Explore the vast range of titles available.

In the past decade, a growing body of literature has reported promising results for prostate-specific membrane antigen (PSMA)-targeted radionuclide imaging and therapy in prostate cancer. First clinical studies evaluating the efficacy of [177Lu]Lu-PSMA radioligand therapy (PSMA-RLT) demonstrated favorable results in prostate cancer patients. [177Lu]Lu-PSMA is generally well tolerated due to its limited side effects. While PSMA is highly overexpressed in prostate cancer cells, varying degrees of PSMA expression have been reported in other malignancies as well, particularly in the tumor-associated neovasculature. Hence, it is anticipated that PSMA-RLT could be explored for other solid cancers. Here, we describe the current knowledge of PSMA expression in other solid cancers and define a perspective towards broader clinical implementation of PSMA-RLT. This review focuses specifically on salivary gland cancer, glioblastoma, thyroid cancer, renal cell carcinoma, hepatocellular carcinoma, lung cancer, and breast cancer. An overview of the (pre)clinical data on PSMA immunohistochemistry and PSMA PET/CT imaging is provided and summarized. Furthermore, the first clinical reports of non-prostate cancer patients treated with PSMA-RLT are described.

Purpose This retrospective study aimed (1) to compare the diagnostic accuracy of whole-body FDG PET/CT for initial breast cancer staging with the accuracy of a conventional, multimodal imaging algorithm, and (2) to assess potential alteration in patient management based on the FDG PET/CT findings. Methods Patients with primary breast cancer (106 women, mean age 57 ± 13 years) underwent whole-body FDG PET/CT and conventional imaging (X-ray mammography, MR mammography, chest plain radiography, bone scintigraphy and breast, axillary and liver ultrasonography). The diagnostic accuracies of FDG PET/CT and a conventional algorithm were compared. Diagnostic accuracy was assessed in terms of primary tumour detection rate, correct assessment of primary lesion focality, T stage and the detection rates for lymph node and distant metastases. Histopathology, imaging or clinical follow-up served as the standards of reference. Results FDG PET/CT was significantly more accurate for detecting axillary lymph node and distant metastases ( p  = 0.0125 and p  < 0.005, respectively). No significant differences were detected for other parameters. Synchronous tumours or locoregional extraaxillary lymph node or distant metastases were detected in 14 patients (13%) solely by FDG PET/CT. Management of 15 patients (14%) was altered based on the FDG PET/CT findings, including 3 patients with axillary lymph node metastases, 5 patients with extraaxillary lymph node metastases, 4 patients with distant metastases and 3 patients with synchronous malignancies. Conclusion Full-dose, intravenous contrast-enhanced FDG PET/CT was more accurate than conventional imaging for initial breast cancer staging due to the higher detection rate of metastases and synchronous tumours, although the study had several limitations including a retrospective design, a possible selection bias and a relevant false-positive rate for the detection of axillary lymph node metastases. FDG PET/CT resulted in a change of treatment in a substantial proportion of patients.

Background: Panobinostat, a pan-deacetylase inhibitor, overcomes imatinib resistance in preclinical models of gastrointestinal stromal tumours (GIST). Here we determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of panobinostat in combination with imatinib (IM) for treatment of patients with refractory GIST. Methods: Following a 7-day run-in phase of IM (400 mg per day), escalating doses of panobinostat were added following a ‘3 plus 3’ design. Twelve heavily pretreated GIST patients were enrolled in two dose levels. Results: Most common adverse events were thrombocytopenia, anaemia, fatigue, creatinine elevation, nausea, emesis and diarrhoea. Twenty micrograms of panobinostat and 400 mg IM were declared the MTD. Pharmacologically active concentrations of panobinostat and IM were achieved as evidenced by histone H3 acetylation in blood mononuclear cells in vivo and inhibition of the IM-resistant KIT (D816) mutation in vitro . In FDG-PET-CT scans after IM run-in and following 3 weeks panobinostat treatment, 1 out of 11 evaluable patients showed a metabolic partial response, 7 patients were metabolically stable and 3 patients progressed. Longest treatment duration was 17 weeks (median 6). Conclusion: Panobinostat and IM can be administered at doses achieving target inhibition in vivo . Further clinical exploration of patients with treatment-refractory GIST is warranted. Correlative studies in this trial may help to optimise dosing schedules in GIST.

Abstract PurposeFeatures of polycystic ovarian syndrome (PCOS) including sonographic aspects, androgens, LH and LH/FSH ratio as well as Anti-Mullerian Hormone (AMH) were evaluated according to their diagnostic potency in detecting different degrees of PCOS severity.Methods80 women with PCOS diagnosed according to the Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group 2003 and 48 controls were enrolled between 2011 and 2013. PCOS patients fulfilling all Rotterdam criteria were defined as having severe PCOS (n = 59), while patients showing oligo-/amenorrhoea and polycystic ovaries but without hyperandrogenemia were defined as having mild PCOS (n = 21). All patients were treated at the University Hospital of Essen, Germany.ResultsThe strongest group difference between controls and severe PCOS patients was observed for AMH showing an age-adjusted odds ratio of 2.56 [95 % confidence interval (CI) 2.00–3.27; p < 0.0001]. Age-adjusted receiver operating characteristic analysis showed that the area under the curve (AUC) of 0.88 (95 % CI: 0.80–0.95) for AMH and 0.94 (95 % CI 0.88–0.98) for antral follicle count did not differ significantly in their ability to discriminate between severe PCOS patients and controls. AMH showed higher AUC estimates than androgens, ovarian volume, LH and LH/FSH ratio and an AUC of 0.80 (95 % CI: 0.65–0.91) for detecting mild PCOS.ConclusionsTo our knowledge, this is the first study comparing the diagnostic potency of AMH, sonographic aspects, androgens, and LH/FSH ratio according to different PCOS subgroups while accounting for the age-dependency of AMH. In cases where vaginal scans are not feasible or in patients without hyperandrogenemia AMH may be used as a surrogate parameter in PCOS diagnosis, superior to androgens and gonadotropins.

IntroductionPrecision medicine expands the treatment options for metastatic castration-resistant prostate cancer (mCRPC) by targeting druggable genetic aberrations. Aberrations can be identified following molecular analysis of metastatic tissue. Bone metastases, commonly present in mCRPC, hinder precision medicine due to a high proportion of biopsies with insufficient tumor cells for next-generation DNA sequencing. We aimed to investigate the feasibility of incorporating advanced target planning and needle guidance in bone biopsies and whether this procedure increases biopsy tumor yield and success rate of molecular analysis as compared to the current standards, utilizing only CT guidance.Materials and MethodsIn a pilot study, ten mCRPC patients received 68Ga-prostate-specific membrane antigen (PSMA)-PET/CT and diffusion-weighted MRI as biopsy planning images. These datasets were fused for targeting metastatic lesions with high tumor densities. Biopsies were performed under cone-beam CT (CBCT) guidance. Feasibility of target planning and needle guidance was assessed, and success of molecular analysis and tumor yield were reported.ResultsFusion target planning and CBCT needle guidance were feasible. Nine out of ten biopsies contained prostate cancer cells, with a median of 39% and 40% tumor cells by two different sequencing techniques. Molecular analysis was successful in eight of ten patients (80%). This exceeds previous reports on CT-guided biopsies that ranged from 33 to 44%. In two patients, important druggable aberrations were found.DiscussionA biopsy procedure using advanced target planning and needle guidance is feasible and can increase the success rate of molecular analysis in bone metastases, thereby having the potential of improving treatment outcome for patients with mCRPC.Level of EvidenceLevel 4, case series.

[177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolongs radiographic progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer previously treated with androgen receptor pathway inhibitor (ARPI) and taxane therapy. We aimed to investigate the efficacy of 177Lu-PSMA-617 in patients with taxane-naive metastatic castration-resistant prostate cancer. In this phase 3, randomised, controlled trial conducted at 74 sites across Europe and North America, taxane-naive patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer who had progressed once on a previous ARPI were randomly allocated (1:1) to open-label, intravenous 177Lu-PSMA-617 at a dosage of 7·4 GBq (200 mCi) ± 10% once every 6 weeks for six cycles, or a change of ARPI (to abiraterone or enzalutamide, administered orally on a continuous basis per product labelling). Crossover from ARPI change to 177Lu-PSMA-617 was allowed after centrally confirmed radiographic progression. The primary endpoint was radiographic progression-free survival, defined as the time from randomisation until radiographic progression or death, assessed in the intention-to-treat population. Safety was a secondary endpoint. This study is registered with ClinicalTrials.gov (NCT04689828) and is ongoing. In this primary report of the study, we present primary (first data cutoff) and updated (third data cutoff) analyses of radiographic progression-free survival; all other data are based on the third data cutoff. Overall, of the 585 patients screened, 468 met all eligibility criteria and were randomly allocated between June 15, 2021 and Oct 7, 2022 to receive 177Lu-PSMA-617 (234 [50%] patients) or ARPI change (234 [50%]). Baseline characteristics were mostly similar between groups; median number of 177Lu-PSMA-617 cycles was 6·0 (IQR 4·0–6·0). Of patients assigned to ARPI change, 134 (57%) crossed over to receive 177Lu-PSMA-617. In the primary analysis (median time from randomisation to first data cutoff 7·26 months [IQR 3·38–10·55]), the median radiographic progression-free survival was 9·30 months (95% CI 6·77–not estimable) in the 177Lu-PSMA-617 group versus 5·55 months (4·04–5·95) in the ARPI change group (hazard ratio [HR] 0·41 [95% CI 0·29–0·56]; p<0·0001). In the updated analysis at time of the third data cutoff (median time from randomisation to third data cutoff 24·11 months [IQR 20·24–27·40]), median radiographic progression-free survival was 11·60 months (95% CI 9·30–14·19) in the 177Lu-PSMA-617 group versus 5·59 months (4·21–5·95) in the ARPI change group (HR 0·49 [95% CI 0·39–0·61]). The incidence of grade 3–5 adverse events was lower in the 177Lu-PSMA-617 group (at least one event in 81 [36%] of 227 patients; four [2%] grade 5 [none treatment related]) than the ARPI change group (112 [48%] of 232; five [2%] grade 5 [one treatment related]). 177Lu-PSMA-617 prolonged radiographic progression-free survival relative to ARPI change, with a favourable safety profile. For patients with PSMA-positive metastatic castration-resistant prostate cancer who are being considered for a change of ARPI after progression on a previous ARPI, 177Lu-PSMA-617 may be an effective treatment alternative. Novartis.

In VISION, the prostate-specific membrane antigen (PSMA)-targeted radioligand therapy lutetium-177 [177Lu]Lu-PSMA-617 (vipivotide tetraxetan) improved radiographic progression-free survival and overall survival when added to protocol-permitted standard of care in patients with metastatic castration-resistant prostate cancer. Here, we report additional health-related quality of life (HRQOL), pain, and symptomatic skeletal event results. This multicentre, open-label, randomised, phase 3 trial was conducted at 84 cancer centres in nine countries in North America and Europe. Eligible patients were aged 18 years or older; had progressive PSMA-positive metastatic castration-resistant prostate cancer; an Eastern Cooperative Oncology Group (ECOG) performance status score of 0–2; and had previously received of at least one androgen receptor pathway inhibitor and one or two taxane-containing regimens. Patients were randomly assigned (2:1) to receive either [177Lu]Lu-PSMA-617 plus protocol-permitted standard of care ([177Lu]Lu-PSMA-617 group) or standard of care alone (control group) using permuted blocks. Randomisation was stratified by baseline lactate dehydrogenase concentration, liver metastases, ECOG performance status, and androgen receptor pathway inhibitor inclusion in standard of care. Patients in the [177Lu]Lu-PSMA-617 group received intravenous infusions of 7·4 gigabecquerel (GBq; 200 millicurie [mCi]) [177Lu]Lu-PSMA-617 every 6 weeks for four cycles plus two optional additional cycles. Standard of care included approved hormonal treatments, bisphosphonates, and radiotherapy. The alternate primary endpoints were radiographic progression-free survival and overall survival, which have been reported. Here we report the key secondary endpoint of time to first symptomatic skeletal event, and other secondary endpoints of HRQOL assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-5L, and pain assessed with the Brief Pain Inventory-Short Form (BPI-SF). Patient-reported outcomes and symptomatic skeletal events were analysed in all patients who were randomly assigned after implementation of measures designed to reduce the dropout rate in the control group (on or after March 5, 2019), and safety was analysed according to treatment received in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, NCT03511664, and is active but not recruiting. Between June 4, 2018, and Oct 23, 2019, 831 patients were enrolled, of whom 581 were randomly assigned to the [177Lu]Lu-PSMA-617 group (n=385) or control group (n=196) on or after March 5, 2019, and were included in analyses of HRQOL, pain, and time to first symptomatic skeletal event. The median age of patients was 71 years (IQR 65–75) in the [177Lu]Lu-PSMA-617 group and 72·0 years (66–76) in the control group. Median time to first symptomatic skeletal event or death was 11·5 months (95% CI 10·3–13·2) in the [177Lu]Lu-PSMA-617 group and 6·8 months (5·2–8·5) in the control group (hazard ratio [HR] 0·50, 95% CI 0·40–0·62). Time to worsening was delayed in the [177Lu]Lu-PSMA-617 group versus the control group for FACT-P score (HR 0·54, 0·45–0·66) and subdomains, BPI-SF pain intensity score (0·52, 0·42–0·63), and EQ-5D-5L utility score (0·65, 0·54–0·78). Grade 3 or 4 haematological adverse events included decreased haemoglobin (80 [15%] of 529 assessable patients who received [177Lu]Lu-PSMA-617 plus standard of care vs 13 [6%] of 205 who received standard of care only), lymphocyte concentrations (269 [51%] vs 39 [19%]), and platelet counts (49 [9%] vs five [2%]). Treatment-related adverse events leading to death occurred in five (1%) patients who received [177Lu]Lu-PSMA-617 plus standard of care (pancytopenia [n=2], bone marrow failure [n=1], subdural haematoma [n=1], and intracranial haemorrhage [n=1]) and no patients who received standard of care only. [177Lu]Lu-PSMA-617 plus standard of care delayed time to worsening in HRQOL and time to skeletal events compared with standard of care alone. These findings support the use of [177Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer who received previous androgen receptor pathway inhibitor and taxane treatment. Advanced Accelerator Applications (Novartis).

In the PSMAfore study, lutetium-177 [177Lu]Lu-PSMA-617 (vipivotide tetraxetan) significantly improved radiographic progression-free survival compared with change of androgen receptor pathway inhibitor (ARPI) in taxane-naive patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer. Here, we present in-depth analyses of time to worsening of health-related quality of life (HRQOL) and pain, and time to first symptomatic skeletal events. PSMAfore, an open-label, randomised, phase 3 trial, was conducted at 74 investigator sites (including hospitals with nuclear medicine departments and the research facilities where patients were recruited) across 14 countries. Eligible patients had metastatic castration-resistant prostate cancer, were candidates for ARPI change after one progression on a previous ARPI, had at least one PSMA-positive and no exclusionary PSMA-negative metastatic lesions by gallium-68 [68Ga]Ga-PSMA-11 PET–CT, were aged 18 years or older, and had an Eastern Cooperative Oncology Group performance status of 0–1. Patients were randomly assigned (1:1) to [177Lu]Lu-PSMA-617 (7·4 GBq; every 6 weeks for six cycles) or ARPI change (oral abiraterone or enzalutamide per local labelling). The primary endpoint was radiographic progression-free survival. Secondary endpoints included time to worsening in self-reported HRQOL (assessed using the Functional Assessment of Cancer Therapy-Prostate [FACT-P] and EQ-5D-5L) and pain (assessed using the Brief Pain Inventory-Short Form [BPI-SF]) and time to the first symptomatic skeletal event. All analyses were done using the intention-to-treat principle. The study met the primary endpoint of radiographic progression-free survival (reported previously), and overall survival follow-up is ongoing; present analyses are from the third interim analysis of overall survival. This trial is registered with ClinicalTrials.gov, NCT04689828. Between June 15, 2021, and Oct 7, 2022, 468 patients (426 [91%] were White and 12 [3%] were Black or African American) were randomly assigned to [177Lu]Lu-PSMA-617 (n=234) or ARPI change (n=234). Median follow-up time from randomisation to the third interim analysis data cutoff date (Feb 27, 2024) was 24·11 months (IQR 20·24–27·60) in the [177Lu]Lu-PSMA-617 group and 24·13 months (20·24–27·37) in the ARPI change group. [177Lu]Lu-PSMA-617 delayed time to worsening in all assessed FACT-P, EQ-5D-5L, and BPI-SF scales and subscales versus ARPI change. In the [177Lu]Lu-PSMA-617 versus ARPI change groups, median time to worsening in FACT-P total score was 7·46 months (95% CI 6·08–8·54) versus 4·27 months (3·45–4·50; hazard ratio [HR] 0·61 [95% CI 0·50–0·75]), in EQ-5D-5L utility score was 6·28 months (4·70–7·89) versus 3·88 months (3·25–4·44; 0·67 [0·54–0·82]), and in BPI-SF pain intensity was 5·03 months (4·40–6·80) versus 3·65 months (3·09–4·37; 0·72 [0·59–0·88]). [177Lu]Lu-PSMA-617 also delayed symptomatic skeletal events versus ARPI change: median time to first symptomatic skeletal event was not reached (95% CI not estimable [NE]–NE) in the [177Lu]Lu-PSMA-617 group versus 17·97 months (14·26–NE) in the ARPI change group (HR 0·41 [0·26–0·63]). The most common grade 3 or worse treatment-emergent adverse event was anaemia (14 [6%] of 227 patients in the [177Lu]Lu-PSMA-617 group vs 16 [7%] of 232 patients in the ARPI change group). There were no treatment-related deaths in the [177Lu]Lu-PSMA-617 group and one in the ARPI change group (cerebrovascular accident). [177Lu]Lu-PSMA-617 might delay worsening of patient-reported outcomes and prevent symptomatic skeletal events versus ARPI change in taxane-naive patients with PSMA-positive metastatic castration-resistant prostate cancer whose disease has progressed once on a previous ARPI. Novartis.

Alanine, serine, cysteine-preferring transporter 2 (ASCT2; SLC1A5) mediates uptake of glutamine, a conditionally essential amino acid in rapidly proliferating tumour cells. Uptake of glutamine and subsequent glutaminolysis is critical for activation of the mTORC1 nutrient-sensing pathway, which regulates cell growth and protein translation in cancer cells. This is of particular interest in breast cancer, as glutamine dependence is increased in high-risk breast cancer subtypes. Pharmacological inhibitors of ASCT2-mediated transport significantly reduced glutamine uptake in human breast cancer cell lines, leading to the suppression of mTORC1 signalling, cell growth and cell cycle progression. Notably, these effects were subtype-dependent, with ASCT2 transport critical only for triple-negative (TN) basal-like breast cancer cell growth compared with minimal effects in luminal breast cancer cells. Both stable and inducible shRNA-mediated ASCT2 knockdown confirmed that inhibiting ASCT2 function was sufficient to prevent cellular proliferation and induce rapid cell death in TN basal-like breast cancer cells, but not in luminal cells. Using a bioluminescent orthotopic xenograft mouse model, ASCT2 expression was then shown to be necessary for both successful engraftment and growth of HCC1806 TN breast cancer cells in vivo . Lower tumoral expression of ASCT2 conferred a significant survival advantage in xenografted mice. These responses remained intact in primary breast cancers, where gene expression analysis showed high expression of ASCT2 and glutamine metabolism-related genes, including GLUL and GLS , in a cohort of 90 TN breast cancer patients, as well as correlations with the transcriptional regulators, MYC and ATF4 . This study provides preclinical evidence for the feasibility of novel therapies exploiting ASCT2 transporter activity in breast cancer, particularly in the high-risk basal-like subgroup of TN breast cancer where there is not only high expression of ASCT2, but also a marked reliance on its activity for sustained cellular proliferation.