Real-World Outcomes of Immunotherapy for Melanoma Brain Metastases in New Zealand.

PURPOSE: Melanoma brain metastases (BMs) are associated with poor survival. Combination immune checkpoint inhibitors (ICIs) with anti-PD1 and anti-CTLA-4 are the international standard-of-care treatment. Most landmark clinical trials excluded real-world patients with symptomatic disease, poor performance status (PS), and steroid use. Despite the high incidence of melanoma in New Zealand (NZ), the only publicly funded systemic treatment is anti-PD1 monotherapy. The real-world outcomes for BMs after ICIs in NZ are unknown. METHODOLOGY: Medical records of patients with melanoma BMs in seven cancer centers across NZ between September 1, 2016, and September 1, 2020, were evaluated. Clinicopathologic characteristics, treatment, intracranial (IC) tumor response rates, IC progression-free survival, and overall survival (OS) are reported. RESULTS: One hundred and forty-four patients received at least one dose of ICI. One hundred and thirty-three (93%) patients received anti-PD1 monotherapy. Almost a quarter of patients had poor baseline PS, 56% were symptomatic, and 33% had corticosteroids. Patients also received local therapies: 61 (42%) patients underwent surgery, 42 (29%) received whole brain radiation, and 47 (33%) received stereotactic radiation. The median OS was 15 months, and a third of patients were alive at 2 years. The toxicity of ICIs was at 28% and 15% for Common Terminology Criteria for Adverse Events grade 1-2 and 3-4 events, respectively. Of the patients who are still alive, 76% of patients remained symptomatic neurologically at last follow-up. CONCLUSION: Most patients in this NZ real-world study were symptomatic and received anti-PD1 monotherapy. Approximately one-third of treated patients are alive at 2 years, but most patients remained symptomatic. This highlights the need for more effective treatment and prospective management of their neurologic rehabilitation needs.

Outcomes of Patients With Diffuse Systemic Sclerosis Eligible for Autologous Stem Cell Transplantation Treated With Conventional Therapy.

OBJECTIVE: The study objective was to determine the event-free survival (EFS) of Australian patients with diffuse cutaneous systemic sclerosis (dcSSc) who met eligibility criteria for autologous stem cell transplant (ASCT) in previously published randomized controlled trials but were not treated with ASCT. METHODS: Patients who met inclusion criteria for the Autologous Stem Cell Transplantation International Scleroderma (ASTIS) and Scleroderma: Cyclophosphamide Or Transplantation (SCOT) trials were identified from the multicenter Australian Scleroderma Cohort Study (ASCS). EFS (survival without cardiac, renal, or pulmonary failure or death) at 4 years was assessed. ASCS patients who had already undergone transplantation were excluded from analysis. RESULTS: Of the 492 patients with dcSSc in the ASCS, 56 met ASTIS inclusion criteria for ASCT (56 of 492 [11.4%]) and 30 met SCOT inclusion criteria (30 of 492 [6.1%]). An additional 11 patients met ASTIS or SCOT inclusion criteria, but they were excluded due to severe organ manifestations. EFS at 4 years in ASCS patients meeting ASTIS inclusion criteria was 83.3% and in ASCS patients meeting SCOT inclusion criteria was 81.2%. EFS at 4 years in ASCS patients who met ASTIS and SCOT inclusion but also exclusion criteria was 46.7% and 45.7%, respectively. CONCLUSION: ASCS patients meeting ASTIS and/or SCOT inclusion criteria who were not treated with ASCT have similar EFS at 4 years as patients receiving ASCT and better EFS than those receiving cyclophosphamide in the ASTIS and SCOT trials. This may reflect confounders unable to be controlled for, including survivor bias, but may also reflect improved standard of care for dcSSc over time.

Towards a novel clinical outcome assessment for systemic lupus erythematosus: first outcomes of an international taskforce.

Systemic lupus erythematosus (SLE) is a disease of high unmet therapeutic need. The challenge of accurately measuring clinically meaningful responses to treatment has hindered progress towards positive outcomes in SLE trials, impeding the approval of potential new therapies. Current primary end points used in SLE trials are based on legacy disease activity measures that were neither specifically designed for the clinical trial context, nor developed according to contemporary recommendations for clinical outcome assessments (COAs), such as that substantial patient input should be incorporated into their design. The Treatment Response Measure for SLE (TRM-SLE) Taskforce is a global collaboration of SLE clinician-academics, patients and patient representatives, industry partners and regulatory experts, established to realize the goal of developing a new COA for SLE clinical trials. The aim of this project is a novel COA designed specifically to measure treatment effects that are clinically meaningful to patients and clinicians, and intended for implementation in a trial end point that supports regulatory approval of novel therapeutic agents in SLE. This Consensus Statement reports the first outcomes of the TRM-SLE project, including a structured process for TRM-SLE development.

A demand-capacity mismatch between rehabilitation need and service provision as a result of the COVID-19 pandemic? Early clinical observations from a large teaching hospital in London.

In this short report the authors characterise inpatient bed occupancy and predicted rehabilitation need of patients cared for in two acute hospitals of a large London NHS Trust during the first wave of the COVID-19 pandemic, including 394 people with confirmed COVID-19. Data were captured on a single day (17th April 2020) from the two Trust hospitals to inform discharge planning in line with national COVID-19 Hospital Discharge Service policy guidance. Our data suggests that the proportion of COVID-19 patients predicted to require rehabilitation upon hospital discharge may be greater than the estimates described in the national COVID-19 Hospital Discharge Service policy guidance; posing the question is there a demand-capacity mismatch between rehabilitation need and service provision as a result of the COVID-19 pandemic?

Investigating strategies to improve clinical trial opportunities for patients with cancer in New Zealand-INSIGHT.

AIMS: Fewer than 5% of adult cancer patients participate in clinical trials, with multiple patient, clinician and institutional barriers identified. This study aimed to explore patient factors that impact access to cancer trials in New Zealand. METHODS: A questionnaire that included demographics and factors that might impact trial participation was circulated via nine district health boards (DHBs) and four cancer foundations to patients with a cancer diagnosis. RESULTS: Between July 2016 and August 2017, 691 patients responded, 62% female and 77% aged >50 years. Most patients (86%) would consider trial participation, which differed by income (p=0.0001) but not by age, tumour type or gender. Patients would consider attending another hospital (44%) or relocating (11%); 10% considered trials a last resort. Advantageous factors to participation included: benefiting others (92%), better treatment (82%), more scans and longer follow-up (47% and 51%). Disincentives included fear of randomisation (78%), treatment toxicities (71%), time and cost of more visits (40%) and unspecified future research (32%). CONCLUSION: Identified barriers to trial participation were similar in New Zealand to other developed countries. In this motivated cohort, patients are very interested in trial participation at any stage of their treatment and did not mind extra travel or tests.

Effect of foot position on balance ability in single-leg stance with and without visual feedback.

The purpose of this study was to determine the natural foot position and to quantify the effect of foot position on balance performance during single-leg stance. Forty healthy subjects participated in this study (age, 18 to 32 years; 24 female). Subjects were asked to perform single-leg balance trials on a balance force plate in their self-selected and four predetermined foot positions with their eyes open and closed. Sway distance, area and velocity were computed for each trial. There was significant interactions between visual conditions and foot position for all sway parameters (P<.001). With the eyes closed, sway parameters were greatest for the self-selected foot position compared to the other foot positions (P<.005). No differences in sway parameters between foot positions were detected for the eyes-open condition. Sway distance, area and velocity were 94%, 400% and 89% greater, respectively, for the eyes-closed than the eyes-open condition. Self-selected foot placement did not produce the most stable single-leg stance. The results of this study indicate that foot position is not important for protocols for assessing balance or for rehabilitation exercises using eyes-open conditions and that assessment protocols and rehabilitation exercises should clearly specify the foot position when using eyes-closed protocols.

Changes in gene expression by trabecular meshwork cells in response to mechanical stretching.

PURPOSE: Trabecular meshwork (TM) cells appear to sense changes in intraocular pressure (IOP) as mechanical stretching. In response, they make homeostatic corrections in the aqueous humor outflow resistance, partially by increasing extracellular matrix (ECM) turnover initiated by the matrix metalloproteinases. To understand this homeostatic adjustment process further, studies were conducted to evaluate changes in TM gene expression that occur in response to mechanical stretching. METHODS: Porcine TM cells were subjected to sustained mechanical stretching, and RNA was isolated after 12, 24, or 48 hours. Changes in gene expression were evaluated with microarrays containing approximately 8000 cDNAs. Select mRNA changes were then compared by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Western immunoblots were used to determine whether some of these changes were associated with changes in protein levels. RESULTS: On the microarrays, 126 genes were significantly upregulated, and 29 genes were significantly downregulated at one or more time points, according to very conservative statistical and biological criteria. Of the genes that changed, several ECM regulatory genes, cytoskeletal-regulatory genes, signal-transduction genes, and stress-response genes were notable. These included several proteoglycans and matricellular ECM proteins composed of common repetitive binding domains. The results of analysis of mRNA changes in more than 20 selected genes by qRT-PCR supported the findings in the microarray analysis. Western immunoblots of several proteins demonstrated protein level changes associated with changes in the level of mRNA. CONCLUSIONS: The expression of a variety of TM genes is significantly affected by mechanical stretching. These include several ECM proteins that contain multiple binding sites and may serve organizational roles in the TM. Several proteins that could contribute to the homeostatic modification of aqueous humor outflow resistance are also upregulated or downregulated.

Human Papillomavirus genotype testing combined with cytology as a 'test of cure' post treatment: the importance of a persistent viral infection.

BACKGROUND: Human Papillomavirus (HPV) testing has been evaluated as a test of cure in patients following treatment of high-grade cervical intraepithelial neoplasia (CIN2+). Studies show that women who are HPV and cytology negative post treatment can be safely returned to routine recall. The management strategy for HPV positive women requires confirmation. OBJECTIVE: To evaluate the clinical utility of the PapilloCheck(®) genotyping assay for predicting disease recurrence in a test of cure setting. STUDY DESIGN: Ninety-eight women (19-52 years) treated for CIN2+ by large loop excision of the transformation zone (LLETZ) were evaluated with samples taken before and 6 months after treatment for HPV testing. Cytology and histology were available from recruitment until 24 months post treatment. RESULTS: Recurrent disease was evident in 4% of patients with 2 cases low-grade and 2 cases of high-grade disease. In women with no disease recurrence, 40% (95% CI 30.42-51.05%) were high risk (HR) HPV negative post LLETZ. Both cases with high-grade disease had persistent HPV16 infection. Genotyping before and after treatment revealed 83% (95% CI 75.74-88.78%) of total viral infections were cleared and 17% (95% CI 11.22-24.26) viral infections persisted. Post treatment, combined cytology and HPV test results predicted CIN2+ with 100% sensitivity, 91.7% specificity, 100% NPV and 20% PPV and measuring viral persistence marginally increased specificity and PPV. CONCLUSION: Post treatment, cytology combined with a single HR HPV test has high sensitivity and specificity for predicting disease recurrence. HPV genotyping before and after LLETZ identifies persistent viral infections and could help refine patient management.

Computed tomography measurement of tophus volume: comparison with physical measurement.

OBJECTIVE: Computed tomography (CT) has high accuracy for tophus detection. This study assessed reliability of CT measurement of tophus volume and compared reproducibility of CT with physical measurement of tophus size. METHODS: Forty-seven hand tophi were analyzed in 20 patients with gout. The longest tophus diameter was recorded by 2 independent observers. All patients proceeded to CT scanning of the hands on a Philips Brilliance scanner (0.8-mm slices). Two independent observers measured tophus volume using the Surface Shaded Display 3-dimensional function on the Philips CT workstation. Five patients underwent repeat physical and CT assessments within 1 week (18 observations). Inter- and intraobserver reproducibility were analyzed by limits of agreement and coefficients of variation. RESULTS: Of the 47 lesions identified as tophi on physical examination, 42 (89%) were also identified on CT. The mean (95% confidence interval [95% CI]) difference between observers for physical measurement was 0.45 mm (-4.07, 4.96) and for CT was 65.2 mm(3) (-293.0, 423.3). The mean (95% CI) difference between visits for physical measurement was -0.72 mm (-5.47, 4.03) and for CT was -13.1 mm(3) (-112.5, 86.3). There was no difference between coefficients of variation for inter- and intraobserver reproducibility for the 2 measurement techniques. For tophi identified by physical and CT assessment, there was good correlation between measurements (r = 0.91, P < 0.0001). CONCLUSION: CT assessment of tophus volume is reliable and reproducible. However, physical measurement correlates well with CT and has equivalent reproducibility. These data support the use of physical measurement as a simple and reliable method to assess tophus size.

The prodomain of BMP-7 targets the BMP-7 complex to the extracellular matrix.

Biochemical and biophysical methods are used to show that BMP-7 is secreted as a stable complex consisting of the processed growth factor dimer noncovalently associated with its two prodomain propeptide chains and that the BMP-7 complex is structurally similar to the small transforming growth factor beta (TGFbeta) complex. Because the prodomain of TGFbeta interacts with latent TGFbeta-binding proteins, a family of molecules homologous to the fibrillins, the prodomain of BMP-7 was tested for binding to fibrillin-1 or to LTBP-1. The BMP-7 prodomain and BMP-7 complex, but not the separated growth factor dimer, interact with N-terminal regions of fibrillin-1. This interaction may target the BMP-7 complex to fibrillin microfibrils in the extracellular matrix. Immunolocalization of BMP-7 in tissues like the kidney capsule and skin reveals co-localization with fibrillin. However, BMP-7 immunolocalization in other tissues known to be active sites for BMP-7 signaling is not apparent, suggesting that immunolocalization of BMP-7 in certain tissues represents specific extracellular storage sites. These studies suggest that the prodomains of TGFbeta-like growth factors are important for positioning and concentrating growth factors in the extracellular matrix. In addition, they raise the possibility that prodomains of other TGFbeta-like growth factors interact with fibrillins and/or LTBPs and are also targeted to the extracellular matrix.

Interaction between amino propeptides of type XI procollagen alpha1 chains.

Type XI collagen is a quantitatively minor yet essential constituent of the cartilage extracellular matrix. The amino propeptide of the alpha1 chain remains attached to the rest of the molecule for a longer period of time after synthesis than the other amino propeptides of type XI collagen and has been localized to the surface of thin collagen fibrils. Yeast two-hybrid system was used to demonstrate that a homodimer of alpha1(XI) amino propeptide (alpha1(XI)Npp) could form in vivo. Interaction was also confirmed using multi-angle laser light scattering, detecting an absolute weight average molar mass ranging from the size of a monomer to the size of a dimer (25,000-50,000 g/mol), respectively. Binding was shown to be saturable by ELISA. An interaction between recombinant alpha1(XI)Npp and the endogenous alpha1(XI)Npp was observed, and specificity for alpha1(XI)Npp but not alpha2(XI)Npp was demonstrated by co-precipitation. The interaction between the recombinant form of alpha1(XI)Npp and the endogenous alpha1(XI)Npp resulted in a stable association during the regeneration of cartilage extracellular matrix by fetal bovine chondrocytes maintained in pellet culture, generating a protein that migrated with an apparent molecular mass of 50-60 kDa on an SDS-polyacrylamide gel.