Carboplatin and Etoposide for the Treatment of Metastatic Prostate Cancer with or without Neuroendocrine Features: A French Single-Center Experience.

BACKGROUND: Chemotherapy using carboplatin and etoposide (CE) is frequently pragmatically proposed to treat metastatic prostate cancer (mPC), both primary small-cell neuroendocrine (PSC-NE) carcinoma and adenocarcinoma with or without neuroendocrine (NE) marker elevation. However, the real benefit of CE is poorly reported in the recent therapeutic context. METHODS: We retrospectively analyzed the efficacy and tolerance of CE chemotherapy in these three different groups of mPC patients. Efficacy endpoints included radiological response, progression-free survival (PFS), and overall survival (OS), as well as PSA response and PFS2/PFS1 ratio in patients with adenocarcinoma. RESULTS: Sixty-nine patients were included in this single-center study (N = 18 with PSC-NE carcinoma and 51 with adenocarcinoma with (N = 18) or without (N = 33) NE marker elevation). Patients with adenocarcinoma were highly pretreated with next-generation hormonal agents (NHAs) and taxanes. In patients with adenocarcinoma, a PSA response ≥50% was observed in six patients (15.8%), four of whom had NE marker elevation. The radiological response was higher in PSC-NE and tended to be higher in adenocarcinoma when NE marker elevation was present. Comparing patients with adenocarcinoma with vs. without NE marker elevation, the median PFS was 3.7 and 2.1 months and the median OS was 7.7 and 4.7 months, respectively. Overall, 62.3% of patients experienced grade 3-4 adverse events (mainly hematological), and three treatment-related deaths were recorded. CONCLUSION: Reports of the clinical results of CE suggest that we should not mix PSC-NE and castration-resistant adenocarcinoma of the prostate. In patients with heavily pretreated adenocarcinoma, the benefit/risk ratio of CE chemotherapy seems unfavorable due to poor response and high toxicity.

Macro- and micro-designed chitosan-alginate scaffold architecture by three-dimensional printing and directional freezing.

While many tissue-engineered constructs aim to treat cartilage defects, most involve chondrocyte or stem cell seeding on scaffolds. The clinical application of cell-based techniques is limited due to the cost of maintaining cellular constructs on the shelf, potential immune response to allogeneic cell lines, and autologous chondrocyte sources requiring biopsy from already diseased or injured, scarce tissue. An acellular scaffold that can induce endogenous influx and homogeneous distribution of native stem cells from bone marrow holds great promise for cartilage regeneration. This study aims to develop such an acellular scaffold using designed, channeled architecture that simultaneously models the native zones of articular cartilage and subchondral bone. Highly porous, hydrophilic chitosan-alginate (Ch-Al) scaffolds were fabricated in three-dimensionally printed (3DP) molds designed to create millimeter scale macro-channels. Different polymer preform casting techniques were employed to produce scaffolds from both negative and positive 3DP molds. Macro-channeled scaffolds improved cell suspension distribution and uptake overly randomly porous scaffolds, with a wicking volumetric flow rate of 445.6 ± 30.3 mm(3) s(-1) for aqueous solutions and 177 ± 16 mm(3) s(-1) for blood. Additionally, directional freezing was applied to Ch-Al scaffolds, resulting in lamellar pores measuring 300 µm and 50 µm on the long and short axes, thus creating micrometer scale micro-channels. After directionally freezing Ch-Al solution cast in 3DP molds, the combined macro- and micro-channeled scaffold architecture enhanced cell suspension uptake beyond either macro- or micro-channels alone, reaching a volumetric flow rate of 1782.1 ± 48 mm(3) s(-1) for aqueous solutions and 440.9 ± 0.5 mm(3) s(-1) for blood. By combining 3DP and directional freezing, we can control the micro- and macro-architecture of Ch-Al to drastically improve cell influx into and distribution within the scaffold, while achieving porous zones that mimic articular cartilage zonal architecture. In future applications, precisely controlled micro- and macro-channels have the potential to assist immediate endogenous bone marrow uptake, stimulate chondrogenesis, and encourage vascularization of bone in an osteochondral scaffold.

Bioinspired Hydroxyapatite/Poly(methyl methacrylate) Composite with a Nacre-Mimetic Architecture by a Bidirectional Freezing Method.

Using a bidirectional freezing technique, combined with uniaxial pressing and in situ polymerization, "nacre-mimetic" hydroxyapatite/poly(methyl methacrylate) (PMMA) composites are developed by processing large-scale aligned lamellar ceramic scaffolds. Structural and mechanical characterization shows "brick-and-mortar" structures, akin to nacre, with interesting combinations of strength, stiffness, and work of fracture, which provide a pathway to making strong and tough lightweight materials.

Biomimetic gradient scaffold from ice-templating for self-seeding of cells with capillary effect.

One of the most important issues in bone tissue engineering is the search for new materials and processing techniques to create novel scaffolds with 3-D porous structures. Although many properties such as biodegradability and porosity have been considered in designing bone scaffolds, very limited attention is paid to their capillary effect. In nature, capillary effect is ubiquitously used by plants and animals to constantly transport water and nutrients based on morphological and/or chemical gradient structures at multiple length-scales. In this work, we developed a modified freeze-casting technique to prepare ceramic scaffolds with gradient channel structures. The results show that our hydroxyapatite (HA) scaffolds have interconnected gradient channels that mimic the porous network of natural bone. More importantly, we demonstrate that such a scaffold has a very unique capillary behavior that promotes the self-seeding of cells when in contact with a cell solution due to spontaneous capillary flow generated from gradient channel structures. The strategy developed here provides a new avenue for designing "smart" scaffolds with complex porous structures and biological functions that mimic natural tissues.

Bioinspired large-scale aligned porous materials assembled with dual temperature gradients.

Natural materials, such as bone, teeth, shells, and wood, exhibit outstanding properties despite being porous and made of weak constituents. Frequently, they represent a source of inspiration to design strong, tough, and lightweight materials. Although many techniques have been introduced to create such structures, a long-range order of the porosity as well as a precise control of the final architecture remain difficult to achieve. These limitations severely hinder the scale-up fabrication of layered structures aimed for larger applications. We report on a bidirectional freezing technique to successfully assemble ceramic particles into scaffolds with large-scale aligned, lamellar, porous, nacre-like structure and long-range order at the centimeter scale. This is achieved by modifying the cold finger with a polydimethylsiloxane (PDMS) wedge to control the nucleation and growth of ice crystals under dual temperature gradients. Our approach could provide an effective way of manufacturing novel bioinspired structural materials, in particular advanced materials such as composites, where a higher level of control over the structure is required.

Unidirectional freezing of ceramic suspensions: in situ X-ray investigation of the effects of additives.

Using in situ X-ray radiography, we investigated unidirectional freezing of titanium dioxide suspensions. We showed how processing additives, which are generally used for ice-templating, strongly modified freezing dynamics during the solidification process. We observed and identified different freezing regimes by varying the amount of dispersant, binder, or poly(ethylene glycol) (PEG). We demonstrated that because each regime corresponds to a given final structure understanding the particle motion and redistribution at the ice-front level was essential. We also examined the transition from a random particles-entrapment regime to a well-defined lamellar regime and proposed and discussed two mechanisms by which additives might affect the solidification process.

Thermoresponsive composite hydrogels with aligned macroporous structure by ice-templated assembly.

Natural tissues, such as bone, tendon, and muscle, have well defined hierarchical structures, which are crucial for their biological and mechanical functions. However, mimicking these structural features still remains a great challenge. In this study, we use ice-templated assembly and UV-initiated cryo-polymerization to fabricate a novel kind of composite hydrogel which have both aligned macroporous structure at micrometer scale and a nacre-like layered structure at nanoscale. Such hydrogels are macroporous, thermoresponsive, and exhibit excellent mechanical performance (tough and high stretchable), attractive properties that are of significant impact on the wide applications of composite hydrogels, especially as tissue-engineering scaffolds. The fabrication method in this study including freeze-casting and cryo-polymerization can also be applied to other materials, which makes it promising for designing and developing smart and multifunctional composite hydrogels with hierar chical structures.