Identification and quantification of chain-pairing variants or mispaired species of asymmetric monovalent bispecific IgG1 monoclonal antibody format using reverse-phase polyphenyl chromatography coupled electrospray ionization mass spectrometry.

Developing a knob-into-hole asymmetric bispecific IgG1 monoclonal antibody (mAb) poses manufacturing challenges due to the expression of chain pairing variants, also called mispaired species, in the desired product. The incorrect pairing of light and heavy chains could result in heterogeneous mispaired species of homodimers, heterodimers, light chain swapping, and low molecular weight species (LMWS). Standard chromatography, capillary electrophoretic, or spectroscopic methods poorly resolve these from the main variants. Here, we report a highly sensitive reverse-phase polyphenyl ultra-high-performance liquid chromatography (RP-UHPLC) method to accurately measure mispaired species of Duet mAb format, an asymmetric IgG1 bispecific mAb, for both process development and quality control analytical tests. Coupled with electrospray ionization mass spectrometry (ESI-MS), it enabled direct online characterization of mispaired species. This single direct assay detected diverse mispaired IgG-like species and LMWS. The method resolved eight disulfide bonds dissociated LMWS and three mispaired LMWS. It also resolved three different types of IgG-like mispaired species, including two homodimers and one heterodimer. The characterization and quantification simultaneously enabled the cell line selection that produces a lesser heterogeneity and lower levels of mispaired species with the desired correctly paired product. The biological activity assessment of samples with increased levels of these species quantified by the method exhibited a linear decline in potency with increasing levels of mispaired species in the desired product. We also demonstrated the utility of the technique for testing in-process intermediate materials to determine and assess downstream purification process capability in removing diverse mispaired IgG-like species and LMWS to a certain level during the downstream purification process. Our investigation demonstrates that adopting this method was vital in developing asymmetric bispecific mAb from the initial stage of cell line development to manufacturing process development. Therefore, this tool could be used in the control strategy to monitor and control mispaired species during manufacturing, thus improving the quality control of the final product.

Low respiratory quotient correlates with high mortality in patients undergoing mechanical ventilation.

OBJECTIVE: Oxygen consumption (VO2), carbon dioxide generation (VCO2), and respiratory quotient (RQ), which is the ratio of VO2 to VCO2, are critical indicators of human metabolism. To seek a link between the patient's metabolism and pathophysiology of critical illness, we investigated the correlation of these values with mortality in critical care patients. METHODS: This was a prospective, observational study conducted at a suburban, quaternary care teaching hospital. Age 18 years or older healthy volunteers and patients who underwent mechanical ventilation were enrolled. A high-fidelity automation device, which accuracy is equivalent to the gold standard Douglas Bag technique, was used to measure VO2, VCO2, and RQ at a wide range of fraction of inspired oxygen (FIO2). RESULTS: We included a total of 21 subjects including 8 post-cardiothoracic surgery patients, 7 intensive care patients, 3 patients from the emergency room, and 3 healthy volunteers. This study included 10 critical care patients, whose metabolic measurements were performed in the ER and ICU, and 6 died. VO2, VCO2, and RQ of survivors were 282 +/- 95 mL/min, 202 +/- 81 mL/min, and 0.70 +/- 0.10, and those of non-survivors were 240 +/- 87 mL/min, 140 +/- 66 mL/min, and 0.57 +/- 0.08 (p = 0.34, p = 0.10, and p < 0.01), respectively. The difference of RQ was statistically significant (p < 0.01) and it remained significant when the subjects with FIO2 < 0.5 were excluded (p < 0.05). CONCLUSIONS: Low RQ correlated with high mortality, which may potentially indicate a decompensation of the oxygen metabolism in critically ill patients.

Understanding the Role of Yes-Associated Protein (YAP) Signaling in the Transformation of Lens Epithelial Cells (EMT) and Fibrosis.

Fibrotic cataracts, posterior capsular opacification (PCO), and anterior subcapsular cataracts (ASC) are mainly attributed to the transforming growth factor-ß (TGFß)-induced epithelial-to-mesenchymal transition (EMT) of lens epithelial cells (LECs). Previous investigations from our laboratory have shown the novel role of non-canonical TGFß signaling in the progression of EMT in LECs. In this study, we have identified YAP as a critical signaling molecule involved in lens fibrosis. The observed increase in nuclear YAP in capsules of human ASC patients points toward the involvement of YAP in lens fibrosis. In addition, the immunohistochemical (IHC) analyses on ocular sections from mice that overexpress TGFß in the lens (TGFßtg) showed a co-expression of YAP and α-SMA in the fibrotic plaques when compared to wild-type littermate lenses, which do not. The incubation of rat lens explants with verteporfin, a YAP inhibitor, prevented a TGFß-induced fiber-like phenotype, α-SMA, and fibronectin expression, as well as delocalization of E-cadherin and ß-catenin. Finally, LECs co-incubated with TGFß and YAP inhibitor did not exhibit an induction in matrix metalloproteinase 2 compared to those LECs treated with TGFß alone. In conclusion, these data demonstrate that YAP is required for TGFß-mediated lens EMT and fibrosis.

Continuous and repeat metabolic measurements compared between post-cardiothoracic surgery and critical care patients.

OBJECTIVE: Using a system, which accuracy is equivalent to the gold standard Douglas Bag (DB) technique for measuring oxygen consumption (VO2), carbon dioxide generation (VCO2), and respiratory quotient (RQ), we aimed to continuously measure these metabolic indicators and compare the values between post-cardiothoracic surgery and critical care patients. METHODS: This was a prospective, observational study conducted at a suburban, quaternary care teaching hospital. Age 18 years or older patients who underwent mechanical ventilation were enrolled. RESULTS: We included 4 post-surgery and 6 critical care patients. Of those, 3 critical care patients died. The longest measurement reached to 12 h and 15 min and 50 cycles of repeat measurements were performed. VO2 of the post-surgery patients were 234 ± 14, 262 ± 27, 212 ± 16, and 192 ± 20 mL/min, and those of critical care patients were 122 ± 20, 189 ± 9, 191 ± 7, 191 ± 24, 212 ± 12, and 135 ± 21 mL/min, respectively. The value of VO2 was more variable in the post-surgery patients and the range of each patient was 44, 126, 71, and 67, respectively. SOFA scores were higher in non-survivors and there were negative correlations of RQ with SOFA. CONCLUSIONS: We developed an accurate system that enables continuous and repeat measurements of VO2, VCO2, and RQ. Critical care patients may have less activity in metabolism represented by less variable values of VO2 and VCO2 over time as compared to those of post-cardiothoracic surgery patients. Additionally, an alteration of these values may mean a systemic distinction of the metabolism of critically ill patients.

How Institution of the Sup-ER Protocol in a Clinic Changed Procedure Patterns in Upper Brachial Plexus (Erb's Type) Birth Injuries.

BACKGROUND: For children with upper brachial plexus birth injury (BPBI; C5, C6, ±C7 roots), most clinics first recommend nonsurgical treatment followed by primary and/or secondary surgical interventions in selected patients. Since 2008, we have used an infant shoulder repositioning protocol (supination-external rotation [Sup-ER]) designed to prevent shoulder internal rotation contracture and its potential effects on the shoulder joint. This study characterizes our clinic's current choice, number, and timing of primary and secondary procedural interventions (including Botox) and compares Sup-ER protocol patients with those of our historical controls. METHODS: The records of all patients with upper BPBI who underwent procedures from 2001 to 2018 were retrospectively reviewed and grouped into a historical (2001-2007, n = 20) and recent (2008-2018, n = 23) cohort. Patient demographics, procedure types and timing, and functional outcomes were collected and analyzed. RESULTS: Since the 2008 institution of the Sup-ER protocol, fewer brachial plexus exploration and grafting (BPEG) surgeries were performed and none in later infancy, where nerve transfers were preferred. There were more and earlier Botox injections. There were fewer tendon transfers, and the preoperative indications were from a higher level of function. CONCLUSIONS: We now see fewer indications for BPEG surgeries overall. After the 3-month-age group, more direct nerve transfers are indicated instead of the BPEG surgery if nerve surgery is required at all. Shoulder tendon transfer rates have decreased. Humeral osteotomies are not seen in our recent group. Glenoid osteotomies within tendon transfers are rare in both groups.

The role of pyruvate-induced enhancement of oxygen metabolism in extracellular purinergic signaling in the post-cardiac arrest rat model.

Purine nucleotide adenosine triphosphate (ATP) is a source of intracellular energy maintained by mitochondrial oxidative phosphorylation. However, when released from ischemic cells into the extracellular space, they act as death-signaling molecules (eATP). Despite there being potential benefit in using pyruvate to enhance mitochondria by inducing a highly oxidative metabolic state, its association with eATP levels is still poorly understood. Therefore, while we hypothesized that pyruvate could beneficially increase intracellular ATP with the enhancement of mitochondrial function after cardiac arrest (CA), our main focus was whether a proportion of the raised intracellular ATP would detrimentally leak out into the extracellular space. As indicated by the increased levels in systemic oxygen consumption, intravenous administrations of bolus (500 mg/kg) and continuous infusion (1000 mg/kg/h) of pyruvate successfully increased oxygen metabolism in post 10-min CA rats. Plasma ATP levels increased significantly from 67 ± 11 nM before CA to 227 ± 103 nM 2 h after the resuscitation; however, pyruvate administration did not affect post-CA ATP levels. Notably, pyruvate improved post-CA cardiac contraction and acidemia (low pH). We also found that pyruvate increased systemic CO2 production post-CA. These data support that pyruvate has therapeutic potential for improving CA outcomes by enhancing oxygen and energy metabolism in the brain and heart and attenuating intracellular hydrogen ion disorders, but does not exacerbate the death-signaling of eATP in the blood.

"Nothing to lose and the possibility of gaining": a qualitative study on the feasibility and acceptability of registry-based randomised controlled trials among cancer patients and clinicians.

BACKGROUND: Randomised controlled trials (RCTs) are considered the "gold standard" for evaluating the effectiveness of interventions in clinical research. However, conventional RCTs are typically complex, expensive, and have narrow eligibility criteria, which limits generalisability. Registry-based randomised controlled trials (RRCTs) are an alternative approach that integrates the internal validity of an RCT with the external validity of a clinical registry by recruiting real-world patients and leveraging an existing registry platform for data collection. As RRCT is a novel research design, there has been limited research on the feasibility and acceptability of RRCTs from the patients' and trial team's perspectives. This study aims to explore patients', clinicians', and study coordinators' perspectives towards participation in and conduct of oncology RRCTs in Australia. METHODS: Thirty-seven semi-structured interviews were conducted with 15 cancer patients, 15 clinicians, and 7 study coordinators. Interviews were audio-recorded and transcribed verbatim. The data were analysed using thematic analysis. RESULTS: Three overarching themes were identified: (1) enablers and barriers to recruitment and enrolment of patients in RRCTs, (2) experiences of patients participating in RRCTs, and (3) recommendations for the implementation of future RRCTs. For patients, altruism and "trust in the clinician" were key reasons to participate in a RRCT. For clinicians and clinical trial coordinators, the RRCT study design was perceived as "simple and straightforward" but "less exciting" than RCTs. Competition from commercially sponsored RCTs poses challenges for investigator-led RRCTs recruitment, particularly if eligible patient numbers are low. There were limited impacts on patients' treatment experiences and clinicians' clinical workflow given that the RRCTs explored different standards of care. Recommendations to improve the enrolment of patients in RRCTs included generating greater buy-in from clinicians by increasing awareness of RRCTs via education initiatives and broader promotion of the "selling point" of RRCTs and providing monetary compensation to hospitals for enrolling patients. CONCLUSIONS: Whilst patients, clinicians, and study coordinators were generally supportive of RRCTs, several barriers to effective RRCT implementation in oncology were identified. Developing strategies to increase acceptance of the methodology by clinicians will help enhance the uptake of RRCTs in Australia and internationally.

Addition of endocrine therapy to dual anti-HER2 targeted therapy in initial treatment of HER2 + /HR + metastatic breast cancer.

PURPOSE: Dual anti-HER2 targeted therapy and chemotherapy is the current first-line standard of care for HER2 + metastatic breast cancer (MBC), with endocrine therapy (ET) the backbone of treatment in hormone receptor positive (HR +) disease. The potential ET benefit in HER2 + /HR + patients is unknown as pivotal dual anti-HER2 clinical trials precluded ET use. METHODS: Real-world data from a multi-site registry of consecutive HER2 + MBC patients treated at clinician discretion were examined. Patients that were HR + (ER + and/or PR +) and had received first-line chemotherapy alongside trastuzumab and pertuzumab were explored. Of 362 patients in the registry, 215 were excluded due to being HR- (n = 210) or not receiving chemotherapy (n = 5). RESULTS: Of the 147 patients included, 91 (62%) received concurrent ET and 56 (38%) had not. Comparing the groups, there were no significant differences in age, performance status, metastatic sites, use of previous therapy and de novo metastatic disease. More patients with ER + PR + disease versus those with ER + PR- or ER-PR + received ET (73 vs 45%). The addition of ET was associated with significantly improved 5-year PFS (HR 0.58, CI 0.37-0.89, p = 0.014) and OS (HR 0.52, CI 0.31-0.90, p = 0.018), with no increase in adverse events noted. CONCLUSION: The addition of ET to first-line dual anti-HER2 therapy post chemotherapy in patients with HER2 + /HR + MBC was associated with major gains in PFS and OS with no safety concerns evident. Further studies of this combination are justified, along with studies of how best to integrate other agents that are active in this patient subset, including CDK4/6 inhibitors.

Taxane-induced neuropathy: How serious is this problem for patients with early breast cancer?

BACKGROUND: Taxanes form the mainstay of breast cancer therapy in the curative setting. Taxane-induced peripheral neuropathy (TIPN) is a common toxicity and confers significant morbidity with no validated therapies. Literature detailing TIPN is inconsistent in reporting its frequency, severity, risk factors, impact upon treatment course, and management practices. METHODS: A retrospective chart review was performed including 348 early-stage breast cancer patients undergoing weekly paclitaxel therapy between 2010 and 2020 in the adjuvant or neoadjuvant setting. The frequency, severity, and impact on treatment from TIPN were analyzed during treatment and at one year follow-up. Clinicopathological and patient factors were collected to identify potential risk factors. RESULTS: 279 out of 348 patients (80.2%) developed TIPN of any grade. One-year follow-up was available for 232 of the original 279 TIPN patients (83.2%). Of these, 52 patients (22.4%) exhibited persisting TIPN of any grade. The presence and severity of TIPN during treatment was significantly associated with a lower median dose intensity (100% versus 82.5% for non-TIPN and all-grade TIPN respectively, p < 0.001). Neoadjuvant treatment (p = 0.038) and body surface area (BSA, p = 0.035) were independently associated with TIPN during treatment. Increased age (p < .001) and pre-treatment diabetes (p = 0.009) were associated with TIPN at one-year follow-up. CONCLUSION: TIPN is common in breast cancer patients undergoing weekly paclitaxel therapy. TIPN results in patients receiving significantly lower dose intensity due to dose reductions and premature treatment cessation. Future prospective studies in similar cohorts are warranted, with a focus on long-term outcomes.

Compliance with Therapeutic Goods Association prescribing information: weekly or second weekly cetuximab for the treatment of metastatic colorectal cancer.

BACKGROUND: Treatment with cetuximab provides a survival benefit for patients with RAS wild-type metastatic colorectal cancer (mCRC). Practice-defining cetuximab studies utilised weekly (q1w) administration. More convenient second weekly (q2w) administration is supported by pharmacokinetic data and a recent meta-analysis, but large head-to-head studies have not been conducted. Therapeutic Goods Association (TGA) prescribing information states cetuximab be administered q1w for all indications. AIM: To assess the real-world use of q1w versus q2w cetuximab schedule and any difference in outcomes. METHODS: We analysed data from a prospective mCRC database at seven Melbourne hospitals from January 2010 to August 2019. Characteristics and outcomes for cetuximab-treated patients were examined, comparing q1w versus q2w schedules. Progression-free survival (PFS) and overall survival (OS) were the primary endpoints. RESULTS: Of 214 eligible patients, 103 (48%) received q1w and 111 (52%) received q2w cetuximab. Q2w cetuximab has been used in >70% of patients from 2015. Q2w was more commonly used in public patients (70% vs 13% in private, P < 0.001), in left-sided primary tumours (83% vs 68%, P = 0.025) and in combination with chemotherapy (73% q2w vs 40% q1w, P < 0.001). Q2w treatment was less common in BRAFV600E mutated tumours (4% vs 13%, P = 0.001). PFS was similar across all lines of therapy, including when analyses were limited to a left-sided primary and there was no difference in OS in multivariate analysis. CONCLUSION: This real-world analysis shows q2w cetuximab has become the dominant method of administration, despite TGA guidance. Our outcome data adds to other data supporting the use of q2w cetuximab as the standard option. Consideration could be given to modifying current TGA advice.

The Development of Small-Caliber Vascular Grafts Using Human Umbilical Artery: An Evaluation of Methods.

Due to the prevalence of cardiovascular disease in the United States, small-caliber vascular grafts for coronary bypass surgery continue to be in high demand. Human umbilical arteries, an underutilized resource, were decellularized using zwitterionic (3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate [CHAPS]) and ionic (sodium dodecyl sulfate [SDS]) detergents and evaluated as potential vascular grafts. Vessels were tested for decellularization efficacy, mechanical integrity, and recellularization potential. Hematoxylin and eosin staining and DNA quantification revealed moderate to successful removal of cells in both conditions. While CHAPS-decellularized vessels displayed collagen structure most similar to intact tissue, both CHAPS- and SDS-decellularized vessels demonstrated burst pressures lower than that of intact tissue. Alcian Blue staining and sulfated glycosaminoglycan (sGAG) quantification indicated the preservation of sGAG content after both decellularization pathways. Both conditions were also capable of recellularization with human umbilical vein endothelial cells, and the use of a basic fibroblast growth factor treatment did not have a significant effect on the density of adhered cells after 5 days. Whole CHAPS-decellularized vessels were successfully recellularized. Additionally, an evaluation of the effects of freeze-thaw cycles was performed. In summary, human umbilical arteries present a promising alternative for small-caliber vascular grafts due to their high availability and ability to be decellularized and recellularized for safe and successful implantation. Impact Statement Coronary heart disease accounts for one of nine deaths in the United States each year. Bypass surgery has been shown to decrease the risk of heart attack; however, many patients do not have a suitable saphenous vein, which is required to redirect blood flow around their blocked arteries. In this study, we evaluate decellularized umbilical artery as a potential small-diameter vascular graft based on its mechanical properties and its recellularization potential.

Leveraging Comprehensive Cancer Registry Data to Enable a Broad Range of Research, Audit and Patient Support Activities.

Traditional cancer registries have often been siloed efforts, established by single groups with limited objectives. There is the potential for registry data to support a broad range of research, audit and education initiatives. Here, we describe the establishment of a series of comprehensive cancer registries across the spectrum of common solid cancers. The experience and learnings of each registry team as they develop, implement and then use collected data for a range of purposes, that informs the conduct and output of other registries in a virtuous cycle. Each registry is multi-site, multi-disciplinary and aims to collect data of maximal interest and value to a broad range of enquiry, which would be accessible to any researcher with a high-quality proposal. Lessons learnt include the need for careful and continuous curation of data fields, with regular database updates, and the need for a continued focus on data quality. The registry data as a standalone resource has supported numerous projects, but linkage with external datasets with patients in common has enhanced the audit and research potential. Multiple projects have linked registry data with matched tissue specimens to support prognostic and predictive biomarker studies, both validation and discovery. Registry-based biomarker trials have been successfully supported, generating novel and practice-changing data. Registry-based clinical trials, particularly randomised studies exploring the optimal use of available therapy options are now complementing the research conducted in traditional clinical trials. More recent projects supported by the registries include health economic studies, personalised patient education material, and increased consumer engagement, including consumer entered data.

Real-World Outcomes of Ribociclib and Aromatase Inhibitor Use in First Line Hormone Receptor Positive, HER2-Negative Metastatic Breast Cancer.

BACKGROUND: International guidelines recommend combining a CDK4/6 inhibitor and endocrine therapy (ET) as first line treatment for hormone receptor (HR) positive, HER2 negative metastatic breast cancer (MBC). Results from MONALEESA-2 demonstrate superior progression free survival (PFS) and overall survival (OS) with ribociclib (CDK4/6 inhibitor) and ET compared to ET alone. Real world outcomes have yet to be reported. MATERIALS AND METHODS: KARMA is a non-interventional registry of Australian patients receiving first-line treatment with ribociclib and aromatase inhibitor (AI), obtained via a Medicine Access Program (MAP) for HR+, HER2- MBC. Outcomes were compared with the ribociclib/letrozole cohort in MONALEESA-2. RESULTS: Data from 160 patients at 17 sites was analysed. Median follow-up is 36.5 months. Compared to MONALEESA-2, patients were numerically younger (54.3 vs. 62 years), with higher rates of bone-only metastases (31% vs. 21%). A total of 63 of 160 (39%) patients remain on treatment. A total of 56% of patients had at least 1 dose reduction, with neutropenia (68%) and abnormal liver enzymes (17%) the most common reasons. A total of 17 of 160 (11%) discontinued treatment due to toxicity, with no treatment related deaths. Median PFS was not reached (95% CI 29.9- NR), with PFS at 12 months and 18 months being 76% and 67% respectively versus 25.3 months, 73% and 63% in MONALEESA-2. CONCLUSION: The ribociclib and AI combination was well tolerated in this real-world setting. The KARMA registry cohort achieved a superior PFS (>36.5 months) to MONALEESA-2, potentially due to more favourable baseline disease characteristics. Less frequent assessment scheduling in this non trial setting may also contribute.

Real-World Outcomes in Patients With Brain Metastases Secondary to HER2-Positive Breast Cancer: An Australian Multi-centre Registry-based Study.

BACKGROUND: The development of brain metastases occurs commonly in HER2-positive metastatic breast cancer and is associated with a poorer prognosis. The advent of HER2-targeted therapy has improved overall survival, but the benefit in patients with brain metastases is unclear, as these patients are often excluded from clinical trials. This study aimed to explore real-world outcomes in patients with brain metastases in HER2-positive MBC. MATERIALS & METHODS: Data was extracted from the TABITHA registry, which consists of patient data collected prospectively from 16 Australian sites from 24th February 2015 to 31st October 2021. Data analysed included characteristics of brain metastases, treatment received and survival outcomes. RESULTS: A total of 135 (37%) of 361 patients with HER2-positive MBC were diagnosed with brain metastases during their clinical course, including 45 (12%) with brain metastases at time of MBC diagnosis. 61 (45%) had ≥4 brain lesions. The most common local therapy given was whole brain radiation therapy (WBRT) (36%) followed by multi-modality treatment with both surgery and radiation therapy (27%). The majority of patients received first-line HER2-targeted treatment with trastuzumab and pertuzumab followed by second-line trastuzumab emtansine (T-DM1) but third-line therapy was heterogenous. The median overall survival in patients who developed brain metastases was significantly shorter than those who did not develop brain metastases (58.9 vs. 96.1 months, P = .02). CONCLUSION: Real-world patients diagnosed with brain metastases in HER2-positive MBC have a relatively poor prognosis, despite advances in HER2-targeted treatment. As the range of HER2-targeted treatment expands, it is important to pursue clinical trials that focus on patients with brain metastases.

Transport and migration of plutonium in different soil types and rainfall regimes.

Leaching and transport of contaminants is a complex interacting system affected by a suite of environmental factors. This study demonstrates the potential significance of weather events and moisture movement when interpreting plutonium (Pu) migration and advective transport in the soil matrix. Using a column transport experiment, two soil types, a sandy soil and clay-rich soil, were spiked with 238Pu as a tracer to observe the effect of simulated tropical and arid rainfall events on Pu mobility. Partition coefficients (Kd) were determined over a period of weeks and under varying rainfall rates to establish the impact of changing weather events on Pu mobility. The variability of these temporal Kds covers six orders of magnitude over a relatively brief time period. This demonstrates the necessity for non-static Kds to accurately describe Pu transport in these systems. The Pu Kds determined by these column transport experiments fall within the bounds of anticipated values (approximately 80-300,000 mL g-1) from immobile (magnitude 106 mL g-1) to moderately mobile (magnitude 101 mL g-1). The overall transport rate, shown by a decrease in calculated Kd, increases in environments where rainfall is more episodic, such as in arid regions as opposed to the consistently abundant rainfall in tropical regions. In contrast to the 238Pu spike, 239+240Pu resulting from contamination from nuclear tests in the sandy soil (aged for >30 years) showed higher mobility; we hypothesise that the ageing of the contamination, in particular Pu-bearing particles, accounts for this significant increase in Pu mobility. Low intensity, high frequency events in tropical sandy soil systems containing Pu particle contamination have the potential to mobilise Pu (>105 decrease in calculated Kd) over shorter periods of weeks, and not years as previously assumed. This increased mobility, when applied to radioecological models using Kd as a site-specific parameter, shows that there is likely to be a continued impact (risk quotient >1) on non-human biota in tropical sandy soil ecosystems.

High-dose chemotherapy for relapsed germ cell tumours: outcomes in low-volume specialized centres.

OBJECTIVE: To report treatment patterns and survival outcomes of patients with relapsed and refractory metastatic germ cell tumours (GCTs) treated with high-dose chemotherapy (HDCT) and autologous stem-cell transplantation in low-volume specialized centres within the widely dispersed populations of Australia and New Zealand between 1999 and 2019. PATIENTS AND METHODS: We conducted a retrospective analysis of 111 patients across 13 institutions. Patients were identified from the Australasian Bone Marrow Transplant Recipient Registry. We reviewed treatment regimens, survival outcomes, deliverability and toxicities. Primary endpoints included overall (OS) and progression-free survival (PFS). Cox proportional hazards models were used to test the association of survival outcomes with patient and treatment factors. RESULTS: The median (range) age was 30 (14-68) years and GCT histology was non-seminomatous in 84% of patients. International Prognostic Factors Study Group (IPFSG) prognostic risk category was very low/low, intermediate, high and very high in 18%, 36%, 25% and 21% of patients, respectively. Salvage conventional-dose chemotherapy (CDCT) was administered prior to HDCT in 59% of patients. Regimens included paclitaxel, ifosfamide, carboplatin and etoposide (50%), carboplatin and etoposide (CE; 28%), carboplatin, etoposide and ifosfamide (CEI; 6%), carboplatin, etoposide and cyclophosphamide (CEC; 5%), CEC-paclitaxel (6%) and other (5%). With a median follow-up of 4.4 years, the 1-, 2- and 5-year PFS rates were 62%, 57% and 52%, respectively, and OS rates were 73%, 65% and 61%, respectively. There were five treatment-related deaths. Progression on treatment occurred in 17%. In a univariable analysis, worse International Germ Cell Cancer Collaborative Group (IGCCCG) and IPFSG prognostic groups were associated with inferior survival outcomes. An association of inferior survival was not found with the number of high-dose cycles received nor when HDCT was delivered after salvage CDCT. CONCLUSION: This large dual-national registry-based study reinforces the efficacy and deliverability of HDCT for relapsed and refractory metastatic GCT in low-volume specialized centres in Australia and New Zealand, with survival outcomes comparable to those found in international practice.

Uptake of bone-modifying agents in patients with HER2+ metastatic breast cancer with bone metastases - prospective data from a multi-site Australian registry.

BACKGROUND: International practice guidelines recommend administration of bone-modifying agents (BMA) in metastatic breast cancer (MBC) patients with bone metastases to reduce skeletal-related events (SRE). Optimal delivery of BMA in routine clinical practice, including agent selection and prescribing intervals, remains unclear. AIM: To describe real-world practice of Australian breast oncologists. METHODS: Prospective data from February 2015 to July 2020 on BMA delivery to MBC patients with bone metastases was analysed from Treatment of Advanced Breast Cancer in the Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Australian Patient (TABITHA), a multi-site Australian HER2+ MBC registry. RESULTS: Of 333 HER2+ MBC patients, 171 (51%) had bone metastases at diagnosis, with a mean age of 58.1 years (range, 32-87). One hundred and thirty (76%) patients received a BMA, with 90 (69%) receiving denosumab and 40 (31%) receiving a bisphosphonate. Patients who received a BMA were more likely to have received concurrent first-line systemic anti-HER2 therapy (95% vs 83%; P = 0.04), to present with bone-only metastases at diagnosis (24% vs 7%; P = 0.02) and less likely to have visceral metastases (51% vs 71%; P = 0.03). Ten of 40 (25%) bisphosphonate patients and 45 of 90 (50%) denosumab patients received their BMA at the recommended 4-weekly interval. Prescribing intervals varied over time. Adverse events reported were consistent with clinical trial data. CONCLUSION: Three-quarters of Australian HER2+ MBC patients with bone metastases receive a BMA, often at different schedules than guidelines recommend. Further studies, including all MBC subtypes, are warranted to better understand clinicians' prescribing rationale and potential consequences of current prescribing practice on SRE incidence.

Traumatic Left Ventricular Aneurysm and Ventricular Septal Defect in a Child.

Cardiac injuries following blunt trauma are rare but potentially lethal in children. We present a 23-month-old child who sustained an aneurysm of the left ventricle free wall and ventricular septum with associated ventricular septal defect following blunt trauma. She underwent successful surgical repair 6 weeks following her date of injury. Surgical decision-making surrounding this case is discussed.