Im vorliegenden Text erfolgt zunächst eine Diskussion der Bedingungen einer psychoanalytischen Kulturforschung. Dabei wird berührt, wie ein Transfer der Methode auf außerklinische Felder erfolgen ...kann und in welcher Weise Theorie dabei ins Spiel kommt. In Auseinandersetzung mit Freuds Der Untergang des Ödipuskomplexes werden drei Elemente hervorgehoben: der Umgang mit der sexuellen Differenz, die Nachträglichkeit in der Kastrationsdrohung und das „Unentdeckte“ des weiblichen Genitals. Dies wird dazu genutzt, für den Umgang mit Untergangsvorstellungen die Bedeutung eines Anerkennens des Ungewussten zu unterstreichen. In einem „Ödipuskomplex des Untergangs“ ist entscheidend, wie mit Differenz und Negativität umgegangen werden kann.
Guiding the beta-emitting isotope lutetium-177 to prostate cancer lesions with the prostate-specific membrane antigen–targeted radioligand
177
Lu-PSMA-617 plus using standard care was compared with ...standard care in patients with metastatic castration-resistant prostate cancer. The radioligand therapy prolonged progression-free and overall survival. Adverse effects were more common, but quality of life was maintained.
Up to 30% of patients with metastatic castration-resistant prostate cancer have deleterious mutations in genes involved in homologous recombination repair of DNA damage. The use of the PARP inhibitor ...olaparib in such patients was associated with longer progression-free survival and a longer time to pain progression than control therapy.
We discovered that rare tumor cells in primary prostate cancer possess genomic features of castration-resistant prostate cancer. This represents a novel resistance mechanism distinct from the widely ...held notion that prostate cancer becomes resistant to hormonal therapy through a therapy-induced adaptation mechanism.
Hormonal therapy targeting the androgen receptor inhibits prostate cancer (PCa), but the tumor eventually recurs as castration-resistant prostate cancer (CRPC).
To understand the mechanisms by which subclones within early PCa develop into CRPC.
We isolated epithelial cells from fresh human PCa cases, including primary adenocarcinoma, locally recurrent CRPC, and metastatic CRPC, and utilized single-cell RNA sequencing to identify subpopulations destined to become either CRPC-adeno or small cell neuroendocrine carcinoma (SCNC).
We revealed dynamic transcriptional reprogramming that promotes disease progression among 23226 epithelial cells using single-cell RNA sequencing, and validated subset-specific progression using immunohistochemistry and large cohorts of publically available genomic data.
We identified a small fraction of highly plastic CRPC-like cells in hormone-naïve early PCa and demonstrated its correlation with biochemical recurrence and distant metastasis, independent of clinical characteristics. We show that progression toward castration resistance was initiated from subtype-specific lineage plasticity and clonal expansion of pre-existing neuroendocrine and CRPC-like cells in early PCa.
CRPC-like cells are present early in the development of PCa and are not exclusively the result of acquired evolutionary selection during androgen deprivation therapy. The lethal CRPC and SCNC phenotypes should be targeted earlier in the disease course of patients with PCa.
Here, we report the presence of pre-existing castration-resistant prostate cancer (CRPC)-like cells in primary prostate cancer, which represents a novel castration-resistant mechanism different from the adaptation mechanism after androgen deprivation therapy (ADT). Patients whose tumors harbor increased pre-existing neuroendocrine and CRPC-like cells may become rapidly resistant to ADT and may require aggressive early intervention.
The PROfound trial showed that olaparib prolonged imaging-based progression-free survival among patients whose tumors contained defects in the homologous recombination repair genes
BRCA1
,
BRCA2
, or
...ATM
. With longer follow-up, the trial now shows that olaparib prolonged overall survival in these patients. Toxic effects included anemia, nausea, and asthenia.
Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) have rising prostate-specific antigen (PSA) and castrate testosterone levels, with no radiological findings of metastatic ...disease on computed tomography and bone scan. Given recent drug approvals for nmCRPC, with many other therapeutics and imaging modalities being developed, management of nmCRPC is a rapidly evolving field that merits detailed investigation.
To review current nmCRPC management practices and identify opportunities for improving care of nmCRPC patients.
A literature search up to July 2018 was conducted, including clinical trials and clinical practice guidelines (National Comprehensive Cancer Network, European Society for Medical Oncology, European Association of Urology, Prostate Cancer Clinical Trials Working Group, Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence). Keywords included prostate cancer, nonmetastatic, castration resistance, rising PSA, and biochemical relapse.
Recommendations regarding indications for, and frequency of, imaging and PSA testing, as well as for initiating systemic therapy in nmCRPC are based on PSA rise kinetics and symptoms. Both enzalutamide and apalutamide have been shown to significantly increase metastasis-free survival in phase III placebo-controlled randomised trials in nmCRPC patients with PSA doubling time (DT) ≤10 mo. The expected impact of new imaging techniques in the assessment of nmCRPC is also reviewed.
nmCRPC is a heterogeneous disease; while observation may be an option for some patients, enzalutamide and apalutamide may be appropriate to treat nmCRPC patients with PSA-DT ≤10 mo. The emergence of more accurate imaging modalities as well as circulating tumour biomarker assays will likely redefine the assessment of nmCRPC in the near future.
Herein, we review key literature and clinical practice guidelines to summarise the optimal management of patients with prostate cancer and rising prostate-specific antigen despite castrate testosterone levels, but with no evidence of distant metastasis on traditional imaging. New drugs are being developed for this disease setting; novel imaging and tumour biomarker blood tests are likely to define this disease state more accurately.
Nonmetastatic castration-resistant prostate cancer is a heterogeneous clinical state defined by rising prostate-specific antigen on androgen deprivation therapy but without imaging evidence of metastatic disease. New systemic therapies prolong time to metastatic disease. More sensitive imaging modalities will likely redefine this state in the near future.
Treatment of Advanced Prostate Cancer Teo, Min Yuen; Rathkopf, Dana E; Kantoff, Philip
Annual review of medicine,
01/2019, Letnik:
70, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The therapeutic landscape of prostate cancer has been transformed over the last decade by new therapeutics, advanced functional imaging, next-generation sequencing, and better use of existing ...therapies in early-stage disease. Until 2004, progression on androgen deprivation therapy for metastatic disease was treated with the addition of secondary hormonal manipulation; in the last decade, six systemic agents have been approved for the treatment of castration-resistant prostate cancer. We review clinical trials and survival benefit for these therapies and assess how the understanding of the disease shifted as these therapies were developed. We also discuss advances in noncastrate disease states, identification of biomarkers for prognosis and treatment selection, and opportunities in locoregional therapy to delay androgen deprivation therapy.
Progressive metastatic castration-resistant prostate cancer is a highly lethal disorder and new effective therapeutic agents that improve patient outcomes are urgently needed. Lutetium-177 ...177Lu-PSMA-617, a radiolabelled small molecule, binds with high affinity to prostate-specific membrane antigen (PSMA) enabling beta particle therapy targeted to metastatic castration-resistant prostate cancer. We aimed to investigate the safety, efficacy, and effect on quality of life of 177Lu-PSMA-617 in men with metastatic castration-resistant prostate cancer who progressed after standard treatments.
In this single-arm, single-centre, phase 2 trial, we recruited men (aged 18 years and older) with metastatic castration-resistant prostate cancer and progressive disease after standard treatments, including taxane-based chemotherapy and second-generation anti-androgens, from the Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Patients underwent a screening PSMA and FDG-PET/CT to confirm high PSMA-expression. Eligible patients had progressive disease defined by imaging (according to Response Evaluation Criteria In Solid Tumours RECIST or bone scan) or new pain in an area of radiographically evident disease, and were required to have an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or lower. Eligible patients received up to four cycles of intravenous 177Lu-PSMA-617, at six weekly intervals. The primary endpoint was PSA response according to Prostate Cancer Clinical Trial Working Group criteria defined as a greater than 50% PSA decline from baseline and toxicity according to CTCAE. Additional primary endpoints were imaging responses (as measured by bone scan, CT, PSMA, and FDG PET/CT) and quality of life (assessed with the EORTC-Q30 and Brief Pain Inventory-Short Form questionnaires), all measured up to 3 months post completion of treatment. This trial is registered with the Australian New Zealand Clinical Trials Registry, number 12615000912583.
Between Aug 26, 2015, and Dec 8, 2016, 43 men were screened to identify 30 patients eligible for treatment. 26 (87%) had received at least one line of previous chemotherapy (80% docetaxel and 47% cabazitaxel) and 25 (83%) received prior abiraterone acetate, enzalutamide, or both. The mean administered radioactivity was 7·5 GBq per cycle. 17 (57%) of 30 patients (95% CI 37–75) achieved a PSA decline of 50% or more. There were no treatment-related deaths. The most common toxic effects related to 177Lu-PSMA-617 were grade 1 dry mouth recorded in 26 (87%) patients, grade 1 and 2 transient nausea in 15 (50%), and G1–2 fatigue in 15 (50%). Grade 3 or 4 thrombocytopenia possibly attributed to 177Lu-PSMA-617 occurred in four (13%) patients. Objective response in nodal or visceral disease was reported in 14 (82%) of 17 patients with measurable disease. Clinically meaningful improvements in pain severity and interference scores were recorded at all timepoints. 11 (37%) patients experienced a ten point or more improvement in global health score by the second cycle of treatment.
Our findings show that radionuclide treatment with 177Lu-PSMA-617 has high response rates, low toxic effects, and reduction of pain in men with metastatic castration-resistant prostate cancer who have progressed after conventional treatments. This evidence supports the need for randomised controlled trials to further assess efficacy compared with current standards of care.
None.
In a trial, the median metastasis-free survival among men with nonmetastatic, castration-resistant prostate cancer and a short PSA doubling time was 36.6 months with enzalutamide and 14.7 months with ...placebo. Falls and heart problems were more common with enzalutamide.
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