Renal cell carcinoma (RCC) is composed of several histopathological entities. There are more than 1,000 new cases in Switzerland every year, one third of which are diagnosed at an advanced stage. The development of chemotherapy had no impact on its overall prognosis. Since the mid-2000s, treatment of metastatic RCC was transformed by the arrival of targeted therapies. In the early 90s, high dose interleukine-2 (IL-2) allowed first cases of complete response, demonstrating the immunogenicity of RCC. More than twenty years after its first steps, immunotherapy progressed due to the recently approved nivolumab (an anti-PD1 monoclonal antibody) in second line of treatment. This review outlines the progress that has been made in the understanding and treatment of this pathology.
LBA5000 Background: PEACE-1 demonstrated that combining ADT and docetaxel with abiraterone acetate plus prednisone (AAP) improves both overall survival (OS) and radiographic progression-free-survival (rPFS) in men with de novo mCSPC. The present analysis examines the second pre-planned primary endpoint of PEACE-1 in the low-volume population: the impact of prostate irradiation (RT) in men receiving intensified systemic treatment. Methods: PEACE-1 is an academic, multicentre, international, 2x2 design, phase 3 trial. The co-primary endpoints for each question were rPFS and OS. The standard of care (SOC) was ADT alone or ADT plus docetaxel (Doce) at investigator’s discretion until 2017, then accrual was restricted to men receiving ADT+Doce. RT (74 Gy/37 fractions) was delivered after Doce completion when applicable. SOC included continuous ADT, with or without Doce at 75 mg/m² every 3 weeks for 6 cycles. AAP, 1000 mg/day with prednisone 10 mg/day was given to men randomized to the AAP arms until disease progression or intolerance. The overall type I error testing the RT effect was 5% (4.9% for OS, 0.1% for rPFS). In the low-volume population, 299 and 213 events were required to detect an HR of 0.62 for rPFS and 0.68 for OS with 80% power, respectively. Results: Between 11/2013 and 12/2018, 1172 men were randomized to receive either SOC (+/- AAP) plus RT (n=584) or SOC (+/- AAP) without RT (n=588). 505 patients had low-volume disease (0-3 bone metastases +/- lymph nodes), 252 in the RT arms, 253 in the non-RT arms. Baseline characteristics were similar across arms. With a median follow-up of 6.1 years, 303 rPFS and 214 OS events were recorded for the low-volume population. A qualitative interaction between RT and AAP was observed for rPFS (p=0.026) and therefore, each experimental arm was assessed individually. RT did not improve rPFS with a median of 3 years (99.9%CI 2.3-4.8) for SOC vs 2.6 (1.7-4.6) for SOC+RT; HR=1.12 (0.68-1.85). When compared individually to SOC, rPFS was improved by SOC+AAP+RT (median 7.5 years (99.9%CI: 4.0-NR); HR=0.49, [0.28-0.87], p<0.0001) and borderline improved by SOC+AAP (median 4.4 years (95% CI: 2.5-7.6); HR=0.74, [0.44-1.26], p=0.066). The HR between AAP arms was 0.66 [0.36-1.19]. For OS the predefined threshold for a statistical interaction was not reached (p=0.11). OS was not improved by RT: median OS was 6.9 years (95.1%CI: 5.9-7.5) without RT vs 7.5 (6.0-NR) with RT (HR=0.97 [0.74-1.27], p=0.81). Median OS was 7.1 years in the SOC arm and not yet reached in the SOC+AAP+RT arm. Data on the RT prevention effect on severe urinary symptoms are pending. Conclusions: Combining prostate RT to systemic treatment did not improve OS in men with de novo mCSPC and low metastatic burden. However, best outcomes (rPFS and OS) were observed in men receiving SOC+AAP+RT. The impact of RT on severe urinary symptom prevention will be presented. Clinical trial information: NCT01957436 .
Four proteins have been identified recently as diiron carboxylate proteins on the basis of conservation of six amino acids (four carboxylate residues and two histidines) constituting an iron-binding motif. Unlike previously identified proteins with this motif, biochemical studies indicate that each of these proteins is membrane bound, although homology modeling rules out a transmembrane mode of binding. Therefore, the predicted structure of each protein [the alternative oxidase (AOX), the plastid terminal oxidase (PTOX), the diiron 5-demethoxyquinone hydroxylase (DMQ hydroxylase), and the aerobic Mg-protoporphyrin IX monomethylester hydroxylase (MME hydroxylase)] is that of a protein bound monotopically to one leaflet of the membrane bilayer. Three of these enzymes utilize a quinol substrate, with two oxidizing the quinol (AOX and PTOX) and one hydroxylating it (DMQ hydroxylase). MME hydroxylase is involved in synthesis of the isocyclic ring of chlorophyll. Two enzymes are involved in respiration (AOX and, indirectly, the diiron DMQ hydroxylase through ubiquinone biosynthesis) and two in photosynthesis, through their roles in carotenoid and chlorophyll biosynthesis (PTOX and MME hydroxylase, respectively). We discuss what is known about each enzyme as well as our expectations based on their identification as interfacially bound proteins with a diiron carboxylate active site.
Leydig cell tumours (LCTs) of the testis are rare. Their origin is still unknown. This case report describes a potential relationship between LCT and prolonged exposure to Finasteride.
Objectives: We investigated spatial patterns between primary and recurrent tumor sites and assessed long-term toxicity after dose escalation stereotactic body radiation therapy (SBRT) to the dominant intra-prostatic nodule (DIN). Materials and methods: In 33 patients with intermediate–high-risk prostate cancer (PCa), doses up to 50 Gy were administered to the DIN. Recurrence sites were determined and compared to the original tumor development sites through multiparametric MRI and 68Ga-labeled prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (68Ga-PSMA-PET/CT) images. Overlap rates, categorized as 75% or higher for full overlap, and 25–74% for partial overlap, were assessed. Long-term toxicity is reported. Results: All patients completed treatment, with only one receiving concomitant androgen deprivation therapy (ADT). Recurrences were diagnosed after a median of 33 months (range: 17–76 months), affecting 13 out of 33 patients (39.4%). Intra-prostatic recurrences occurred in 7 patients (21%), with ≥75% overlap in two, a partial overlap in another two, and no overlap in the remaining three patients. Notably, five patients with intra-prostatic recurrences had synchronous bone and/or lymph node metastases, while six patients had isolated bone or lymph node metastasis without intra-prostatic recurrences. Extended follow-up revealed late grade ≥ 2 GU and GI toxicity in 18% (n = 6) and 6% (n = 2) of the patients. Conclusions: Among patients with intermediate–high-risk PCa undergoing focal dose-escalated SBRT without ADT, DIN recurrences were infrequent. When present, these recurrences were typically located at the original site or adjacent to the initial tumor. Conversely, relapses beyond the DIN and in extra-prostatic (metastatic) sites were prevalent, underscoring the significance of systemic ADT in managing this patient population. Advances in knowledge: Focal dose-escalated prostate SBRT prevented recurrences in the dominant nodule; however, extra-prostatic recurrence sites were frequent.
Ubiquinone (Coenzyme Q) plays an important role in the mitochondrial respiratory chain and also acts as an antioxidant in its reduced form, protecting cellular membranes from peroxidation. De novo disulfide bond generation in the E. coli periplasm involves a transient complex consisting of DsbA, DsbB, and ubiquinone (UQ). It is hypothesized that a charge-transfer complex intermediate is formed between the UQ ring and the DsbB-C44 thiolate during the reoxidation of DsbA, which gives a distinctive ∼500 nm absorbance band. No enzymological precedent exists for an UQ-protein thiolate charge-transfer complex, and definitive evidence of this unique reaction pathway for DsbB has not been fully demonstrated. In order to study the UQ-8-DsbB complex in the presence of native lipids, we have prepared isotopically labeled samples of precipitated DsbB (WT and C41S) with endogenous UQ-8 and lipids, and we have applied advanced multidimensional solid-state NMR methods. Double-quantum filter and dipolar dephasing experiments facilitated assignments of UQ isoprenoid chain resonances not previously observed and headgroup sites important for the characterization of the UQ redox states: methyls (∼20 ppm), methoxys (∼60 ppm), olefin carbons (120−140 ppm), and carbonyls (150−160 ppm). Upon increasing the DsbB(C41S) pH from 5.5 to 8.0, we observed a 10.8 ppm upfield shift for the UQ C1 and C4 carbonyls indicating an increase of electron density on the carbonyls. This observation is consistent with the deprotonation of the DsbB-C44 thiolate at pH 8.0 and provides direct evidence of the charge-transfer complex formation. A similar trend was noted for the UQ chemical shifts of the DsbA(C33S)-DsbB(WT) heterodimer, confirming that the charge-transfer complex is unperturbed by the DsbB(C41S) mutant used to mimic the intermediate state of the disulfide bond generating reaction pathway.
The current standard treatment for early stage (I-III) renal cell cancer (RCC) is surgery. While the prognosis of stage I tumors is excellent, stage II and particularly stage III have a high risk of relapse. The adjuvant treatment of patients with RCC remains an area of investigation, with patient selection being a key aspect. There are currently two prognostic nomograms to establish the risk of relapse in patients with resected RCC. The results of earlier studies of adjuvant therapy, including the use chemotherapy and/or immunotherapy after nephrectomy have failed to show any benefit in the outcome of patients at risk of developing local recurrence or distant metastases. Two recent phase III trials with vaccines (autologous tumor cell vaccine and autologous tumor-derived heat shock protein peptide complex-96) have shown promising, albeit still preliminary, results. In the metastatic RCC setting, recent advances in the molecular understanding of oncogenic pathways have led to the development of new therapeutic strategies with the use of targeted therapies in the adjuvant setting. Neoadjuvant treatment is another treatment modality currently being evaluated for patients with early disease and in patients with metastatic RCC with inoperable primary tumors. The questions that remain unanswered include activity of these agents in early stages of the disease, patient selection, optimal start time of the adjuvant treatment, and finally, the optimal length of treatment.
The University Hospital of Lausanne has heavily invested in the development of interdisciplinary oncology centers to improve the quality of care, and structure research and training. By integrating specialist nurses, it follows international recommendations. These specialists' nurses rephrase the information given by the doctor and ensure patients' understanding. They assess the patient's psychosocial situation and provides guidance if necessary. They support the patient in making informed choices about treatment and coping strategies. In addition to the outpatient clinics planned in accordance with the care pathway, she can be contacted between appointments to answer questions or concerns of any kind. This article shows the added value of these nurses in the care of oncology patients.
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