Publications

BackgroundLutetium-177 (177Lu) prostate-specific membrane antigen (177Lu-PSMA) is a novel targeted treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). Predictors of outcomes after 177Lu-PSMA to enhance its clinical implementation are yet to be identified. We aimed to develop nomograms to predict outcomes after 177Lu-PSMA in patients with mCRPC.MethodsIn this multicentre, retrospective study, we screened patients with mCRPC who had received 177Lu-PSMA between Dec 10, 2014, and July 19, 2019, as part of the previous phase 2 trials (NCT03042312, ACTRN12615000912583) or compassionate access programmes at six hospitals and academic centres in Germany, the USA, and Australia. Eligible patients had received intravenous 6·0–8·5 GBq 177Lu-PSMA once every 6–8 weeks, for a maximum of four to six cycles, and had available baseline [68Ga]Ga-PSMA-11 PET/CT scan, clinical data, and survival outcomes. Putative predictors included 18 pretherapeutic clinicopathological and [68Ga]Ga-PSMA-11 PET/CT variables. Data were collected locally and centralised. Primary outcomes for the nomograms were overall survival and prostate-specific antigen (PSA)-progression-free survival. Nomograms for each outcome were computed from Cox regression models with LASSO penalty for variable selection. Model performance was measured by examining discrimination (Harrell's C-index), calibration (calibration plots), and utility (patient stratification into low-risk vs high-risk groups). Models were validated internally using bootstrapping and externally by calculating their performance on a validation cohort.FindingsBetween April 23, 2019, and Jan 13, 2020, 414 patients were screened; 270 (65%) of whom were eligible and were divided into development (n=196) and validation (n=74) cohorts. The median duration of follow-up was 21·5 months (IQR 13·3–30·7). Predictors included in the nomograms were time since initial diagnosis of prostate cancer, chemotherapy status, baseline haemoglobin concentration, and [68Ga]Ga-PSMA-11 PET/CT parameters (molecular imaging TNM classification and tumour burden). The C-index of the overall survival model was 0·71 (95% CI 0·69–0·73). Similar C-indices were achieved at internal validation (0·71 [0·69–0·73]) and external validation (0·72 [0·68–0·76]). The C-index of the PSA-progression-free survival model was 0·70 (95% CI 0·68–0·72). Similar C-indices were achieved at internal validation (0·70 [0·68–0·72]) and external validation (0·71 [0·68–0·74]). Both models were adequately calibrated and their predictions correlated with the observed outcome. Compared with high-risk patients, low-risk patients had significantly longer overall survival in the validation cohort (24·9 months [95% CI 16·8–27·3] vs 7·4 months [4·0–10·8]; p<0·0001) and PSA-progression-free survival (6·6 months [6·0–7·1] vs 2·5 months [1·2–3·8]; p=0·022).InterpretationThese externally validated nomograms that are predictive of outcomes after 177Lu-PSMA in patients with mCRPC might help in clinical trial design and individual clinical decision making, particularly at institutions where 177Lu-PSMA is introduced as a novel therapeutic option.FundingProstate Cancer Foundation.

&lt;p&gt;Tables S1-S8 and Figures S1-S4&lt;/p&gt;

&lt;div&gt;AbstractPurpose:&lt;p&gt;Successful implementation of genomic testing in clinical practice is critical for identification of men with metastatic castration-resistant prostate cancer (mCRPC) eligible for olaparib and future molecularly targeted therapies.&lt;/p&gt;Patients and Methods:&lt;p&gt;An investigational clinical trial assay, based on the FoundationOneCDx tissue test, was used to prospectively identify patients with qualifying homologous recombination repair gene alterations in the phase III PROfound study. Evaluation of next-generation sequencing (NGS) tissue test outcome against preanalytic parameters was performed to identify key factors influencing NGS result generation.&lt;/p&gt;Results:&lt;p&gt;A total of 4,858 tissue samples from 4,047 patients were tested and reported centrally. NGS results were obtained in 58% (2,792/4,858) of samples (69% of patients). Of samples submitted, 83% were primary tumor samples (96% were archival and 4% newly obtained). Almost 17% were metastatic tumor samples (60% were archival and 33% newly obtained). NGS results were generated more frequently from newly obtained compared with archival samples (63.9% vs. 56.9%) and metastatic compared with primary samples (63.9% vs. 56.2%). Although generation of an NGS result declined with increasing sample age, approximately 50% of samples ages &gt;10 years generated results. While higher tumor content and DNA yield resulted in greater success in obtaining NGS results, other factors, including selection and preservation of samples, may also have had an impact.&lt;/p&gt;Conclusions:&lt;p&gt;The PROfound study shows that tissue testing to identify homologous recombination repair alterations is feasible and that high-quality tumor tissue samples are key to obtaining NGS results and identifying patients with mCRPC who may benefit from olaparib treatment.&lt;/p&gt;&lt;/div&gt;

Abstract A sentinel lymph node biopsy is a surgical staging procedure performed for patients with primary cutaneous melanoma who are clinically lymph‐node negative to determine whether there is low volume nodal metastasis in the draining lymph node field. A systematic review was recently performed to update the Australian clinical practice guidelines for the diagnosis and management of melanoma, addressing the question, ‘When is a sentinel lymph node biopsy indicated?’ This article discusses the findings of the systematic review and the evidence base for the updated guidelines.

Abstract Replying to GCC Koh et al., Nature Genetics ( www.nature.com/articles/s41588-023-01602-9 ) and the comments by Simon Boulton in Nature Genetics ( www.nature.com/articles/s41588-023-01611-8 ). The drug CX-5461 [Pidnarulex] is an inhibitor of RNA polymerase I and topoisomerase II and a DNA G-quadruplex stabilizer. Koh et al. recently reported that CX-5461 induces extensive, non-selective collateral mutagenesis in vitro at magnitudes surpassing known environmental carcinogens, raising concerns about its potential to promote secondary cancers. Mindful that the report of Koh et al. was exclusively an in vitro study, we applied the same ultra-sensitive, error-corrected TwinStrand Duplex Sequencing approach and analyses (methods) to a longitudinal series of clinical specimens from four patients who participated in the Phase I dose-escalation trial of CX-5461 in advanced haematologic malignancies [ACTRN12613001061729]. In contrast to the findings of Koh et al. we found no evidence that clinical administration of CX-5461 significantly increased mutational burden in patient samples, nor did we observe the reported mutational signature. These results suggest that the mutagenic effects described in vitro do not translate to the clinical setting. This is particularly important given that several clinical trials, including a Phase Ib study of CX-5461 in patients with solid tumours [ NCT04890613 ] and a National Cancer Institute sponsored Phase I trial [ NCT06606990 ] are currently enrolling patients. These ongoing and planned clinical efforts highlight both the therapeutic promise of CX-5461 and the importance of evaluating this agent within rigorous and clinically relevant frameworks.

Introduction: Alpiniae oxyphyllae Fructus (AOF) has been abundantly utilized for the treatment of diarrhea, dyspepsia, kidney asthenia, and abdominal pain in China. AOF is effective for treating AD in clinical trials, but its exact mode of action is yet unknown. Methods: In this study, metabolomics was combined to ascertain the alterations in plasma metabolism in APP/PS1 transgenic mice, the therapy of AOF on model mice, and the dynamic variations in 15 bile acids (BAs) concentration. Results: 31 differential biomarkers were finally identified in APP/PS1 group vs. the WT group. The levels of 16 metabolites like sphinganine (Sa), lyso PE (20:2), lysoPC (17:0), glycocholic acid (GCA), deoxycholicacid (DCA) were increased in APP/PS1 group, and those of 15 metabolites like phytosphingosine, cer (d18:0/14:0), and fumaric acid were reduced in APP/PS1 group. After AOF treatment, 29 of the 31 differential metabolites showed a tendency to be back-regulated, and 15 metabolites were significantly back-regulated, including sphinganine (Sa), lyso PE (20:2), glycocholic acid (GCA), deoxycholic acid (DCA). The relationship between BAs level and AD had been received increasing attention in recent years, and we also found notable differences between DCA and GCA in different groups. Therefore, a BAs-targeted metabonomic way was established to determine the level of 15 bile acids in different groups. The consequence demonstrated that primary BAs (CA, CDCA) declined in APP/PS1 model mice. After 3 months of AOF administration, CA and CDCA levels showed an upward trend. Conjugated primary bile acids (TCA, GCA, TCDCA, GCDCA), and secondary bile acids (DCA, LCA, GDCA, TDCA, TLCA GLCA) ascended in APP/PS1 group. After 3 months of AOF treatment, the levels of most BAs decreased to varying degrees. Notably, the metabolic performance of DCA and GCA in different groups was consistent with the predictions of untargeted metabolomics, validating the correctness of untargeted metabolomics. Discussion: According to metabolic pathways of regulated metabolites, it was prompted that AOF ameliorated the symptom of AD mice probably by regulating bile acids metabolism. This study offers a solid foundation for further research into the AOF mechanism for the therapy of AD.