Retrospective study assessing the role of the androgen receptor in clear cell renal cell cancer patients treated with VEGFR inhibitors in monotherapy.

BACKGROUND AND PURPOSE: Despite that incorporating antiangiogenic in combination with immune-checkpoint inhibitors as the standard first-line treatment for advanced clear cell renal cell cancer (ccRCC) yields promising outcomes, these regimens often lead to significant toxicity. However, a subgroup of patients has shown responsiveness to VEGFR tyrosine-kinase inhibitors (TKIs) in monotherapy, leading to the question of whether employing combination therapies can significantly enhance overall survival in all patients over monotherapy. Thus, we aim to identify gene expression signatures that can predict TKI response within subpopulations that might benefit from single-agent therapies, to minimize unnecessary exposure to combination therapies and their associated toxicities, as well as to discover new potential therapeutic targets to improve ccRCC treatment. Based on prior data, the androgen receptor (AR) might meet both conditions. PATIENTS AND METHODS: We evaluated the association between AR expression, assessed through NanoString® technology-derived mRNA counts, and the clinical outcomes of 98 ccRCC patients treated with first-line antiangiogenics and determined its association with other genes implicated in ccRCC tumorigenesis. RESULTS: Higher AR-expression correlates significantly with better prognosis and survival based on the MSKCC risk score, and longer PFS. Furthermore, we have identified a gene set signature associated with AR-overexpression and several genes involved in angiogenesis and transcriptional targets of the hypoxia-inducible factor, a cornerstone of ccRCC. CONCLUSIONS: AR-overexpression and its association with other genes could favor a transcriptomic signature set to aid in identifying patients suitable for TKI in monotherapy, rather than aggressive combinations, enhancing thus, precision and personalized therapeutic decisions.

SEOM-GG clinical guidelines for the management of germ-cell testicular cancer (2023).

Testicular germ cell tumors are the most common tumors in adolescent and young men. They are curable malignancies that should be treated with curative intent, minimizing acute and long-term side effects. Inguinal orchiectomy is the main diagnostic procedure, and is also curative for most localized tumors, while patients with unfavorable risk factors for recurrence, or those who are unable or unwilling to undergo close follow-up, may require adjuvant treatment. Patients with persistent markers after orchiectomy or advanced disease at diagnosis should be staged and classified according to the IGCCCG prognostic classification. BEP is the most recommended chemotherapy, but other schedules such as EP or VIP may be used to avoid bleomycin in some patients. Efforts should be made to avoid unnecessary delays and dose reductions wherever possible. Insufficient marker decline after each cycle is associated with poor prognosis. Management of residual masses after chemotherapy differs between patients with seminoma and non-seminoma tumors. Patients at high risk of relapse, those with refractory tumors, or those who relapse after chemotherapy should be managed by multidisciplinary teams in experienced centers. Salvage treatment for these patients includes conventional-dose chemotherapy (TIP) and/or high-dose chemotherapy, although the best regimen and strategy for each subgroup of patients is not yet well established. In late recurrences, early complete surgical resection should be performed when feasible. Given the high cure rate of TGCT, oncologists should work with patients to prevent and identify potential long-term side effects of the treatment. The above recommendations also apply to extragonadal retroperitoneal and mediastinal tumors.

Criteria and indicators to evaluate quality of care in genitourinary tumour boards.

PURPOSE: Genitourinary (GU) multidisciplinary tumour boards (GUMTBs) are key components of patient care, as they might lead to changes in treatment plan, improved survival, and increased adherence to guidelines. However, there are no guidelines on how GUMTBs should operate or how to assess their quality of performance. METHODS: A systematic literature review was conducted to identify criteria and indicators to evaluate quality in GUMTBs. A scientific committee-comprising 12 GU cancer specialists from seven disciplines-proposed a list of criteria and developed indicators, evaluated in two rounds of Delphi method. Appropriateness and utility of indicators were scored using a 9-point Likert scale. Consensus was defined as at least two-thirds of Delphi respondents selecting a score sub-category that encompassed the median score of the group. RESULTS: Forty-five criteria were selected to evaluate the quality of GUMTBs covering five dimensions: organisation, personnel, protocol and documentation, resources, and interaction with patients. Then, 33 indicators were developed and evaluated in the first round of Delphi, leading to a selection of 26 indicators in two dimensions: function, governance and resources, and GUMTB sessions. In the second round, consensus was reached on the appropriateness of all 26 indicators and on the utility of 24 of them. Index cards for criteria and indicators were developed to be used in clinical practice. CONCLUSIONS: Criteria and indicators were developed to evaluate the quality of GUMTBs, aiming to serve as a guide to improve quality of care and health outcomes in patients with GU cancer.

Neoadjuvant chemotherapy with dose-dense MVAC in muscle-invasive bladder cancer: a tertiary center experience.

PURPOSE: Neoadjuvant chemotherapy in muscle-invasive bladder cancer (MIBC) patients has proven beneficial in overall survival. However, the optimal regimen is still a matter of debate. MATERIALS AND METHODS: In this retrospective analysis, we evaluate the results obtained in 42 patients treated in our center with 4 cycles of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) followed by radical cystectomy from August 2015 to October 2020. All patients had cT2 or higher non-metastatic MIBC. Clinical and pathological outcomes are reported. RESULTS: Of the 42 patients, 90.5% were men (n = 38) and the mean age was 65 years. All of them had ECOG 0-1 at diagnosis and most tumors had an initial clinical stage T2N0 (76%). Thirty-six patients (85.7%) completed 4 cycles of neoadjuvant treatment, and 21.4% required a dose reduction. The most frequent adverse event (AE) was grade 1-2 asthenia (81%), while neutropenia was the most frequent grade 3 or higher AE (38%). Complete pathological response (ypT0, ypN0) was achieved in 50% of patients (n = 21), and down-staging was observed in 57.1% (n = 24). Only one patient presented radiological progressive disease during neoadjuvant treatment (2.4%), and after a mean follow-up time of 31.5 months, 33.3% of patients experienced disease recurrence. CONCLUSIONS: Neoadjuvant chemotherapy with 4 cycles of dd-MVAC is an effective regimen with high rates of pathological complete responses and down-staging along with an acceptable toxicity profile. DD-MVAC should be considered as an alternative to cisplatin and gemcitabine in patients with good clinical performance status.

Outcomes with atezolizumab in metastatic urothelial cancer: real-world data from a single institution.

PURPOSE: Immune checkpoint inhibitors (ICIs) have been incorporated in the treatment of metastatic urothelial carcinoma (mUC) upon platinum-based chemotherapy according to the positive results of large clinical trials. Nevertheless, results from unselected populations reflecting real-world data (RWD) are highly informative to the clinician. We reviewed daily clinical practice outcomes in patients with mUC who received atezolizumab in our institution. METHODS: Here we evaluated the clinical activity and safety of atezolizumab in an unselected population of mUC patients who received atezolizumab between 2018 and 2022 reflecting RWD. Efficacy and safety information were retrospectively collected. RESULTS: A total of 63 patients were included. The mean age was 68 years and the objective response rate was 14.3%. The median progression-free survival was 3 months and the median overall survival 6 months. At 1 year, 42% of the patients were alive. ECOG (0 vs 1) and neutrophil-lymphocytes ratio < 2 at the start of ICI were positive prognostic factors that discriminated between long vs short survivors. Overall tolerance was good with no new safety signals. Five patients (17%) had treatment-related adverse events grade ≥ 2 that required corticosteroids. CONCLUSION: In this retrospective study, atezolizumab was an effective and tolerable treatment option for patients with mUC after progression to platinum-based chemotherapy. Yet, patient selection remains critical to improve outcomes.

Anisotropic Band-Edge Absorption of Millimeter-Sized Zn(3-ptz)2 Single-Crystal Metal-Organic Frameworks.

Metal-organic frameworks (MOFs) have emerged as promising tailor-designed materials for developing next-generation solid-state devices with applications in linear and nonlinear coherent optics. However, the implementation of functional devices is challenged by the notoriously difficult process of growing large MOF single crystals of high optical quality. By controlling the solvothermal synthesis conditions, we succeeded in producing large individual single crystals of the noncentrosymmetric MOF Zn(3-ptz)2 (MIRO-101) with a deformed octahedron habit and surface areas of up to 37 mm2. We measured the UV-vis absorption spectrum of individual Zn(3-ptz)2 single crystals across different lateral incidence planes. Millimeter-sized single crystals have a band gap of E g = 3.32 eV and exhibit anisotropic absorption in the band-edge region near 350 nm, whereas polycrystalline samples are fully transparent in the same frequency range. Using solid-state density functional theory (DFT), the observed size dependence in the optical anisotropy is correlated with the preferred orientation adopted by pyridyl groups under conditions of slow crystal self-assembly. Our work thus paves the way for the development of optical polarization switches based on metal-organic frameworks.

Measures to evaluate quality of care in renal cancer: results of a Delphi study in Spain.

PURPOSE: To review current measures for renal cancer care and develop a comprehensive and updated list of measures for their practical use in Spain. METHODS: The study was developed by Fundación ECO, a Spanish foundation aiming to improve oncology quality of care. A systematic literature review was carried out to identify measures and knowledge gaps. A scientific committee composed of nine experts reviewed the literature findings and added measures. A preliminary list of 42 measures was evaluated with the Delphi method to gather feedback from 47 medical oncology experts in Spain. Experts scored the appropriateness of the measures and ranked their priority in two consecutive online surveys. The scientific committee reviewed the Delphi results and developed the measures. A technical group from Universidad Francisco de Vitoria conducted and oversaw the Delphi method. RESULTS: The Delphi method led to consensus on all 42 measures. The scientific committee used a prioritisation matrix to select 25 of these measures for evaluating quality of care in renal cancer. These measures regarded structure, process, and outcome and covered general management, diagnosis, treatment, follow-up, and evaluation of health outcomes. Easy-to-use index cards were developed for all 25 measures, including their definition, formula, acceptable level of attainment, and rationale. CONCLUSIONS: This manuscript aims to provide healthcare professionals with expert- and evidence-based measures that are useful for evaluating quality of care in renal cancer in Spain and cover all aspects and stages.

Millimeter-Scale Zn(3-ptz)2 Metal-Organic Framework Single Crystals: Self-Assembly Mechanism and Growth Kinetics.

The solvothermal synthesis of metal-organic frameworks (MOFs) often proceeds through competing crystallization pathways, and only partial control over the crystal nucleation and growth rates is possible. It challenges the use of MOFs as functional devices in free-space optics, where bulk single crystals of millimeter dimensions and high optical quality are needed. We develop a synthetic protocol to control the solvothermal growth of the MOF [Zn(3-ptz)2] n (MIRO-101), to obtain large single crystals with projected surface areas of up to 25 mm2 in 24 h, in a single reaction with in situ ligand formation. No additional cooling and growth steps are necessary. We propose a viable reaction mechanism for the formation of MIRO-101 crystals under acidic conditions, by isolating intermediate crystal structures that directly connect with the target MOF and reversibly interconverting between them. We also study the nucleation and growth kinetics of MIRO-101 using ex situ crystal image analysis. The synthesis parameters that control the size and morphology of our target MOF crystal are discussed. Our work deepens our understanding of MOF growth processes in solution and demonstrates the possibility of building MOF-based devices for future applications in optics.

Azide-Based High-Energy Metal-Organic Frameworks with Enhanced Thermal Stability.

We describe the structure and properties of [Zn(C6H4N5)N3] n , a new nonporous three-dimensional high-energy metal-organic framework (HE-MOF) with enhanced thermal stability. The compound is synthesized by the hydrothermal method with in situ ligand formation under controlled pH and characterized using single-crystal X-ray diffraction, elemental analysis, and Fourier transform infrared. The measured detonation temperature (T det = 345 °C) and heat of detonation (ΔH det = -0.380 kcal/g) compare well with commercial explosives and other nitrogen-rich HE-MOFs. The velocity and pressure of denotation are 5.96 km/s and 9.56 GPa, respectively. Differential scanning calorimetry analysis shows that the denotation of [Zn(C6H4N5)N3] n occurs via a complex temperature-dependent mechanism.

Crystal structure and Hirshfeld surface analysis of tris-(2,2'-bi-pyridine)-nickel(II) bis-(1,1,3,3-tetra-cyano-2-eth-oxy-propenide) dihydrate.

The title compound, [Ni(C10H8N2)3](C9H5N4O)2·2H2O, crystallizes as a racemic mixture in the monoclinic space group C2/c. In the crystal, the 1,1,3,3-tetracyano-2-ethoxypropenide anions and the water molecules are linked by O-H⋯N hydrogen bonds, forming chains running along the [010] direction. The bpy ligands of the cation are linked to the chain via C-H⋯π(cation) inter-actions involving the CH3 group. The inter-molecular inter-actions were investigated by Hirshfeld surface analysis and two-dimensional fingerprint plots.

Hexa-aqua-zinc(II) dinitrate bis-[5-(pyridinium-3-yl)tetra-zol-1-ide].

Hexa-aqua-zinc(II) dinitrate 5-(pyridinium-3-yl)tetra-zol-1-ide, [Zn(H2O)6](NO3)2·2C6H5N5, crystallizes in the space group P . The asymmetric unit contains one zwitterionic 5-(pyridinium-3-yl)tetra-zol-1-ide mol-ecule, one NO3- anion and one half of a [Zn(H2O)6]2+ cation ( symmetry). The pyridinium and tetra-zolide rings in the zwitterion are nearly coplanar, with a dihedral angle of 5.4 (2)°. Several O-H⋯N and N-H⋯O hydrogen-bonding inter-actions exist between the [Zn(H2O)6]2+ cation and the N atoms of the tetra-zolide ring, and between the nitrate anions and the N-H groups of the pyridinium ring, respectively, giving rise to a three-dimensional network. The 5-(pyridinium-3-yl)tetra-zol-1-ide mol-ecules show parallel-displaced π-π stacking inter-actions; the centroid-centroid distance between adjacent tetra-zolide rings is 3.6298 (6) Šand that between the pyridinium and tetra-zolide rings is 3.6120 (5) Å.

pH-Controlled Assembly of 3D and 2D Zinc-Based Metal-Organic Frameworks with Tetrazole Ligands.

We report the synthesis and structural diversity of Zn(II) metal-organic framework (MOF) with in situ formation of tetrazole ligand 3-ptz [3-ptz = 5-(3-pyridyl)tetrazolate] as a function pH. By varying the initial reaction pH, we obtain high-quality crystals of the noncentrosymmetric three-dimensional MOF Zn(3-ptz)2 , mixed phases involving the zinc-aqua complex [Zn(H2O)4(3-ptz)2]·4H2O, and two-dimensional MOF crystals Zn(OH)(3-ptz) with a tunable microrod morphology, keeping reaction time, temperature, and metal-ligand molar ratio constant. Structures are characterized by X-ray diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy, and UV-vis spectroscopy. We discuss the observed structural diversity in terms of the relative abundance of hydroxo-zinc species in solution for different values of pH.

Biological markers of cisplatin resistance in advanced testicular germ cell tumours.

INTRODUCTION: Germ cell tumours (GCTs) of the testis show exquisite sensitivity to treatment with cisplatin. Despite the high cure rates provided by platinum-based chemotherapy, 10-20% of patients die from progressive disease. Although various cellular pathways may influence cisplatin efficacy, their actual impact has not been comprehensively investigated in advanced GCTs. The objective of the present study was to clarify the role of the expression status of proteins involved in the Rb and p53 tumour suppressor pathways in sensitivity and resistance of GCTs to cisplatin-based chemotherapy. MATERIALS AND METHODS: Paraffin-embedded tumour tissues from 84 patients with advanced GCT treated with cisplatin-based chemotherapy were analysed. Immunohistochemical expression of proteins p53 and mdm2, and the G1-phase cyclins D1 and D2 (CD1 and CD2) was assessed and correlated with the clinical course. RESULTS: The percentages of positive expression of p53, mdm2, CD1 and CD2 were 56, 57, 37.5 and 55%, respectively. From univariate analysis, there was no significant association between p53, mdm2 or CD1 expression and outcome. Instead, positive CD2 expression was found to be marginally associated with shorter median duration of progression-free survival (PFS) (p=0.06). In multivariate analysis, none of the molecular markers retained statistical significance with treatment response or survival. CONCLUSIONS: Tissular expression of p53, mdm2 and CD1 is not associated with prognosis or treatment response in patients with advanced GCT. Aberrant CD2 expression appears to further determine a shorter PFS. Larger and further studies are required to validate CD2 as a marker of cisplatin resistance.

Expression of EGFR, HER-2/neu and KIT in germ cell tumours.

BACKGROUND: Germ cell tumours (GCTs) represent an extraordinarily chemosensitive malignancy. However, 20-30% of patients with advanced disease cannot be cured by currently available treatments. The role of tyrosine kinase receptors has been widely studied in other malignancies. Yet, limited information is available on GCTs. METHODS: One hundred and nine paraffin-embedded GCTs in 84 patients were assessed by immunohistochemistry for epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER-2)/neu and KIT (CD117) expression. Univariate and multivariate analyses were performed to evaluate their role as predictive and/or prognostic factors. RESULTS: EGFR and HER-2/neu staining was detected in 28% and 13% of tumours, respectively, predominantly in nonseminomatous GCTs. KIT protein was almost universally expressed in seminomas (97%), being virtually absent in choriocarcinoma and teratocarcinoma subtypes. EGFR expression showed inverse association with tumour response of borderline significance. With a median follow-up of 10.6 years, no significant association was observed between the expression of any of these markers and relapse-free or overall survival. CONCLUSIONS: EGFR, HER-2/neu and KIT have differential patterns of expression in GCTs according to histological subtypes. The expression of these markers in our series had no prognostic or predictive significance.

Mixed paratesticular liposarcoma with osteosarcoma elements.

Spermatic cord sarcomas (SCS) are very infrequent and sometimes misdiagnosed malignancies. Moreover, their optimal management remains undefined with ongoing controversy about the indications for adjuvant therapy. Histologically, liposarcomas are the most common type. Osteosarcoma is rarely observed in this location and combined tumours with this component have not been described. We present a case of SCS with mixed differentiation with both liposarcoma and osteosarcoma elements.