoantibody profiles should undergo screening endoscopies for GAVE. [ABSTRACT FROM AUTHOR]

Purpose: Previous external beam radiation therapy (EBRT) is theoretically contraindicated for yttrium-90 (90Y) radioembolization (RE) because the liver has a lifetime tolerance to radiation before becoming vulnerable to radiation-induced liver disease. We analyzed the safety of RE as salvage treatment in patients who had previously undergone EBRT. Methods and Materials: Between June 2004 and December 2010, a total of 31 patients who had previously undergone EBRT were treated with RE. Three-dimensional treatment planning with dose–volume histogram (DVH) analysis of the liver was used to calculate the EBRT liver dose. Liver-related toxicities including RE-induced liver disease (REILD) were reviewed and classified according to Common Terminology Criteria for Adverse Events version 4.02. Results: The mean EBRT and RE liver doses were 4.40 Gy (range, 0-23.13 Gy) and 57.9 Gy (range, 27.0-125.9 Gy), respectively. Patients who experienced hepatotoxicity (≥grade2; n=12) had higher EBRT mean liver doses (7.96 ± 8.55 Gy vs 1.62 ± 3.39 Gy; P=.037), the only independent predictor in multivariate analysis. DVH analysis showed that the fraction of liver exposed to ≥30 Gy (V30) was the strongest predictor of hepatotoxicity (10.14% ± 12.75% vs 0.84% ± 3.24%; P=.006). All patients with V30 >13% experienced hepatotoxicity. Fatal REILD (n=2) occurred at the 2 highest EBRT mean liver doses (20.9 Gy and 23.1 Gy) but also at the highest cumulative liver doses (91.8 Gy and 149 Gy). Conclusions: Prior exposure of the liver to EBRT may lead to increased liver toxicity after RE treatment, depending on fractional liver exposure and dose level. The V30 was the strongest predictor of toxicity. RE appears to be safe for the treatment of hepatic malignancies only in patients who have had limited hepatic exposure to prior EBRT. [ABSTRACT FROM AUTHOR]

Objectives: We evaluated the safety and efficacy of oral treprostinil in preventing progression of SSc-associated calcinosis., Methods: This prospective open-label study enrolled 12 SSc patients meeting 2013 ACR/EULAR classification criteria with confirmed clinical and radiographic evidence of one or more calcinosis deposit in the hands. Patients received oral treprostinil for 1 year. Primary endpoints were safety/tolerability and percentage of patients without radiographic progression of calcinosis at 1 year (<25% increase in Scleroderma Clinical Trials Consortium radiographic score). Secondary endpoints included 1-year changes in Scleroderma HAQ (SHAQ), Cochin Hand Functional Scale, Medical Outcomes Survey Short Form 36 (SF-36), Raynaud Condition Score and patient/physician assessment of calcinosis severity., Results: Twelve female patients were enrolled, half with diffuse cutaneous disease; median age was 55 years (range 35-68 years). Five patients completed the study. Seven patients withdrew due to intolerable adverse effects (n = 3), intercurrent unrelated illness (n = 2, cirrhosis, cancer), progressive SSc (n = 1) and personal reasons (n = 1). Most patients developed headaches and gastrointestinal adverse effects. Four of 11 (36%) patients with 1-year follow-up hand radiographs experienced progression of calcinosis. Of five who completed treatment, calcinosis was stable in four (80%) with progression in one. Based on SF-36 Physical and Mental Component and Domain scores, transition question and SF-6D utility score, all patients who finished the trial reported overall improvement or no change compared with baseline., Conclusion: Oral treprostinil was poorly tolerated in SSc patients with calcinosis. Of five patients who completed treatment, most (80%) had documented stability of calcinosis on hand radiographs at 1 year., Clinicaltrials.gov Identifier: NCT02663895., (Published by Oxford University Press on behalf of the British Society for Rheumatology 2021. This work is written by US Government employees and is in the public domain in the US.)