Front-Line Therapeutic Strategy in Metastatic Hormone Sensitive Prostate Cancer: An Updated Therapeutic Algorithm.

Prostate carcinoma (PC), the second most diagnosed cancer globally, saw approximately 1,414,000 new cases in 2020, with 17% being de novo metastatic. In these cases, the 5-year relative survival rate is 32%. Metastatic hormone-sensitive prostate cancer (mHSPC) includes those with metastatic disease at initial diagnosis or after initial therapy without long-term androgen deprivation therapy (ADT), eventually progressing to castration-resistant prostate cancer (CRPC). The established therapeutic principle of ADT has persisted for 80 years, with luteinizing hormone-releasing hormone (LHRH) agonists like leuprorelin being commonly used. LHRH antagonists, such as degarelix, have also emerged. Recent advances in mHSPC treatment involve combination strategies with drugs proven effective in CRPC, considering prognostic factors like disease volume and presentation. This review outlines pivotal trials leading to drug approvals in mHSPC and proposes a treatment decision algorithm for the same, based on statement from the Tuscan Interdisciplinary Uro-Oncological Group. A multidisciplinary approach is crucial to tailor treatment intensity and weigh risks and benefits effectively.

Assessing the effectiveness and safety of lenvatinib and everolimus in advanced renal cell carcinoma: insights from the RELIEVE study's analysis of heavily pretreated patients.

Background: The treatment of heavily pretreated patients with metastatic renal cell carcinoma (mRCC) represents an unmet medical need and is still challenging. Objectives: The primary objective was to assess the effectiveness of the lenvatinib plus everolimus combination and the secondary objective was the toxicity profile of this combination. Design: We conducted a longitudinal retrospective study examining mRCC patients pre-treated with one or more lines of therapy among different cancer centers in Italy. Methods: The study included patients who received the combination of lenvatinib plus everolimus as either a second-line treatment or beyond. We assessed progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), response rate (RR), and toxicity profile. In addition, we explored the potential relationship between treatment effectiveness and clinical and laboratory parameters. Results: In all, 33 patients were assessed, the median age was 60 years, 57% had an Eastern Cooperative Oncology Group performance status of 1-2 and. 63% received ⩾ 3 prior lines of therapy. 62% were 'intermediate risk' according to the International Metastatic Renal Cell Carcinoma Database Consortium and 30% were 'poor risk'. The RR was 42% (no complete response), 18% stable disease. Median OS was 11.2 months (95% CI 6.8-19.9), median PFS was 6.7 months (95% CI 0.6-30.8), and median TTF was 6.7 months (95% CI 4.8-16.6). A shorter OS was significantly associated with lymph node metastases (p = 0.043, 95% CI), neutrophils/ lymphocytes ratio (NLR) ⩾ 3 (p = 0.007), hemoglobin/red cell distribution width ratio cutoff value <0.7 was significant (p = 0.03) while a shorter PFS was associated with lung (p = 0.048) and brain metastases (p = 0.023). The most frequent G1 toxicity was diarrhea (24%), G2 was fatigue (30%), and hypertension and skin toxicity (6%) for G3. Conclusion: Our findings suggest a clinically relevant effectiveness of lenvatinib plus everolimus combination with an acceptable toxicity profile for heavily pretreated patients with mRCC.

Three-Dimensional Printed Filters Based on Poly(ethylene glycol) Diacrylate Hydrogels Doped with Silver Nanoparticles for Removing Hg(II) Ions from Water.

Nowadays, due to water pollution, more and more living beings are exposed to dangerous compounds, which can lead to them contracting diseases. The removal of contaminants (including heavy metals) from water is, therefore, a necessary aspect to guarantee the well-being of living beings. Among the most used techniques, the employment of adsorbent materials is certainly advantageous, as they are easy to synthesize and are cheap. In this work, poly(ethylene glycol) diacrylate (PEGDA) hydrogels doped with silver nanoparticles (AgNPs) for removing Hg(II) ions from water are presented. AgNPs were embedded in PEGDA-based matrices by using a photo-polymerizable solution. By exploiting a custom-made 3D printer, the filters were synthesized. The kinetics of interaction was studied, revealing that the adsorption equilibrium is achieved in 8 h. Subsequently, the adsorption isotherms of PEGDA doped with AgNPs towards Hg(II) ions were studied at different temperatures (4 °C, 25 °C, and 50 °C). In all cases, the best isotherm model was the Langmuir one (revealing that the chemisorption is the driving process and the most favorable one), with maximum adsorption capacities equal to 0.55, 0.57, and 0.61 mg/g, respectively. Finally, the removal efficiency was evaluated for the three temperatures, obtaining for 4 °C, 25 °C, and 50 °C the values 94%, 94%, and 86%, respectively.

PERSIAN trial (NCT05717660): an ongoing randomized trial testing androgen deprivation therapy, apalutamide and stereotactic body radiotherapy. An alternative "triplet" for oligometastatic hormone sensitive prostate cancer patients.

Earlier treatment intensification with systemic potent androgen receptor inhibition has been shown to improve clinical outcomes in metastatic hormone sensitive prostate cancer. Nonetheless, oligometastatic patients may benefit from local treatment approaches such as stereotactic body radiotherapy (SBRT). Aiming to explore the benefit of SBRT in this scenario, we designed this trial to specifically test the hypothesis that SBRT will improve clinical outcomes in select population affected by metachronous oligometastatic HSPC treated with androgen deprivation therapy + apalutamide. Enrolled patients will be randomized to receive the standard systemic treatment alone or in combination with SBRT on all metastatic sites of disease. Here we report the protocol design and an overview of the ongoing trials testing different integration strategies between RT and systemic therapies.

Results of the observational prospective RealFLOT study.

BACKGROUND: Perioperative FLOT (5-fluorouracil, oxaliplatin and docetaxel) has recently become the gold standard treatment for fit patients with operable gastric (GC) or gastroesophageal (GEJ) adenocarcinoma, getting a 5-year overall survival (OS) of 45%, over 23% with surgery alone. METHODS: RealFLOT is an Italian, multicentric, observational trial, collecting data from patients with resectable GC or GEJ adenocarcinoma treated with perioperative FLOT. Aim of the study was to describe feasibility and safety of FLOT, pathological complete response rate (pCR), surgical outcomes and overall response rate (ORR) in an unselected real-world population. Additional analyses evaluated the correlation between pCR and survival and the prognostic role of microsatellite instability (MSI) status. RESULTS: Of 206 patients enrolled that received perioperative FLOT at 15 Italian centers, 124 (60.2%) received at least 4 full-dose cycles, 190 (92.2%) underwent surgery, and 142 (68.9%) started the postoperative phase. Among patients who started the postoperative phase, 105 (51.0%) received FLOT, while 37 (18%) received de-intensified regimens, depending on clinical condition or previous toxicities. pCR was achieved in 7.3% of cases. Safety profile was consistent with literature. Neutropenia was the most common G 3-4 adverse event (AE): 19.9% in the preoperative phase and 16.9% in the postoperative phase. No toxic death was observed and 30-day postoperative mortality rate was 1.0%. ORR was 45.6% and disease control rate (DCR) was 94.2%. Disease-free survival (DFS) and OS were significantly longer in case of pCR (p = 0.009 and p = 0.023, respectively). A trend towards better DFS was observed among MSI-H patients. CONCLUSIONS: These real-world data confirm the feasibility of FLOT in an unselected population, representative of the clinical practice. pCR rate was lower than expected, nevertheless we confirm pCR as a predictive parameter of survival. In addition, MSI-H status seems to be a positive prognostic marker also in patients treated with taxane-containing triplets.

Additive Manufactured Scaffolds for Bone Tissue Engineering: Physical Characterization of Thermoplastic Composites with Functional Fillers.

Thermoplastic polymer-filler composites are excellent materials for bone tissue engineering (TE) scaffolds, combining the functionality of fillers with suitable load-bearing ability, biodegradability, and additive manufacturing (AM) compatibility of the polymer. Two key determinants of their utility are their rheological behavior in the molten state, determining AM processability and their mechanical load-bearing properties. We report here the characterization of both these physical properties for four bone TE relevant composite formulations with poly(ethylene oxide terephthalate)/poly(butylene terephthalate (PEOT/PBT) as a base polymer, which is often used to fabricate TE scaffolds. The fillers used were reduced graphene oxide (rGO), hydroxyapatite (HA), gentamicin intercalated in zirconium phosphate (ZrP-GTM) and ciprofloxacin intercalated in MgAl layered double hydroxide (MgAl-CFX). The rheological assessment showed that generally the viscous behavior dominated the elastic behavior (G″ > G') for the studied composites, at empirically determined extrusion temperatures. Coupled rheological-thermal characterization of ZrP-GTM and HA composites showed that the fillers increased the solidification temperatures of the polymer melts during cooling. Both these findings have implications for the required extrusion temperatures and bonding between layers. Mechanical tests showed that the fillers generally not only made the polymer stiffer but more brittle in proportion to the filler fractions. Furthermore, the elastic moduli of scaffolds did not directly correlate with the corresponding bulk material properties, implying composite-specific AM processing effects on the mechanical properties. Finally, we show computational models to predict multimaterial scaffold elastic moduli using measured single material scaffold and bulk moduli. The reported characterizations are essential for assessing the AM processability and ultimately the suitability of the manufactured scaffolds for the envisioned bone regeneration application.

3D additive manufactured composite scaffolds with antibiotic-loaded lamellar fillers for bone infection prevention and tissue regeneration.

Bone infections following open bone fracture or implant surgery remain a challenge in the orthopedics field. In order to avoid high doses of systemic drug administration, optimized local antibiotic release from scaffolds is required. 3D additive manufactured (AM) scaffolds made with biodegradable polymers are ideal to support bone healing in non-union scenarios and can be given antimicrobial properties by the incorporation of antibiotics. In this study, ciprofloxacin and gentamicin intercalated in the interlamellar spaces of magnesium aluminum layered double hydroxides (MgAl) and α-zirconium phosphates (ZrP), respectively, are dispersed within a thermoplastic polymer by melt compounding and subsequently processed via high temperature melt extrusion AM (~190 °C) into 3D scaffolds. The inorganic fillers enable a sustained antibiotics release through the polymer matrix, controlled by antibiotics counterions exchange or pH conditions. Importantly, both antibiotics retain their functionality after the manufacturing process at high temperatures, as verified by their activity against both Gram + and Gram - bacterial strains. Moreover, scaffolds loaded with filler-antibiotic do not impair human mesenchymal stromal cells osteogenic differentiation, allowing matrix mineralization and the expression of relevant osteogenic markers. Overall, these results suggest the possibility of fabricating dual functionality 3D scaffolds via high temperature melt extrusion for bone regeneration and infection prevention.

The Rheology of PEOT/PBT Block Copolymers in the Melt State and in the Thermally-Induced Sol/Gel Transition. Implications on the 3D-Printing Bio-Scaffold Process.

Poly(ethyleneoxideterephthalate)/poly(butyleneterephthalate) (PEOT/PBT) segmented block copolymers are widely used for the manufacturing of 3D-printed bio-scaffolds, due to a combination of several properties, such as cell viability, bio-compatibility, and bio-degradability. Furthermore, they are characterized by a relatively low viscosity at high temperatures, which is desired during the injection stages of the printing process. At the same time, the microphase separated morphology generated by the demixing of hard and soft segments at intermediate temperatures allows for a quick transition from a liquid-like to a solid-like behavior, thus favoring the shaping and the dimensional stability of the scaffold. In this work, for the first time, the rheology of a commercial PEOT/PBT material is studied over a wide range of temperatures encompassing both the melt state and the phase transition regime. Non-isothermal viscoelastic measurements under oscillatory shear flow allow for a quantitative determination of the material processability in the melt state. Additionally, isothermal experiments below the order⁻disorder temperature are used to determine the temperature dependence of the phase transition kinetics. The importance of the rheological characterization when designing the 3D-printing scaffold process is also discussed.

Docetaxel rechallenge in metastatic castration-resistant prostate cancer: any place in the modern treatment scenario? An intention to treat evaluation.

BACKGROUND: We evaluated the possible advantages of a docetaxel (DCT) rechallenge strategy in metastatic castration-resistant prostate cancer (mCRPC) patients, also given the possible earlier positioning of this treatment option in the modern scenario. PATIENTS & METHODS: All mCRPC patients planned for DCT chemotherapy rechallenge in our institutions were evaluated. RESULTS: Of 128 patients, 98 achieved disease control on the initial DCT round. After a treatment holiday of 8.3 months, the 98 responsive patients underwent a second DCT round, with 56 cases achieving again disease control. After a 5.7-month off-treatment period, 32 of these cases underwent a third DCT round, and 16 responded. Lastly, after a further 4.2-month treatment holiday, eight patients underwent a fourth DCT round and two responded. Median time to definitive disease progression for the whole population was 16.4 months. CONCLUSIONS: Rechallenge with DCT may be considered a suitable treatment option for mCRPC patients recurring after a successful DCT chemotherapy. The interest in this strategy may be increased because of the showed efficacy of early DCT chemotherapy in patients with bulky disease (CHAARTED study) and the potential lower efficacy of the new hormonal agents abiraterone acetate and enzalutamide when used in a immediate sequencing.

Immunologic checkpoints blockade in renal cell, prostate, and urothelial malignancies.

Genitourinary (GU) tumors, and in particular renal cell and prostate cancer, represent one of the most dynamic areas in oncology from the scientific point of view. One of the most recent treatment approaches for GU tumors has focused on a series of molecules known as immune checkpoints and the possibility of manipulating immune responses against tumor cells by blocking these molecules with monoclonal antibodies (mAbs). Cytotoxic T lymphocyte antigen-4 (CTLA-4), and the immune checkpoint inhibitor mAbs ipilimumab and tremelimumab, represent the prototypes of this new growing class of agents called immunomodulating antibodies, while programmed death/ligand 1 (PD-1/PD-L1) also has garnered a significant interest as a new immune checkpoints to target in urothelial cancer, with the anti-PD-1/PD-L1 inhibitor mAbs nivolumab, MPDL-3280, and BMS-936559 as the first agents tested. Here we report the encouraging initial data observed in GU cancers with this new class of agents, which have reinforced the interest of investigating the therapeutic potential of the immune checkpoint modulators in large controlled trials.

Clinical implications for a treatment algorithm and differential indication to hormone therapy and chemotherapy options in metastatic castrate-resistant prostate cancer: a personal view.

Although docetaxel is still considered a mainstay of treatment in metastatic castrate-resistant prostate cancer (mCRPC), in the last few years, new agents have been developed to improve survival in this setting and reach a possible optimal personalized treatment strategy. In this paper, we provide a personal view and an algorithm for mCRPC patients, according to available evidence, personal opinion and experience. Abiratone acetate, cabazitaxel, radium-223, sipuleucel-T and enzalutamide, together with docetaxel, have demonstrated a survival benefit in these patients. The use of rechallenge with docetaxel in mCRPC patients with disease progression after a first response has been considered. These new agents complicated the scenario and posed the challenge to move from the old sequential to a new algorithm-based approach. At this stage, the algorithm is necessarily based on experts' opinion, since the efficacy of a single agent in a specific setting has not been validated by sequential trials.

Axitinib safety in metastatic renal cell carcinoma: suggestions for daily clinical practice based on case studies.

INTRODUCTION: Axitinib , a highly selective inhibitor of vascular endothelial growth factor receptors taken orally, is approved for second-line treatment of advanced renal cell carcinoma (RCC) after failure of prior treatment with sunitinib or a cytokine. We review data for axitinib and discuss strategies to manage or prevent adverse events (AEs) and maximize clinical benefit. AREAS COVERED: A literature search identified key advanced RCC trials of axitinib and other targeted therapies. Each author also contributed a clinical case study to illustrate management approaches in patients who received axitinib following sunitinib in the AXIS Phase III trial. Axitinib has demonstrated a predictable and manageable AE profile in clinical trials; most commonly reported treatment-related events are diarrhea, hypertension, fatigue, nausea, vomiting and dysphonia. Case studies demonstrate that successful management requires patient awareness of potential AEs, regular monitoring and dose modification for specific AEs. EXPERT OPINION: Improvement in progression-free survival with axitinib versus sorafenib in a Phase III trial supports preferred selection of axitinib in the second-line setting. The safety profile of axitinib versus mammalian target of rapamycin inhibitors and sorafenib also provides the opportunity to personalize treatment in advanced RCC based on the likelihood for specific AEs to occur and on prior toxicities in the first-line setting.

GOAL: an inverse toxicity-related algorithm for daily clinical practice decision making in advanced kidney cancer.

Metastatic renal cell carcinoma (mRCC), considered almost an orphan disease only six years ago, appears today a very dynamic pathology. The recently switch to the actual overcrowded scenario defined by seven active drugs has driven physicians to an incertitude status, due to difficulties in defining the best possible treatment strategy. This situation is mainly related to the absence of predictive biomarkers for any available or new therapy. Such issue, associated with the nearly absence of published face-to-face studies, draws a complex picture frame. In order to solve this dilemma, decisional algorithms tailored on drug efficacy data and patient profile are recognized as very useful tools. These approaches try to select the best therapy suitable for every patient profile. On the contrary, the present review has the "goal" to suggest a reverse approach: basing on the pivotal studies, post-marketing surveillance reports and our experience, we defined the polarizing toxicity (the most frequent toxicity in the light of clinical experience) for every single therapy, creating a new algorithm able to identify the patient profile, mainly comorbidities, unquestionably unsuitable for each single agent presently available for either the first- or the second-line therapy. The GOAL inverse decision-making algorithm, proposed at the end of this review, allows to select the best therapy for mRCC by reducing the risk of limiting toxicities.

A simple and effective method to form metallic nanoparticles onto composites made up of organic polymers and layered inorganic ion exchangers as fillers.

A new easy method for the preparation of polymeric nanocomposites supporting metal nanoparticles is presented. The method concerns the use of a layered inorganic ion exchanger converted in the proper metallic form and exfoliated to act as filler of organic polymers with twofold aim of obtaining a composite (or nanocomposite) and to have metal ions that can be suitably reduced with a proper reducing agent to form metal nanoparticles. This strategy has been applied to the system polyvinylidene fluoride (PVDF) filled with layered a-zirconium phosphate in copper form. Several physical techniques (X-ray powder diffraction, atomic force microscopy, high resolution transmission electron microscopy) have been used to characterize the Cu-nanoparticles, whose dimensions range from 5 to 200 nm for those placed inside or on the surface of the polymeric matrix respectively, depending on the dispersion degree of the inorganic filler. The method is simple and can be used for different polymeric matrices and/or metal ions in order to produce metal/polymer systems with promising technological application.

Biologic tools to personalize treatment in genitourinary cancers.

BACKGROUND: Genitourinary (GU) cancers are a major healthcare issue in modern oncology. In the last decade many efforts have been made to develop new treatment options but with the possible exception of renal cell carcinoma, very few steps ahead have been taken. At the same time, a wide variety of molecular markers, potentially helpful in identifying patient subpopulation most likely to benefit from a specific treatment have been identified. Our goal is to clarify if biomarkers could be used at present to personalize treatment for GU cancers. MATERIALS AND METHODS: Literature was search using PubMed and EMBASE using different terms and combinations regarding possible prognostic and predictive markers in renal, prostate and urothelial cancers. RESULTS: 3546 articles were retrieved. After excluding duplications, preclinical studies and factors without possible predictive value 654 publications remain. N-telopeptide, HER2/neu, EGFR, and p53 in prostate cancer, sVEGF-A for RCC and EMMPRIN and Survivin in urothelial cancer were among those identified. After a careful examination of published data, none of them reached a sufficient evidence to be suggested for use outside of clinical trials. CONCLUSIONS: To date any reliable biomarkers has been validated for tailored treatments approaches in GU cancer. Future studies focusing on this issue are urgently needed.

Intravesical gemcitabine therapy for superficial transitional cell carcinoma: results of a Phase II prospective multicenter study.

OBJECTIVES: To determine the tolerability and efficacy after 1 year of weekly intravesical gemcitabine therapy in patients with intermediate-risk and high-risk superficial transitional cell carcinoma. METHODS: A total of 116 patients with intermediate-risk and high-risk bladder cancer who had undergone transurethral resection were treated with one cycle (once a week for 6 weeks) of gemcitabine 2000 mg. Local and systemic tolerability and efficacy were evaluated. RESULTS: In terms of the tolerability of gemcitabine, 14 patients (12.0%) reported urgency, 6 (5.1%) dizziness and slight fever (less than 38 degrees C), 1 (0.8%) severe abdominal pain, with ulcerative lesions of the bladder mucosa at cystoscopy, and 1 (0.8%) parosmia. The remaining 94 patients (81.3%) did not report any local side effects during the treatment period. In terms of efficacy, recurrence developed in 29 patients (25.4%) a mean of 7 months after transurethral resection; 85 patients (74.6%) were disease free after 12 months. The univariate analysis showed a greater level of efficacy in patients with a first occurrence (P = 0.0408), patients who had had no previous treatment (P = 0.0368), and patients with Stage pTa superficial transitional cell carcinoma (P = 0.0018). The multivariate analysis did not reveal any significant data. No significant differences were found between the intermediate-risk and high-risk patients in tolerability or efficacy. No recurrence developed in 18 (75%) of 24 intermediate-risk bacille Calmette-Guérin-refractory or 7 (43.7%) of 16 high-risk bacille Calmette-Guérin-refractory patients. CONCLUSIONS: The results of our study have confirmed the good tolerability and 1 year efficacy of intravesical gemcitabine. The treatment schedule proposed resulted in high patient compliance, and the results can be compared with the results of studies using other intravesical treatments.