An analysis of iris pattern as a risk factor for skin cancer development in immunosuppressed renal transplant recipients.

INTRODUCTION: Renal transplant recipients are at increased risk of keratinocyte skin cancers with a tendency to have multiple, aggressive and difficult to treat tumours. The eye and the skin share the same embryological ectoderm. Iris pattern has recently been reported as a predictive risk factor for skin cancer in non-immunosuppressed Southern European (Grigore et al., J Eur Acad Dermatol Venereol, 2018, 1662) and Irish populations (Ridge et al., J Eur Acad Dermatol Venereol, 2022, e542). AIMS: To analyse if an individual's iris pattern is an independent risk factor for the development of keratinocyte skin cancers in renal transplant recipients. METHODS: Iris patterns of 110 renal transplant recipients were evaluated using the Simionescu visual three-step technique (iris periphery, colarette and iris freckling [Simionescu et al., Ann Res Rev Biol, 2014, 2525]). Established risk factors for skin cancer in transplant patients were recorded as confounding factors. RESULTS: Observational cross-sectional study including 110 renal transplant population. Thirty-one participants had skin cancer. In the skin cancer group, iris periphery was blue/grey in 74.3% (p = 0.053, OR 2.5), the colarette was light brown in 57.1% (p < 0.0043) and iris freckles were present in 55%(p = 0.044). Dark brown and blue colarettes were observed in controls. Binary Logistic Regression analysis showed light brown colarette is a significant independent risk factor for skin cancer (OR 4.54, p < 0.02, CI 1.56-10.57). CONCLUSION: Within this renal transplant population a blue iris periphery, light brown colarette and presence of freckling confers an independent risk for keratinocyte skin cancer. Iris pattern is a useful tool for identification of transplant patients at risk of keratinocyte skin cancer and an easy-to-use technique for risk evaluation in this cohort. This is the first study looking at iris pattern and keratinocyte skin cancer risk in renal transplant population.

Screening and treating pre-operative anaemia and suboptimal iron stores in elective colorectal surgery: a cost effectiveness analysis.

Our study investigated whether pre-operative screening and treatment for anaemia and suboptimal iron stores in a patient blood management clinic is cost effective. We used outcome data from a retrospective cohort study comparing colorectal surgery patients admitted pre- and post-implementation of a pre-operative screening programme. We applied propensity score weighting techniques with multivariable regression models to adjust for differences in baseline characteristics between groups. Episode-level hospitalisation costs were sourced from the health service clinical costing data system; the economic evaluation was conducted from a Western Australia Health System perspective. The primary outcome measure was the incremental cost per unit of red cell transfusion avoided. We compared 441 patients screened in the pre-operative anaemia programme with 239 patients not screened; of the patients screened, 180 (40.8%) received intravenous iron for anaemia and suboptimal iron stores. The estimated mean cost of screening and treating pre-operative anaemia was AU$332 (£183; US$231; €204) per screened patient. In the propensity score weighted analysis, screened patients were transfused 52% less red cell units when compared with those not screened (rate ratio = 0.48, 95%CI 0.36-0.63, p < 0.001). The mean difference in total screening, treatment and hospitalisation cost between groups was AU$3776 lower in the group screened (£2080; US$2629; €2325) (95%CI AU$1604-5947, p < 0.001). Screening elective patients pre-operatively for anaemia and suboptimal iron stores reduced the number of red cell units transfused. It also resulted in lower total costs than not screening patients, thus demonstrating cost effectiveness.

Associations of nadir haemoglobin level and red blood cell transfusion with mortality and length of stay in surgical specialties: a retrospective cohort study.

Few studies have investigated if, and how, red cell transfusion and anaemia interact. We analysed 60,955 admissions to three metropolitan hospitals in Western Australia between 2008 and 2017 to determine whether the relationship between red cell transfusion and outcomes in surgical patients differed by lowest (nadir) level of haemoglobin. At levels above 100 g.l-1 , in-hospital, 30-day and 1-year mortality were higher with transfusion, the adjusted odds ratios (ORs) (95%CI) being 8.80 (4.43-17.45) p < 0.001 and 3.68 (1.93-7.02) p < 0.001 and the adjusted hazard ratio (95%CI) being 1.83 (1.28-2.61) p = 0.001, respectively. Likewise, between 90 g.l-1 and 99 g.l-1 , in-hospital, 30-day and 1-year mortality were higher with transfusion, the adjusted odds ratio (95%CI) being 3.76 (2.23-6.34) p < 0.001 and 1.96 (1.23-3.12) p < 0.001 and the adjusted hazard ratio (95%CI) being 1.34 (1.05-1.70) p = 0.017, respectively. Length of stay was longer with transfusion at nadir haemoglobin levels above 100 g.l-1 and in the following ranges: 90-99 g.l-1 , 80-89 g.l-1 , 70-79 g.l-1 and 60-69 g.l-1 , the adjusted rate ratio (95%CI) being 1.38 (1.25-1.53) p < 0.001, 1.18 (1.10-1.27) p < 0.001, 1.17 (1.13-1.22) p < 0.001, 1.07 (1.02-1.12) p = 0.003 and 1.24 (1.13-1.36) p < 0.001, respectively. Mortality was higher with red cell transfusion at haemoglobin levels greater than 90 g.l-1 , whereas at all levels below 90 g.l-1 mortality was not significantly higher or lower. Length of stay was longer with transfusion at nadir haemoglobin levels of 60 g.l-1 or above. Our results suggest that nadir haemoglobin modified the relationship between red cell transfusion and outcomes and adds to the evidence recommending caution before transfusing red cells.

Activity and safety of crizotinib in patients with alveolar soft part sarcoma with rearrangement of TFE3: European Organization for Research and Treatment of Cancer (EORTC) phase II trial 90101 'CREATE'.

Background: Alveolar soft part sarcoma (ASPS) is an orphan malignancy associated with a rearrangement of transcription factor E3 (TFE3), leading to abnormal MET gene expression. We prospectively assessed the efficacy and safety of the MET tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic ASPS. Patients and methods: Eligible patients with reference pathology-confirmed ASPS received oral crizotinib 250 mg bd. By assessing the presence or absence of a TFE3 rearrangement, patients were attributed to MET+ and MET- sub-cohorts. The primary end point was the objective response rate (ORR) according to local investigator. Secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate, overall survival (OS) and safety. Results: Among 53 consenting patients, all had a centrally confirmed ASPS and 48 were treated. A total of 45 were eligible, treated and assessable. Among 40 MET+ patients, 1 achieved a confirmed partial response (PR) that lasted 215 days and 35 had stable disease (SD) as best response (ORR: 2.5%, 95% CI 0.6% to 80.6%). Further efficacy end points in MET+ cases were DCR: 90.0% (95% CI 76.3% to 97.2%), 1-year PFS rate: 37.5% (95% CI 22.9% to 52.1%) and 1-year OS rate: 97.4% (95% CI 82.8% to 99.6%). Among 4 MET- patients, 1 achieved a PR that lasted 801 days and 3 had SD (ORR: 25.0%, 95% CI 0.6% to 80.6%) for a DCR of 100% (95% CI 39.8% to 100.0%). The 1-year PFS rate in MET- cases was 50% (95% CI 5.8% to 84.5%) and the 1-year OS rate was 75% (95% CI 12.8% to 96.1%). One patient with unknown MET status due to technical failure achieved SD but stopped treatment due to progression after 17 cycles. The most common crizotinib-related adverse events were nausea [34/48 (70.8%)], vomiting [22/48 (45.8%)], blurred vision [22/48 (45.8%)], diarrhoea (20/48 (41.7%)] and fatigue [19/48 (39.6%)]. Conclusion: According to European Organization for Research and Treatment of Cancer (EORTC) efficacy criteria for soft tissue sarcoma, our study demonstrated that crizotinib has activity in TFE3 rearranged ASPS MET+ patients. Clinical trial number: EORTC 90101, NCT01524926.

Activity and safety of crizotinib in patients with advanced clear-cell sarcoma with MET alterations: European Organization for Research and Treatment of Cancer phase II trial 90101 'CREATE'.

BACKGROUND: Clear-cell sarcoma (CCSA) is an orphan malignancy, characterized by a specific t(12;22) translocation, leading to rearrangement of the EWSR1 gene and overexpression of MET. We prospectively investigated the efficacy and safety of the tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic CCSA. PATIENTS AND METHODS: Patients with CCSA received oral crizotinib 250 mg twice daily. Primary end point was objective response rate (ORR), secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS), OS rate and safety. The study design focused on MET+ disease with documented rearrangement of the EWSR1 gene by fluorescence in situ hybridization. RESULTS: Among 43 consenting patients with the local diagnosis of CCSA, 36 had centrally confirmed CCSA, 28 of whom were eligible, treated and assessable. Twenty-six out of the 28 patients had MET+ disease, of whom one achieved a confirmed partial response and 17 had stable disease (SD) (ORR 3.8%, 95% confidence interval: 0.1-19.6). Further efficacy end points in MET+ CCSA were DCR: 69.2% (48.2% to 85.7%), median PFS: 131 days (49-235), median OS: 277 days (232-442). The 3-, 6-, 12- and 24-month PFR was 53.8% (34.6-73.0), 26.9% (9.8-43.9), 7.7% (1.3-21.7) and 7.7% (1.3-21.7), respectively. Among two assessable MET- patients, one had stable disease and one had progression. The most common treatment-related adverse events were nausea [18/34 (52.9%)], fatigue [17/34 (50.0%)], vomiting [12/34 (35.3%)], diarrhoea [11/34 (32.4%)], constipation [9/34 (26.5%)] and blurred vision [7/34 (20.6%)]. CONCLUSIONS: The PFS with crizotinib in MET+ CCSA is similar to results achieved first-line in non-selected metastatic soft tissue sarcomas with single-agent doxorubicin. The PFS is similar to results achieved with pazopanib in previously treated sarcoma patients. CLINICAL TRIAL NUMBER: EORTC 90101, EudraCT number 2011-001988-52, NCT01524926.

Doxorubicin-based adjuvant chemotherapy in soft tissue sarcoma: pooled analysis of two STBSG-EORTC phase III clinical trials.

BACKGROUND: The EORTC-STBSG coordinated two large trials of adjuvant chemotherapy (CT) in localized high-grade soft tissue sarcoma (STS). Both studies failed to demonstrate any benefit on overall survival (OS). The aim of the analysis of these two trials was to identify subgroups of patients who may benefit from adjuvant CT. PATIENTS AND METHODS: Individual patient data from two EORTC trials comparing doxorubicin-based CT to observation only in completely resected STS (large resection, R0/marginal resection, R1) were pooled. Prognostic factors were assessed by univariate and multivariate analyses. Patient outcomes were subsequently compared between the two groups of patients according to each analyzed factor. RESULTS: A total of 819 patients had been enrolled with a median follow-up of 8.2 years. Tumor size, high histological grade and R1 resection emerged as independent adverse prognostic factors for relapse-free survival (RFS) and OS. Adjuvant CT is an independent favorable prognostic factor for RFS but not for OS. A significant interaction between benefit of adjuvant CT and age, gender and R1 resection was observed for RFS and OS. Males and patients >40 years had a significantly better RFS in the treatment arms, while adjuvant CT was associated with a marginally worse OS in females and patients <40 years. Patients with R1 resection had a significantly better RFS and OS favoring adjuvant CT arms. CONCLUSION: Adjuvant CT is not associated with a better OS in young patients or in any pathology subgroup. Poor quality of initial surgery is the most important prognostic and predictive factor for utility of adjuvant CT in STS. Based on these data, we conclude that adjuvant CT for STS remains an investigational procedure and is not a routine standard of care.

Assessment of psoriatic plaque in vivo with correlation mapping optical coherence tomography.

BACKGROUND/PURPOSE: Vascular abnormalities play an acute role in the pathogenesis of psoriasis. In order to characterize vascular involvement in psoriasis and its regular clinical assessment in vivo, non-invasive high speed imaging with high resolution and high sensitivity is needed. METHODS: The correlation mapping optical coherence tomography (cmOCT) technique was used for in vivo microcirculation imaging of human forearm under normal and psoriatic conditions. The cmOCT technique developed by our group uses dense scanning OCT image acquisition and post-processing software based on correlation statistics. The frequency domain OCT system was used for imaging which acquires a 3D volume of 1024 × 1024 A-scans, each of 512 pixels deep in approximately 70 s. The cmOCT technique processes the resulting OCT volume within 116 s using a 7 × 7 kernel. RESULTS: 3D structural and functional (microcirculation) maps of the healthy tissue and the psoriatic plaque were obtained using the cmOCT technique. The presented results indicate that cmOCT allows not only the identification of the microvessels, but also produces more detailed microvascular networks showing how the blood vessels relate to each other in healthy tissue and within the plaque. The microcirculation pattern within the plaque is totally different from the healthy tissue. The distinct changes are also observed in vessel density, tortuosity, and orientation. CONCLUSION: The cmOCT provides high sensitivity and imaging speed for in vivo microcirculation imaging within the human skin under normal and diseased conditions.

Rationale and design of a UK database for a rare cancer type: the GEM Registry for gastrointestinal stromal tumours.

BACKGROUND: Despite advances in the management of and changes in clinical practice, little is known about the epidemiology, patterns of care and outcomes of gastrointestinal stromal tumour (GIST) patients in the UK. Patient registries are receiving increasing attention as they can provide important information on clinical practice and patient outcomes. The rationale and study design of the GIST Epidemiology and Management (GEM) Registry, which forms part of the routine clinical practice for GISTs in several UK centres, are described. METHODS: The GEM Registry is a secure web-based registry system designed around a Microsoft Access core using SQL interface. Demographic, surgical, histopathological and clinical data will be captured including treatment outcomes and survival. The registry was piloted in six centres and following further fine tuning of the data sets, ethical committee submission and approval was completed. RESULTS: The GEM National Registry is the first of its kind to be implemented in rare cancers in UK. The registry is being rolled out initially in selected centres with the aim to expand to other centres. The first publication reporting analyses of the central data set is anticipated for the summer of 2013. CONCLUSION: GEM Registry will enable us to obtain a clear picture of incidence/prevalence of GISTS in UK. Clinicians will be able to review the prognostic and predictive value of variables in a large prospective data set. The data can be used for planning the delivery and improving the quality of care. This information is likely to inform clinical practice and, in years to come, guide the development and implementation of clinical trials for novel tyrosine kinase inhibitors. The results will not only benefit the GIST community, but also serve as a basis for the study of other rare tumour types.

Patterns of recurrence of gastrointestinal stromal tumour (GIST) following complete resection: implications for follow-up.

AIM: To determine the frequency, time course and sites of recurrence following surgical resection of gastrointestinal stromal tumours (GIST) and to evaluate the performance of a risk-based surveillance protocol in detection of recurrence. METHODS: Eighty-one patients on surveillance following complete resection of GIST were included. Patients were stratified into risk groups according to accepted histopathological criteria. Computed tomography (CT) examinations were retrospectively reviewed to determine rates, sites and imaging characteristics of recurrence and to assess compliance with the local follow-up protocol. RESULTS: The median time of follow-up was 41 months. Nineteen patients suffered recurrence, all of whom were in the high-risk group. Fifty-eight percent of relapses occurred within 1 year and 84% within 3 years. Even within the high-risk group, patients with relapse had significantly larger (mean 15 versus 10.4 cm, p < 0.05) and more mitotically active primary tumours (mean 33.7 versus 5.6 mitoses per 50 high-power fields; p < 0.05) than those with no relapse. Relapse was to the liver in 12 cases (63%) and to the omentum and mesentery in nine cases (47%), and was asymptomatic in three-quarters of patients. CONCLUSIONS: The high incidence of GIST recurrence in the high-risk group in the first 3 years after surgery supports the use of intensive imaging surveillance in this period. Relapse is often asymptomatic and commonly occurs to the liver, omentum and mesentery. Stratification by tumour factors may enable improved tailoring of surveillance protocols within the high-risk group in the future.

Acute myeloid leukaemia in Western Australia 1991-2005: a retrospective population-based study of 898 patients regarding epidemiology, cytogenetics, treatment and outcome.

BACKGROUND: Patient characteristics and cytogenetics of acute myeloid leukaemia (AML) in clinical trials do not reflect that of the general population. There has not been a large population-based study that has examined cytogenetic features and outcomes of AML in Australia. AIM: Investigation of epidemiological, prognostic, treatment and outcome data in adults diagnosed with AML in Western Australia between 1991 and 2005. METHODS: Patients were identified utilising the Western Australia Cancer Registry, cytogenetic databases and hospital inpatient discharge diagnoses. Data were retrospectively collected from patients presenting to tertiary hospitals on patient characteristics, karyotype, induction therapy, remission, transplantation and survival. RESULTS: A total of 987 patients with AML was identified, of which 91% (898) attended a tertiary hospital. Median age was 67 years and 45% of cases represented secondary AML. Cytogenetic analysis was available in 81% of patients. Frequent karyotypes were normal (38.8%), complex (13.8%) and -7/add(7q)/del(7q) (12.1%). Aggressive therapy was initiated in 62.6%. Less than 15% were enrolled in clinical trials. Overall 16.5% received a stem cell transplant. Median overall survival for all patients was 5.6 months. In patients treated aggressively, complete remission was achieved in 56.9% and median overall survival was 12.2 months. Age, secondary disease and karyotype were significantly predictive of remission and overall survival. CONCLUSION: Age distribution, remission and survival rates were comparable with published population-based studies. High median age was reflected in the rate of secondary AML and trial eligibility. These findings highlight the need for prospective data collection.

Localization to Xq27 of a susceptibility gene for testicular germ-cell tumours.

Testicular germ-cell tumours (TGCT) affect 1 in 500 men and are the most common cancer in males aged 15-40 in Western European populations. The incidence of TGCT has risen dramatically over the last century. Known risk factors for TGCT include a history of undescended testis (UDT), testicular dysgenesis, infertility, previously diagnosed TGCT (ref. 7) and a family history of the disease. Brothers of men with TGCT have an 8-10-fold risk of developing TGCT (refs 8,9), whereas the relative risk to fathers and sons is fourfold (ref. 9). This familial relative risk is much higher than that for most other types of cancer. We have collected samples from 134 families with two or more cases of TGCT, 87 of which are affected sibpairs. A genome-wide linkage search yielded a heterogeneity lod (hlod) score of 2.01 on chromosome Xq27 using all families compatible with X inheritance. We obtained a hlod score of 4.7 from families with at least one bilateral case, corresponding to a genome-wide significance level of P=0.034. The proportion of families with UDT linked to this locus was 73% compared with 26% of families without UDT (P=0.03). Our results provide evidence for a TGCT susceptibility gene on chromosome Xq27 that may also predispose to UDT.

Chemotherapy treatment patterns and clinical outcomes in patients with metastatic soft tissue sarcoma. The SArcoma treatment and Burden of Illness in North America and Europe (SABINE) study.

BACKGROUND: To describe chemotherapy treatment patterns and clinical outcomes in metastatic soft tissue sarcoma (mSTS) patients with favorable response to chemotherapy. PATIENTS AND METHODS: Multicenter (25) multi-country (9) retrospective chart review of mSTS patients with favorable response to chemotherapy, defined as stable disease or better following four cycles. RESULTS: Two hundred and thirteen patients (58% female; mean age 54.7 years) received a mean of 2.7 lines of chemotherapy and 5.2 cycles per line. The most common first-line regimens were doxorubicin (34%) and anthracycline plus ifosfamide (30%). Favorable response was achieved by 83% to first-line and 42% and 38% in second- and third-line chemotherapy. The most common reason for chemotherapy discontinuation in lines with a favorable response was reaching a predefined number of cycles in first line (64% of 213) and disease progression in second or later lines (41% of 138). The mean time off chemotherapy was 38.0 weeks after first line, falling to 2.7-6.4 weeks in second or later lines. Median overall and progression-free survival were 23.5 (95% confidence interval 20.5-28.1) and 8.3 (7.4-9.9) months from first favorable response to chemotherapy. CONCLUSIONS: mSTS patients achieving favorable response to chemotherapy have poor outcomes. Additional treatment options are needed.

From blood transfusion to patient blood management: a new paradigm for patient care and cost assessment of blood transfusion practice.

The ageing population in developed countries, including Australia, is putting increasing demands on blood transfusion services. With a falling donor pool there is likely to be a shortage of blood and blood products in the next 20 to 30 years unless there are significant changes in medical practice. The National Health and Medical Research Council/Australasian Society of Blood Transfusion Clinical Practice Guidelines on the Use of Blood Components from 2001 are being redeveloped by the National Health and Medical Research Council/Australian and New Zealand Society of Blood Transfusion as evidence-based patient-focused Patient Blood Management guidelines with the aim of improving patient outcomes by reducing inappropriate blood and blood product use and targeting therapies for improving the management of anaemia and coagulopathies.

When should iron chelation therapy be considered in patients with myelodysplasia and other bone marrow failure syndromes with iron overload?

Despite the absence of a robust evidence base, there is growing consensus that effective treatment of iron overload leads to decreased morbidity and premature mortality in patients with good prognosis myelodysplastic syndromes (MDSs). Furthermore, new treatment modalities, including disease-modifying therapies (lenalidamide and azacytidine) and reduced intensity conditioning therapies for allogeneic blood stem cell transplants, are offering the prospect of longer survival for patients with traditionally less favourable prognosis MDS, who might also benefit from iron chelation. This article proposes assessment of patients with MDS and related bone marrow failure syndromes to determine suitability for iron chelation. Iron chelation therapy options and monitoring are discussed.

Co-axial acoustic-based optical coherence vibrometry probe for the quantification of resonance frequency modes in ocular tissue.

We present a co-axial acoustic-based optical coherence vibrometry probe (CoA-OCV) for vibro-acoustic resonance quantification in biological tissues. Sample vibrations were stimulated via a loudspeaker, and pre-compensation was used to calibrate the acoustic spectrum. Sample vibrations were measured via phase-sensitive swept-source optical coherence tomography (OCT). Resonance frequencies of corneal phantoms were measured at varying intraocular pressures (IOP), and dependencies on Young´s Modulus (E), phantom thickness and IOP were observed. Cycling IOP revealed hysteresis. For E = 0.3 MPa, resonance frequencies increased with IOP at a rate of 3.9, 3.7 and 3.5 Hz/mmHg for varied thicknesses and 1.7, 2.5 and 2.8 Hz/mmHg for E = 0.16 MPa. Resonance frequencies increased with thickness at a rate of 0.25 Hz/µm for E = 0.3 MPa, and 0.40 Hz/µm for E = 0.16 MPa. E showed the most predominant impact in the shift of the resonance frequencies. Full width at half maximum (FWHM) of the resonance modes increased with increasing thickness and decreased with increasing E. Only thickness and E contributed to the variance of FWHM. In rabbit corneas, resonance frequencies of 360-460 Hz were observed. The results of the current study demonstrate the feasibility of CoA-OCV for use in future OCT-V studies.

Interfraction patient motion and implant displacement in prostate high dose rate brachytherapy.

PURPOSE: To quantify movement of prostate cancer patients undergoing treatment, using an in-house developed motion sensor in order to determine a relationship between patient movement and high dose rate (HDR) brachytherapy implant displacement. METHODS: An electronic motion sensor was developed based on a three axis accelerometer. HDR brachytherapy treatment for prostate is delivered at this institution in two fractions 24 h apart and 22 patients were monitored for movement over the interval between fractions. The motion sensors functioned as inclinometers, monitoring inclination of both thighs, and the inclination and roll of the abdomen. The implanted HDR brachytherapy catheter set was assessed for displacement relative to fiducial markers in the prostate. Angle measurements and angle differences over a 2 s time base were binned, and the standard deviations of the resulting frequency distributions used as a metric for patient motion in each monitored axis. These parameters were correlated to measured catheter displacement using regression modeling. RESULTS: The mean implant displacement was 12.6 mm in the caudal direction. A mean of 19.95 h data was recorded for the patient cohort. Patients generally moved through a limited range of angles with a mean of the exception of two patients who spent in excess of 2 h lying on their side. When tested for a relationship between movement in any of the four monitored axes and the implant displacement, none was significant. CONCLUSIONS: It is not likely that patient movement influences HDR prostate implant displacement. There may be benefits to patient comfort if nursing protocols were relaxed to allow patients greater freedom to move while the implant is in situ.