Asymmetric cyclopropanation of styrenes by
tert-butyl diazoacetate followed by ester hydrolysis and Curtius rearrangement gave a series of tranylcypromine analogues as single enantiomers. The
o,-
m- ...and
p-bromo analogues were all more active than tranylcypromine in a LSD1 enzyme assay. The
m- and
p-bromo analogues were micromolar growth inhibitors of the LNCaP prostate cancer cell line as were the corresponding biphenyl analogues prepared from the bromide by Suzuki crosscoupling.
Cabozantinib is approved for the treatment of renal cell carcinoma (RCC). However, prognostic factors are still lacking in this context. The aim of this study was to evaluate prognostic factors in ...RCC patients treated with second- or third-line cabozantinib. A multicenter retrospective real-world study was conducted, involving 32 worldwide centers. A total of 237 patients with histologically confirmed clear-cell and non-clear-cell RCC who received cabozantinib as second- or third-line therapy for metastatic disease were included. We analyzed overall survival (OS), progression-free survival (PFS) and time-to-strategy failure (TTSF) using Kaplan-Meier curves. Cox proportional models were used at univariate and multivariate analyses.The median PFS and OS of cabozantinib were 7.76 months (95% CI 6.51-10.88) and 11.57 months (95% CI 10.90-not reached (NR)) as second-line and 11.38 months (95% CI 5.79-NR) and NR (95% CI 11.51-NR) as third-line therapy. The median TTSF and OS were 11.57 and 15.52 months with the sequence of cabozantinib-nivolumab and 25.64 months and NR with nivolumab-cabozantinib, respectively. The difference between these two sequences was statistically significant only in good-risk patients. In the second-line setting, hemoglobin (Hb) levels (HR= 2.39; 95% CI 1.24-4.60,
= 0.009) and IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) group (HR = 1.72, 95% CI 1.04-2.87,
= 0.037) were associated with PFS while ECOG-PS (HR = 2.33; 95%CI, 1.16-4.69,
= 0.018) and Hb levels (HR = 3.12; 95%CI 1.18-8.26,
= 0.023) correlated with OS at multivariate analysis, while in the third-line setting, only Hb levels (HR = 2.72; 95%CI 1.04-7.09,
= 0.042) were associated with OS. Results are limited by the retrospective nature of the study.This real-world study provides evidence on the presence of prognostic factors in RCC patients receiving cabozantinib.
Radical cystectomy (RC) and radiochemotherapy (RCT) are curative options for muscle-invasive bladder cancer (MIBC). Optimal treatment strategy remains unclear in elderly patients.
Patients aged 80 ...years old and above with T2-T4aN0-2M0-Mx MIBC were identified in the Retrospective International Study of Cancers of the Urothelial Tract (RISC) database. Patients treated with RC were compared with those treated with RCT. The impact of surgery on overall survival (OS) was assessed using a Cox proportional hazard model. Progression included locoregional and metastatic relapse and was considered a time-dependent variable.
Between 1988 and 2015, 92 patients underwent RC and 72 patients had RCT. Median age was 82.5 years (range 80-100) and median follow-up was 2.90 years (range 0.04-11.10). Median OS was 1.99 years (95%CI 1.17-2.76) after RC and 1.97 years (95%CI 1.35-2.64) after RCT (p = .73). Median progression-free survival (PFS) after RC and RCT were 1.25 years (95%CI 0.80-1.75) and 1.52 years (95%CI 1.01-2.04), respectively (p = .54). In multivariate analyses, only disease progression was significantly associated with worse OS (HR = 10.27 (95%CI 6.63-15.91), p < .0001). Treatment modality was not a prognostic factor.
RCT offers survival rates comparable to those observed with RC for patients aged ≥80 years.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Background
Concomitant medications may potentially affect the outcome of cancer patients. In this sub-analysis of the ARON-2 real-world study (NCT05290038), we aimed to assess the impact of ...concomitant use of proton pump inhibitors (PPI), statins, or metformin on outcome of patients with metastatic urothelial cancer (mUC) receiving second-line pembrolizumab.
Methods
We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate. We carried out a survival analysis by a Cox regression model.
Results
A total of 802 patients were eligible for this retrospective study; the median follow-up time was 15.3 months. PPI users compared to non-users showed inferior PFS (4.5 vs. 7.2 months,
p
= 0.002) and OS (8.7 vs. 14.1 months,
p
< 0.001). Concomitant PPI use remained a significant predictor of PFS and OS after multivariate Cox analysis. The use of statins or metformin was not associated with response or survival.
Conclusions
Our study results suggest a significant prognostic impact of concomitant PPI use in mUC patients receiving pembrolizumab in the real-world context. The mechanism of this interaction warrants further elucidation.
Background
The advent of immune-checkpoint inhibitors has challenged previous treatment paradigms for advanced urothelial carcinoma (UC) in the post-platinum setting as well as in the first-line ...setting for cisplatin-ineligible patients. In this study, we investigated the effectiveness of pembrolizumab as first-line treatment for cisplatin-ineligible UC.
Methods
Data from patients aged ≥ 18 years with cisplatin-ineligible UC and receiving first-line pembrolizumab from January 1st 2017 to September 1st 2022 were collected. Cisplatin ineligibility was defined according to the Galsky criteria. Thirty-three Institutions from 18 countries were involved in the ARON-2 study.
Results
Our analysis included 162 patients. The median follow-up time was 18.9 months (95%CI 15.3–76.9). In the overall study population, the median OS was 15.8 months (95%CI 11.3–32.4). The median OS was significantly longer in males versus females while no statistically significant differences were observed between patients aged < 65y versus ≥ 65y and between smokers and non-smokers. According to Recist 1.1 criteria, 26 patients (16%) experienced CR, 32 (20%) PR, 39 (24%) SD and 55 (34%) PD.
Conclusions
Our data confirm the role of pembrolizumab as first-line therapy for cisplatin-unfit patients. Further studies investigating the biological and immunological characteristics of UC patients are warranted in order to optimize the outcome of patients receiving immunotherapy in this setting.
Lysine‐specific demethylase 1 (LSD1/KDM1A) oxidatively removes methyl groups from histone proteins, and its aberrant activity has been correlated with cancers including acute myeloid leukemia (AML). ...We report a novel series of tranylcypromine analogues with a carboxamide at the 4‐position of the aryl ring. These compounds, such as 5 a and 5 b with benzyl and phenethylamide substituents, respectively, had potent sub‐micromolar IC50 values for the inhibition of LSD1 as well as cell proliferation in a panel of AML cell lines. The dose‐dependent increase in cellular expression levels of H3K4me2, CD86, CD11b and CD14 supported a mechanism involving LSD1 inhibition. The tert‐butyl and ethyl carbamate derivatives of these tranylcypromines, although inactive in LSD1 inhibition, were of similar potency in cell‐based assays with a more rapid onset of action. This suggests that carbamates can act as metabolically labile tranylcypromine prodrugs with superior pharmacokinetics.
Para‐chuting in on cancer: Second‐generation tranylcypromine analogues containing a para‐carboxamide substituent in the phenyl ring potently inhibit the LSD1 demethylase and a panel of AML cell lines. Carbamate derivatives were inactive against the enzyme but retained cellular potency, thus suggesting a prodrug mechanism.
Background
Fit patients with metastatic urothelial carcinoma (mUC) receive first‐line platinum‐based combination chemotherapy (fPBC) as standard of care and may receive additional later‐line ...chemotherapy after progression. Our study compares outcomes with subsequent platinum‐based chemotherapy (sPBC) versus subsequent non‐platinum‐based chemotherapy (sNPBC).
Materials and Methods
Patients from 27 international centers in the Retrospective International Study of Cancers of the Urothelium (RISC) who received fPBC for mUC and at least two cycles of subsequent chemotherapy were included in this study. A multivariable Cox proportional hazards model compared overall survival (OS) and progression‐free survival (PFS).
Results
One hundred thirty‐five patients received sPBC and 161 received sNPBC. Baseline characteristics were similar between groups, except patients who received sPBC had higher baseline hemoglobin, higher disease control rate with fPBC, and longer time since fPBC. OS was superior in the sPBC group (median 7.9 vs 5.5 months) in a model adjusting for comorbidity burden, performance status, liver metastases, number of fPBC cycles received, best response to fPBC, and time since fPBC (hazard ratio, 0.72; 95% confidence interval, 0.53–0.98; p = .035). There was no difference in PFS. More patients in the sPBC group achieved disease control than in the sNPBC group (57.4% vs 44.8%; p = .041). Factors associated with achieving disease control in the sPBC group but not the sNPBC group included longer time since fPBC, achieving disease control with fPBC, and absence of liver metastases.
Conclusion
After receiving fPBC for mUC, patients who received sPBC had better OS and disease control. This may help inform the choice of subsequent chemotherapy in patients with mUC.
Implications for Practice
Patients with progressive metastatic urothelial carcinoma after first‐line platinum‐based combination chemotherapy may now receive immuno‐oncology agents, erdafitinib, enfortumab vedotin, or sacituzumab govitecan‐hziy; however, those ineligible for these later‐line therapies or who progress after receiving them may be considered for subsequent chemotherapy. In this retrospective study of 296 patients, survival outcomes and disease control rates were better in those receiving subsequent platinum‐based rechallenge compared with non–platinum‐based chemotherapy, suggesting that patients should receive platinum rechallenge if clinically able. Disease control with platinum rechallenge was more likely with prior first‐line platinum having achieved disease control, longer time since first‐line platinum, and absence of liver metastases.
This article examines differences in outcomes for patients treated with platinum‐based combination chemotherapy for metastatic urothelial carcinoma who later received subsequent platinum‐based chemotherapy or subsequent non‐platinum‐based chemotherapy. Clinical factors associated with better outcomes are reported.
Cisplatin is one of the most ototoxic chemotherapy drugs, resulting in a permanent and irreversible hearing loss in up to 50% of patients. Cisplatin and gentamicin are thought to damage hearing ...through a common mechanism, involving reactive oxygen species in the inner ear. Aspirin has been shown to minimise gentamicin-induced ototoxicity. We, therefore, tested the hypothesis that aspirin could also reduce ototoxicity from cisplatin-based chemotherapy.
A total of 94 patients receiving cisplatin-based chemotherapy for multiple cancer types were recruited into a phase II, double-blind, placebo-controlled trial and randomised in a ratio of 1:1 to receive aspirin 975 mg tid and omeprazole 20 mg od, or matched placebos from the day before, to 2 days after, their cisplatin dose(s), for each treatment cycle. Patients underwent pure tone audiometry before and at 7 and 90 days after their final cisplatin dose. The primary end-point was combined hearing loss (cHL), the summed hearing loss at 6 kHz and 8 kHz, in both ears.
Although aspirin was well tolerated, it did not protect hearing in patients receiving cisplatin (p-value = 0.233, 20% one-sided level of significance). In the aspirin arm, patients demonstrated mean cHL of 49 dB (standard deviation SD 61.41) following cisplatin compared with placebo patients who demonstrated mean cHL of 36 dB (SD 50.85). Women had greater average hearing loss than men, and patients treated for head and neck malignancy experienced the greatest cHL.
Aspirin did not protect from cisplatin-related ototoxicity. Cisplatin and gentamicin may therefore have distinct ototoxic mechanisms, or cisplatin-induced ototoxicity may be refractory to the aspirin regimen used here.
•Aspirin was well tolerated.•Aspirin did not protect hearing at the doses and in the schedule investigated here.•Cisplatin and gentamicin may have distinct ototoxic mechanisms.•Qualitative data suggest protective aspirin effect but low power for hypothesis.•Cisplatin-induced ototoxicity results in significant morbidity.
Background
Immune checkpoint inhibitors have changed previous treatment paradigm of advanced urothelial carcinoma (UC). The ARON-2 study (NCT05290038) aimed to assess the real-world effectiveness of ...pembrolizumab in patients recurred or progressed after platinum-based chemotherapy.
Patients and Methods
Medical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were retrospectively collected from 88 institutions in 23 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Cox proportional hazards models were adopted to explore the presence of prognostic factors.
Results
In total, 836 patients were included: 544 patients (65%) received pembrolizumab after progression to first-line platinum-based chemotherapy in the metastatic setting (cohort A) and 292 (35%) after recurring within < 12 months since the completion of adjuvant or neoadjuvant chemotherapy (cohort B). The median follow-up time was 15.3 months. The median OS and the ORR were 10.5 months and 31% in the overall study population, 9.1 months and 29% in cohort A and 14.6 months and 37% in cohort B. At multivariate analysis, ECOG-PS ≥ 2, bone metastases, liver metastases and pembrolizumab setting (cohort A vs B) proved to be significantly associated with worst OS and PFS. Stratified by the presence of 0, 1–2 or 3–4 prognostic factors, the median OS was 29.4, 12.5 and 4.1 months (
p
< 0.001), while the median PFS was 12.2, 6.4 and 2.8 months, respectively (
p
< 0.001).
Conclusions
Our study confirms that pembrolizumab is effective in the advanced UC real-world context, showing outcome differences between patients recurred or progressed after platinum-based chemotherapy.
Abstract Background Although cisplatin-based neoadjuvant chemotherapy (NAC) improves survival of unselected patients with muscle-invasive bladder cancer (MIBC), only a minority responds to therapy ...and chemoresistance remains a major challenge in this disease setting. Objective To investigate the clinical significance of oncofetal chondroitin sulfate (ofCS) glycosaminoglycan chains in cisplatin-resistant MIBC and to evaluate these as targets for second-line therapy. Design, setting, and participants An ofCS-binding recombinant VAR2CSA protein derived from the malaria parasite Plasmodium falciparum (rVAR2) was used as an in situ, in vitro, and in vivo ofCS-targeting reagent in cisplatin-resistant MIBC. The ofCS expression landscape was analyzed in two independent cohorts of matched pre- and post-NAC–treated MIBC patients. Intervention An rVAR2 protein armed with cytotoxic hemiasterlin compounds (rVAR2 drug conjugate VDC 886) was evaluated as a novel therapeutic strategy in a xenograft model of cisplatin-resistant MIBC. Outcome measurements and statistical analysis Antineoplastic effects of targeting ofCS. Results and limitations In situ, ofCS was significantly overexpressed in residual tumors after NAC in two independent patient cohorts ( p < 0.02). Global gene-expression profiling and biochemical analysis of primary tumors and cell lines revealed syndican-1 and chondroitin sulfate proteoglycan 4 as ofCS-modified proteoglycans in MIBC. In vitro, ofCS was expressed on all MIBC cell lines tested, and VDC886 eliminated these cells in the low-nanomolar IC50 concentration range. In vivo, VDC886 effectively retarded growth of chemoresistant orthotopic bladder cancer xenografts and prolonged survival ( p = 0.005). The use of cisplatin only for the generation of chemoresistant xenografts are limitations of our animal model design. Conclusions Targeting ofCS provides a promising second-line treatment strategy in cisplatin-resistant MIBC. Patient summary Cisplatin-resistant bladder cancer overexpresses particular sugar chains compared with chemotherapy-naïve bladder cancer. Using a recombinant protein from the malaria parasite Plasmodium falciparum , we can target these sugar chains, and our results showed a significant antitumor effect in cisplatin-resistant bladder cancer. This novel treatment paradigm provides therapeutic access to bladder cancers not responding to cisplatin.
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