A phase II study (AARDVARC) of AZD4635 in combination with durvalumab and cabazitaxel in patients with progressive, metastatic, castration-resistant prostate cancer.

BACKGROUND: This phase II nonrandomized study evaluated the efficacy and safety of AZD4635 in combination with durvalumab (Arm A) or durvalumab plus cabazitaxel (Arm B) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel and ≥1 novel hormonal agent. PATIENTS AND METHODS: The primary endpoint was radiographic progression-free survival (rPFS) per RECIST v1.1 (soft tissue) or the Prostate Cancer Clinical Trials Working Group 3 (bone). Secondary endpoints included safety, tolerability, overall survival, confirmed prostate-specific antigen (PSA50) response, pharmacokinetics, and objective response rate. Enrollment in Arm A was stopped following a sponsor decision unrelated to safety. The study was stopped based on the planned futility analysis due to low PSA50 response in Arm B. RESULTS: In the final analysis (1 November 2021), 30 patients were treated (Arm A, n = 2; Arm B, n = 28). The median rPFS in Arm B was 5.8 months (95% confidence interval 4.2-not calculable). Median rPFS was 5.8 months versus 4.2 months for patients with high versus low blood-based adenosine signature. The most common treatment-related adverse events in Arm B were nausea (50.0%), diarrhea (46.4%), anemia and neutropenia (both 35.7%), asthenia (32.1%), and vomiting (28.6%). Overall, AZD4635 in combination with durvalumab or AZD4635 in combination with cabazitaxel and durvalumab showed limited efficacy in patients with mCRPC. CONCLUSIONS: Although the safety profile of both combinations was consistent with known safety data of the individual agents, the results of this trial do not support further development of the combinations.

Overall survival from tebentafusp versus nivolumab plus ipilimumab in first-line metastatic uveal melanoma: a propensity score-weighted analysis.

BACKGROUND: Tebentafusp demonstrated a superior overall survival (OS) benefit [hazard ratio (HR) 0.51] compared to investigator's choice (82% pembrolizumab) in a randomized, phase III trial (IMCgp100-202; N = 378) in untreated metastatic uveal melanoma (mUM). The 1-year OS rates for tebentafusp and pembrolizumab were 73% and 59%, respectively. In the single-arm GEM1402 (N = 52), the 1-year OS rate for nivolumab plus ipilimumab (N+I) in mUM was 52%. Due to limitations in conducting randomized trials in mUM, we compared OS on tebentafusp or pembrolizumab (IMCgp100-202) to N+I (GEM1402) in untreated mUM using propensity scoring methods. PATIENTS AND METHODS: Analyses were adjusted using propensity score-based inverse probability of treatment weighting (IPTW), balancing age, sex, baseline lactate dehydrogenase (LDH), baseline alkaline phosphatase, disease location, Eastern Cooperative Oncology Group status, and time from primary diagnosis to metastasis. OS was assessed using IPT-weighted Kaplan-Meier and Cox proportional hazard models. Sensitivity analyses using alternative missing data and weights methods were conducted. RESULTS: The primary IPTW analysis included 240 of 252 patients randomized to tebentafusp from IMCgp100-202 and 45 of 52 N+I-treated patients from GEM-1402. Key baseline covariates, including LDH, were generally well balanced before weighting. The IPTW-adjusted OS favored tebentafusp, HR 0.52 [95% confidence interval (CI) 0.35-0.78]; 1-year OS was 73% for tebentafusp versus 50% for N+I. Sensitivity analyses showed consistent superior OS for tebentafusp with all IPTW HRs ≤0.61. IPTW analysis of pembrolizumab versus N+I showed no significant difference in OS (HR 0.72; 95% CI 0.50-1.06). CONCLUSIONS: Tebentafusp was previously shown to provide an OS benefit compared to checkpoint inhibitors or chemotherapy in untreated mUM. Propensity score analysis demonstrated a similar OS benefit for tebentafusp compared with N+I. These data further support tebentafusp as the standard of care in previously untreated human leukocyte antigen (HLA)-A∗02:01+ adult patients with mUM.

Chemotherapy and PARP inhibitors in heavily pretreated BRCA1/2 mutation ovarian cancer (BMOC) patients.

OBJECTIVES: The hallmarks of germline(g) and/or somatic(s) BRCA1/2 mutation ovarian cancer (BMOC) patients are increased sensitivity to platinum-based chemotherapy (PCT) and PARP inhibitors (PARPi). There is little information on the effectiveness of chemotherapy in heavily pretreated (≥3 CT lines) g/sBMOC patients. METHODS: g/sBMOC patients who received CT from 2006 to 2016 at 4 cancer centers in Spain were selected. Overall survival (OS) and time to progression (TTP) were calculated with Kaplan Meier and Cox models. RESULTS: 135 g/sBMOC patients were identified (6% sBRCA1/2 mutations). The median number of chemotherapy lines was 2 (1-7). The 6-years OS rate was 69.4% and 71% in BRCA1 or BRCA2 mutation carriers (p = 0.98). A total of 57 (42%) patients had ≥3 CT lines (3-7), which encompassed a total of 155 treatments. The median overall TTP across all treatment lines beyond 2nd line was 10.2 months (CI 95% 8.4-11.9 months). In the platinum-sensitive setting, TTP was improved with PCT plus PARPi (17.1 m), PCT (12.6 m) or PARPi (12.4 m) versus non-PCT (4.9 m; p < 0.001 all comparisons). In the platinum-resistant setting, these differences in TTP were not statistically significant. A multivariate model confirmed that primary platinum-free interval (PFI) > 12 months and exposure to PCT and PARPi associated with improved outcomes. PARPi exposure did not compromise benefit of subsequent CT beyond 2nd relapse. CONCLUSIONS: Heavily pretreated g/sBMOC demonstrated CT sensitivity, including for non-PCT choices. Primary platinum-free interval (PFI) >12 months and exposure to both platinum-based chemotherapy and PARPi associate with improved prognosis in heavily pretreated g/sBMOC patients.

Evaluation of oncogenic cysteinyl leukotriene receptor 2 as a therapeutic target for uveal melanoma.

Uveal melanoma is a rare, but deadly, form of eye cancer that arises from melanocytes within the uveal tract. Although advances have emerged in treatment of the primary tumour, patients are still faced with vision loss, eye enucleation and lethal metastatic spread of the disease. Approximately 50% of uveal melanoma patients develop metastases, which occur most frequently in the liver. Metastatic patients encounter an extremely poor prognosis; as few as 8% survive beyond 2 years. Understanding of the genetic underpinnings of this fatal disease evolved in recent years with the identification of new oncogenic mutations that drive uveal melanoma pathogenesis. Despite this progress, the lack of successful therapies or a proven standard-of-care for uveal melanoma highlights the need for new targeted therapies. This review focuses on the recently identified CYSLTR2 oncogenic mutation in uveal melanoma. Here, we evaluate the current status of uveal melanoma and investigate how to better understand the role of this CYSLTR2 mutation in the disease and implications for patients harbouring this mutation.

Correction to: SEOM clinical guidelines for the treatment of metastatic prostate cancer (2017).

The original article shows two mistakes, which are listed here.

SEOM clinical guidelines for the treatment of metastatic prostate cancer (2017).

Androgen deprivation treatment was the only treatment available for metastatic prostate cancer until recently, with docetaxel as the only treatment with a proven survival benefit in castration-resistant prostate cancer (CRPC). Several drugs have been approved in the castration-resistant disease (sipuleucel-T, cabazitaxel, abiraterone, enzalutamide, radium-223). More recently, docetaxel and abiraterone have been moved to the hormone-sensitive disease setting, achieving better patient survival. The purpose of this article is to define the state of the art in the treatment of prostate carcinoma.

Pembrolizumab for advanced melanoma: experience from the Spanish Expanded Access Program.

BACKGROUND: The programmed death (PD-1) inhibitor pembrolizumab has been recently approved for the treatment of advanced melanoma. We evaluated the clinical activity of pembrolizumab in melanoma patients treated under the Spanish Expanded Access Program. METHODS: Advanced melanoma patients who failed to previous treatment lines were treated with pembrolizumab 2 mg/kg every three weeks. Patients with brain metastases were not excluded if they were asymptomatic. Data were retrospectively collected from 21 centers in the Spanish Melanoma Group. RESULTS: Sixty-seven advanced melanoma patients were analyzed. Most patients were stage M1c (73.1%), had high LDH levels (55.2%) and had ECOG PS 1 or higher (59.7%). For cutaneous melanoma patients, median overall survival was 14.0 months; the 18-month overall survival rate was 47.1%. Overall response rate was 27%, including three patients with complete responses (6.5%). Median response duration was not reached, with 83.3% of responses ongoing (3.5 m+ to 20.4 m+). From ten patients included with brain metastases, four (40%) had an objective response, two (20%) of them achieved a complete response. Significant prognostic factors for overall survival were LDH level, ECOG PS and objective response. There were no serious adverse events. CONCLUSION: Although this was a heavily pretreated cohort, pembrolizumab activity at the approved dose and schedule was confirmed in the clinical setting with long-term responders, also including patients with brain metastases.

Transscleral resection without hypotensive anaesthesia vs iodine-125 plaque brachytherapy in the treatment of choroidal melanoma.

AimsThe aim of this study was to compare transscleral resection technique performed without hypotensive anaesthesia (TSRWH) with iodine-125 brachytherapy (IBT) in the treatment of choroidal melanoma.Patients and methodsThis was a retrospective surgical cohort study. Nineteen eyes treated with TSRWH were matched with 53 eyes treated with IBT according to: tumour size, distance to fovea, distance to optic nerve, and follow-up time. Best-corrected visual acuity (BCVA), local recurrence, secondary enucleation, metastasis, overall and specific survival, and complications were evaluated.ResultsPatients treated with TSRWH had significantly better BCVA than those treated with IBT. The local recurrence risk was significantly higher when ciliary body was involved (HR=11.4, 95% CI 2.24-49.7, P=0.04). Metastatic disease was observed in 14 of 53 patients (26.4%) in the IBT group vs 3 patients (15.8%) in the TSRWH group (P=0.531). Multivariate analysis showed that iris involvement (HR=16.0, 95% CI 4.2-170.2, P=0.033) and large tumour (HR=2.3, 95% CI 1.2-4.8, P=0.04) increased the probability of metastasis. During follow-up, six patients (11.3%) in IBT group died vs two (10.5%) in the TSRWH group (P≥0.999). Nine patients required secondary enucleation: 5 (9.4%) in the IBT group vs 4 (21.1%) in the TSRWH group (P=0.231). The most common complications in IBT group were radiation-induced retinopathy (45.3%), neovascular glaucoma (28.3%), and macular oedema (24.5%), whereas rhegmatogenous retinal detachment (21.1%), ocular hypertension (21.1%), and submacular haemorrhage (15.8%) were the most frequent complications after TSRWH.ConclusionTSRWH is a technically challenging procedure. However, when performed successfully, this technique achieves better preservation of visual acuity than IBT and without the limitations inherent in hypotensive anaesthesia.

ErbBs inhibition by lapatinib blocks tumor growth in an orthotopic model of human testicular germ cell tumor.

In this work, we have analyzed the expression of different members of the ErbB family in human samples of testicular germ cell tumors (GCTs). We observed expression of ErbB1 or ErbB2 in different tumor subtypes, but we also found high expression of ErbB3 in all GCTs tested. This pattern of expression was maintained when primary tumors were orthotopically implanted in nude mice. We have chosen a choriocarcinoma model characterized by high levels of ErbB1, but also of ErbB2 and ErbB3, to assay the in vivo effect of ErbB inhibitors on tumoral growth. Our results showed a complete lack of effect (refractoriness) to the pure ErbB1 receptor inhibitors cetuximab and gefitinib. While these inhibitors blocked ErbB1 phosphorylation, ErbB2 phosphorylation was not affected, suggesting an ErbB1-independent activation of this receptor. To confirm the importance of ErbB2 activation, animals were treated with lapatinib, a dual ErbB1 and ErbB2 inhibitor. Lapatinib treatment caused a 50% inhibition in tumor growth, an effect correlated with a blockade of both ErbB1 and ErbB2 phosphorylation levels, and of downstream signaling pathways (Akt, ERKs and Stat3). ErbB2 activation could still occur due to the formation of ErbB2/ErbB3 heterodimers, and ErbB3 activation was completely inhibited by lapatinib. Finally, combined inhibition of ErbB1 (gefitinib) and ErbB3 activities (knockdown expression by shRNA) inhibited tumoral testicular cells proliferation in a similar way to lapatinib. Our results explain why lapatinib but not anti-ErbB1 agents might be effective for treatment of testicular GCT patients.

[Descriptive analysis of cutaneous recurrence patterns in patients with melanoma]. / Análisis descriptivo de los patrones de recidiva cutánea en los pacientes con melanoma.

BACKGROUND AND OBJECTIVES: Few studies have addressed cutaneous recurrence of melanoma. The aim of this retrospective study was to analyze the characteristics and prognostic significance of the different patterns of cutaneous recurrence. MATERIAL AND METHODS: Patients diagnosed with melanoma between 1988 and 2008 at Hospital de Bellvitge, Barcelona, Spain and for whom data were available for at least 2 years of follow-up were included in the study. Local recurrence was defined as melanoma invasion of the skin adjacent to the scar left by excision of the primary tumor, regional metastasis or recurrence as metastasis restricted to the area drained by a regional lymph node station, and distant cutaneous metastasis as metastasis occurring outside this area. The relationship between cutaneous recurrence pattern and age, sex, primary tumor site, tumor subtype, Breslow depth, and ulceration was assessed. RESULTS: Eighty-five out of 1,080 patients (7.87%) had cutaneous recurrence. In 71 of those patients (83.53%; 27 men and 44 women; mean age, 60.68 years), this was the first indication of melanoma recurrence. Thirty-two patients had local recurrence, 32 regional metastasis, and 7 distant metastasis. Significant differences were observed in survival time from diagnosis of the primary tumor (P=.044) and from diagnosis of cutaneous recurrence (P<.001) according to the type of recurrence. CONCLUSIONS: Our results suggest that the pattern of cutaneous recurrence is prognostically significant and related to the site of the primary tumor given that the majority of local and regional recurrences occurred in primary tumors located on the lower limbs and head.

Discovery of myopodin methylation in bladder cancer.

Myopodin is an actin-binding protein that shuttles between the nucleus and the cytoplasm. After identifying an enriched CpG island encompassing the transcription site of myopodin, we aimed at evaluating the potential relevance of myopodin methylation in bladder cancer. The epigenetic silencing of myopodin by hypermethylation was tested in bladder cancer cells (n=12) before and after azacytidine treatment. Myopodin hypermethylation was associated with gene expression, being increased in vitro by this demethylating agent. The methylation status of myopodin promoter was then evaluated by methylation-specific polymerase chain reaction (MS-PCR) analyses. Myopodin was revealed to be frequently methylated in a large series of 466 bladder tumours (68.7%). Myopodin methylation was significantly associated with tumour stage (p<0.0005) and tumour grade (p=0.037). Myopodin expression patterns were analysed by immunohistochemistry on tissue arrays containing bladder tumours for which myopodin methylation was assessed (n=177). The presence of low nuclear myopodin expression alone (p = 0.031) or combined with myopodin methylation (p=0.008) was associated with poor survival. Moreover, myopodin methylation in 164 urinary specimens distinguished patients with bladder cancer from controls with a sensitivity of 65.0%, a specificity of 79.8%, and a global accuracy of 75.3%. Thus, myopodin was identified to be epigenetically modified in bladder cancer. The association of myopodin methylation and nuclear expression patterns with cancer progression and clinical outcome, together with its ability to detect bladder cancer patients using urinary specimens, suggests the utility of incorporating myopodin methylation assessment in the clinical management of patients affected by uroepithelial neoplasias.

Serum deprivation and protein synthesis inhibition induce two different apoptotic processes in N18 neuroblastoma cells.

N18 are murine neuroblastoma cells that underwent cell death upon serum deprivation or inhibition of protein synthesis by means of cycloheximide (CHX). In both cases, an ultrastructural morphology and an internucleosomal pattern of DNA fragmentation typical of apoptosis were found. However, electron microscopy revealed abundant lipid vesicles in the cytoplasm of CHX-treated cells that were not found in their serum-deprived counterparts. In addition, when both types of apoptotic cells were compared by means of flow cytometry and chromatin staining with propidium iodide, the former showed consistently less fluorescence than the latter. Therefore, in N18 cells, both apoptotic processes seemed to differ at a structural level. At a functional level, we found that apoptosis was blocked by the protease inhibitor TLCK in CHX-treated but not in serum-deprived cells. On the other hand, we generated N18 clones that overexpressed Bcl-2 protein. After a period of 48 h we found that identical levels of Bcl-2 protein were able to block apoptosis in serum-deprived but not in CHX-treated cells. In conclusion, two different biochemical pathways leading to apoptosis seem to coexist in N18 neuroblastoma cells.

Association between vitamin D receptor gene polymorphism and relative hypoparathyroidism in patients with chronic renal failure.

To study the influence of vitamin D receptor (VDR) gene polymorphism on parathyroid cell function in chronic renal failure, 85 patients who had serum PTH levels <12 pmol/L (the low intact PTH [iPTH] group) and 46 patients who had serum iPTH levels >60 pmol/L (the high iPTH group) were selected out of a total dialysis population of 170 individuals. As a result of subsequent exclusions based on several criteria in both groups (diabetic patients, serum aluminum levels, serum calcium levels, and time on dialysis), the final low iPTH group consisted of 34 patients and the final high iPTH included 32 patients. A healthy control population (n = 120) and 162 of the 170-patient dialysis population served as control groups. VDR gene polymorphism was determined by digestion with the BsmI enzyme and single-strand conformation polymorphism analysis of PCR amplified fragments. Serum iPTH levels were lower in patients with the BB genotype than in those with the Bb or bb genotype, both in the total dialysis population and when the various exclusion criteria were applied. No differences in genotypic and allelic frequencies were found between the healthy control population and the high iPTH group. However, the genotypic distribution was significantly different in the low iPTH group of patients before and after applying all exclusion criteria (P = 0.037 and P = 0.018, respectively). In the final selected population, the bb genotype was less frequent in the low iPTH group than in the total dialysis population (14.7% versus 36.4%; odds ratio, 0.3; confidence interval, 0.11 to 0.82; P = 0.01). Conversely, the BB genotype was over-represented in the low iPTH group (23.3% versus 19.7%; odds ratio, 1.9; confidence interval, 0.85 to 4.3; P = 0.1). In addition, the bb genotype and the b allele frequencies were lower in the low iPTH group than in the high iPTH group (14.7% versus 34.4%, P = 0.06, and 41.2% versus 60.9%, P = 0.02, respectively), and the BB genotype and the B allele were significantly more frequent in the low PTH group than in the high iPTH group (32.3% versus 12.5%, P = 0.05, and 58.8% versus 39.1%, P = 0.02, respectively). Thus, VDR gene polymorphism influences parathyroid function in chronic renal failure.