Amongst therapeutic radiopharmaceuticals, targeted alpha therapy (TαT) can deliver potent and local radiation selectively to cancer cells as well as the tumor microenvironment and thereby control ...cancer while minimizing toxicity. In this review, we discuss the history, progress, and future potential of TαT in the treatment of prostate cancer, including dosimetry-individualized treatment planning, combinations with small-molecule therapies, and conjugation to molecules directed against antigens expressed by prostate cancer cells, such as prostate-specific membrane antigen (PSMA) or components of the tumor microenvironment. A clinical proof of concept that TαT is efficacious in treating bone-metastatic castration-resistant prostate cancer has been demonstrated by radium-223 via improved overall survival and long-term safety/tolerability in the phase III ALSYMPCA trial. Dosimetry calculation and pharmacokinetic measurements of TαT provide the potential for optimization and individualized treatment planning for a precision medicine-based cancer management paradigm. The ability to combine TαTs with other agents, including chemotherapy, androgen receptor-targeting agents, DNA repair inhibitors, and immuno-oncology agents, is under investigation. Currently, TαTs that specifically target prostate cancer cells expressing PSMA represents a promising therapeutic approach. Both PSMA-targeted actinium-225 and thorium-227 conjugates are under investigation. The described clinical benefit, safety and tolerability of radium-223 and the recent progress in TαT trial development suggest that TαT occupies an important new role in prostate cancer treatment. Ongoing studies with newer dosimetry methods, PSMA targeting, and novel approaches to combination therapies should expand the utility of TαT in prostate cancer treatment.
CD147 (basigin, EMMPRIN) is a multifunctional, highly conserved glycoprotein enriched in pancreatic ductal adenocarcinomas (PDACs) which is associated with poor prognosis in many malignancies. The ...role of CD147 in pancreatic cancer, however, remains elusive.
Silencing of CD147 by RNA interference (RNAi) reduced the proliferation rate of MiaPaCa2 and Panc1 cells. CD147 is required for the function and expression of the monocarboxylate transporters MCT1 and MCT4 that are expressed in human PDAC cells as demonstrated by real-time reverse transcription-PCR (RT-PCR) as well as immunohistology. MCT1 and MCT4 are the natural transporters of lactate, and MiaPaCa2 cells exhibited a high rate of lactate production, which is characteristic for the Warburg effect, an early hallmark of cancer that confers a significant growth advantage. Further induction of lactate production by sodium azide in MiaPaCa2 cells increased MCT1 as well as MCT4 expression. CD147 silencing inhibited the expression and function of MCT1 and MCT4 and resulted in an increased intracellular lactate concentration. Addition of exogenous lactate inhibited cancer cell growth in a dose-dependent fashion. In vivo, knock-down of CD147 in MiaPaCa2 cells by inducible short hairpin RNA (shRNA)-mediated CD147 silencing reduced invasiveness through the chorioallantoic membrane of chick embryos (CAM assay) and inhibited tumourigenicity in a xenograft model in nude mice.
The function of CD147 as an ancillary protein that is required to sustain the expression and function of MCT1 and MCT4 is involved in the association of CD147 expression with the malignant potential of pancreatic cancer cells exhibiting the Warburg effect.
In a prospective, randomized trial involving patients with urothelial carcinoma who had undergone radical surgery, adjuvant nivolumab was compared with placebo. The median disease-free survival was ...20.8 months with nivolumab and 10.8 months with placebo. Treatment-related adverse events of grade 3 or higher were noted in 17.9% of patients in the nivolumab group.
Summary Background Patients with metastatic castration-resistant prostate cancer have few treatment options. We investigated the safety and efficacy of lenalidomide, an immunomodulatory agent with ...anti-angiogenic properties, in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic castration-resistant prostate cancer. Methods In this randomised, double-blind, placebo-controlled, phase 3 study, we randomly assigned chemotherapy-naive patients with progressive metastatic castration-resistant prostate cancer in a 1:1 ratio to receive docetaxel (75 mg/m2 ) on day 1 and prednisone (5 mg twice daily) on days 1–21 and either lenalidomide (25 mg) or placebo once daily on days 1–14 of each 21 day treatment cycle. Permuted block randomisation was done with an interactive voice response system and stratified by Eastern Cooperative Oncology Group performance status, geographic region, and type of disease progression. Clinicians, patients, and investigators were masked to treatment allocation. The primary endpoint was overall survival. Efficacy analysis was by intention to treat. Patients who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov , number NCT00988208. Findings 1059 patients were enrolled and randomly assigned between Nov 11, 2009, and Nov 23, 2011 (533 to the lenalidomide group and 526 to the control group), and 1046 patients received study treatment (525 in the lenalidomide group and 521 in the placebo group). At data cutoff (Jan 13, 2012) after a median follow-up of 8 months (IQR 5–12), 221 patients had died: 129 in the lenalidomide group and 92 in the placebo group. Median overall survival was 17·7 months (95% CI 14·8–18·8) in the lenalidomide group and not reached in the placebo group (hazard ratio HR 1·53, 95% CI 1·17–2·00, p=0·0017). The trial was subsequently closed early due to futility. The number of deaths that occurred during treatment or less than 28 days since the last dose were similar in both groups (18 3% of 525 patients in the lenalidomide group vs 13 2% of 521 patients). 109 (21%) patients in the lenalidomide group and 78 (15%) in the placebo group died more than 28 days from last dose, mainly due to disease progression. At least one grade 3 or higher adverse event was reported in 381 (73%) of 525 patients receiving lenalidomide and 303 (58%) of 521 patients receiving placebo. Grade 3–4 neutropenia (114 22% for lenalidomide vs 85 16% for placebo), febrile neutropenia (62 12% vs 23 4%), diarrhoea (37 7% vs 12 2%), pneumonia (24 5% vs five 1%), dyspnoea (22 4% vs nine 2%), asthenia (27 5% vs 17 3%), and pulmonary embolism (32 6% vs seven 1%) occurred more frequently in the lenalidomide group than in the placebo group. Interpretation Overall survival with the combination of lenalidomide, docetaxel, and prednisone was significantly worse than with docetaxel and prednisone for chemotherapy-naive men with metastatic, castration-resistant prostate cancer. Further research with this treatment combination is not warranted. Funding Celgene Corporation.
Surgery is gold-standard for correction of Peyronie's curvature. Grafting is preferred in advanced deviations. We present our novel surgical technique and early results of grafting with collagen ...fleece. Patients with stable Peyronie's disease (PD) were included. Grafting was performed by a ready-to-use collagen fleece coated with tissue sealant (TachoSil, Nycomed, Konstanz, Germany), following partial plaque excision/incision. Results of correction were documented by artificial erection. In all, n=70 consecutive patients underwent surgery. Mean patient age was 56.4 years (range: 33-72); 88.6% of patients had dorsal deviation, 11.4% lateral or ventral deviation. Grafting after partial plaque excision was performed in 61 patients (87.1%), after plaque incision in 2 (2.9%) patients. In the former patients, mean operative time was 94.2 min (range: 65-165). Totally straightness was achieved in 83.6%. Three patients required surgical drainage because of subcutaneous haematoma formation. After mean early follow-up of 5.2 days (range: 2-15), glans sensation was normal in 56 patients (91.8%). Seven patients (10.0%) underwent Nesbit procedure alone. Grafting by collagen fleece in PD is feasible and promising. Major advantages are decreased operative times and easy application. Moreover, an additional haemostatic effect is provided. However, long-term clinical outcomes are necessary to confirm these encouraging findings.
Background
Intratumoural lymphocytic infiltration is strongly associated with the outcome of many human epithelial cancers. The current paper investigated whether subpopulations of ...tumour-infiltrating T lymphocytes are associated with certain clinicopathological parameters and the prognosis of patients with invasive bladder cancer (BCa).
Patients and methods
The infiltration densities of the adaptive immune markers CD3 (the whole T cell population), FOXP3 (regulatory T cells; Tregs), CD8 (T effector cells) and CD45R0 (T effector memory cells) were analysed by immunohistochemistry and image analysis with tissue microarrays of tumour tissues from 149 patients with invasive BCa treated with radical cystectomy. The findings were correlated with certain clinicopathological parameters.
Results
Higher FOXP3/CD3 OS:
p
= 0.016, HR 1.29, 95 % confidence intervals (95 % CIs 1.05–1.59) and FOXP3/CD8 (OS:
p
= 0.013, HR 1.32, 95 % CIs 1.06–1.65) ratios were significantly associated with briefer overall survival and time to cancer-specific death; the latter ratio represented an independent prognostic factor according to a multivariate analysis adjusted for pathological T and N stages (HR 1.32, 95 % CIs 1.05–1.67,
p
= 0.018). The infiltration densities of individual markers (CD3, CD8, FOXP3 and CD45R0) were not significantly associated with clinicopathological parameters or survival; however, a trend towards a better outcome was observed for higher log-transformed CD8 (
p
= 0.070, HR 0.80, 95 % CIs 0.63–1.02) and CD3 (
p
= 0.113, HR 0.84, 95 % CIs 0.68–1.04) infiltration values.
Conclusions
A high fraction of Tregs amongst CD3- and CD8-positive lymphocytes indicated a poor prognosis, thereby emphasising the important role that Tregs play in the suppression of the anti-tumour immune response. No single lymphocytic marker was significantly correlated with clinical outcomes, but high CD3 and CD8 infiltration showed trends towards better prognosis.
Treatment options are limited for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) with disease recurrence after bacillus Calmette–Guérin (BCG) treatment and who are ineligible ...for/refuse radical cystectomy. FGFR alterations are commonly detected in NMIBC. We evaluated the activity of oral erdafitinib, a selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, versus intravesical chemotherapy in patients with high-risk NMIBC and select FGFR3/2 alterations following recurrence after BCG treatment.
Patients aged ≥18 years with recurrent, BCG-treated, papillary-only high-risk NMIBC (high-grade Ta/T1) and select FGFR alterations refusing or ineligible for radical cystectomy were randomized to 6 mg daily oral erdafitinib or investigator’s choice of intravesical chemotherapy (mitomycin C or gemcitabine). The primary endpoint was recurrence-free survival (RFS). The key secondary endpoint was safety.
Study enrollment was discontinued due to slow accrual. Seventy-three patients were randomized 2 : 1 to erdafitinib (n = 49) and chemotherapy (n = 24). Median follow-up for RFS was 13.4 months for both groups. Median RFS was not reached for erdafitinib 95% confidence interval (CI) 16.9 months-not estimable and was 11.6 months (95% CI 6.4-20.1 months) for chemotherapy, with an estimated hazard ratio of 0.28 (95% CI 0.1-0.6; nominal P value = 0.0008). In this population, safety results were generally consistent with known profiles for erdafitinib and chemotherapy.
Erdafitinib prolonged RFS compared with intravesical chemotherapy in patients with papillary-only, high-risk NMIBC harboring FGFR alterations who had disease recurrence after BCG therapy and refused or were ineligible for radical cystectomy.
•Erdafitinib prolonged RFS versus intravesical chemotherapy in papillary-only FGFR-altered BCG-treated high-risk NMIBC.•At median follow-up of 13.4 months, median RFS was not reached for erdafitinib and was 11.6 months for chemotherapy.•The observed RFS benefit for erdafitinib was further reflected by the 6- and 12-month RFS rates and subgroups tested.•In this population, safety results were generally consistent with known profiles for erdafitinib and chemotherapy.•These trial results validate FGFR inhibition as a promising treatment approach for NMIBC.
An understanding of astrophysical feedback is important for constraining models of galaxy formation and for extracting cosmological information from current and future weak lensing surveys. The ...thermal Sunyaev-Zel'dovich effect, quantified via the Compton-y parameter, is a powerful tool for studying feedback, because it directly probes the pressure of the hot, ionized gas residing in dark matter halos. Cross-correlations between galaxies and maps of Compton-y obtained from cosmic microwave background surveys are sensitive to the redshift evolution of the gas pressure, and its dependence on halo mass. In this work, we use galaxies identified in year one data from the Dark Energy Survey and Compton-y maps constructed from Planck observations. We find highly significant (roughly 12σ) detections of galaxy-y cross-correlation in multiple redshift bins. By jointly fitting these measurements as well as measurements of galaxy clustering, we constrain the halo bias-weighted, gas pressure of the Universe as a function of redshift between 0.15≲z≲0.75. We compare these measurements to predictions from hydrodynamical simulations, allowing us to constrain the amount of thermal energy in the halo gas relative to that resulting from gravitational collapse.
Alterations in the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathway are frequent in urothelial bladder cancer (BLCA) and thus provide a potential target ...for novel therapeutic strategies. We investigated the efficacy of the AKT inhibitor MK-2206 in BLCA and the molecular determinants that predict therapy response.
Biochemical and functional effects of the AKT inhibitor MK-2206 were analysed on a panel of 11 BLCA cell lines possessing different genetic alterations. Cell viability (CellTiter-Blue, cell counts), apoptosis (caspase 3/7 activity) and cell cycle progression (EdU incorporation) were analysed to determine effects on cell growth and proliferation. cDNA or siRNA transfections were used to manipulate the expression of specific proteins such as wild-type or mutant PIK3CA, DUSP1 or CREB. For in vivo analysis, the chicken chorioallantoic membrane model was utilised and tumours were characterised by weight and biochemically for the expression of Ki-67 and AKT phosphorylation.
Treatment with MK-2206 suppressed AKT and S6K1 but not 4E-BP1 phosphorylation in all cell lines. Functionally, only cell lines bearing mutations in the hotspot helical domain of PIK3CA were sensitive to the drug, independent of other genetic alterations in the PI3K or MAPK signalling pathway. Following MK-2206 treatment, the presence of mutant PIK3CA resulted in an increase in DUSP1 expression that induced a decrease in ERK 1/2 phosphorylation. Manipulating the expression of mutant or wild-type PIK3CA or DUSP1 confirmed that this mechanism is responsible for the induction of apoptosis and the inhibition of tumour proliferation in vitro and in vivo, to sensitise cells to AKT target therapy.Conclusion or interpretation:PIK3CA mutations confer sensitivity to AKT target therapy in BLCA by regulating DUSP1 expression and subsequent ERK1/2 dephosphorylation and can potentially serve as a stratifying biomarker for treatment.
Zusammenfassung
Immun-Checkpoint-Inhibitoren (ICI) sind als Erst- und Zweitlinientherapien beim metastasierten bzw. lokal fortgeschrittenen Urothelkarzinom als Standard etabliert. Der perioperative ...Einsatz der Immuntherapie steht nun im Fokus aktueller Entwicklungen und Forschung in der Uroonkologie. Aktuelle Studien untersuchen ICI als Monotherapie oder in Kombination mit Chemotherapie oder Bestrahlung im perioperativen Setting. Dieser Artikel soll einen Überblick über die neuen Studienkonzepte, die aktuell publizierten Daten und daraus entstehenden Therapiekonzepte sowie einen Ausblick auf zukünftige Entwicklungen bieten.
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