James S. Marotta

Intratumoral cancer chemotherapy and immunotherapy: opportunities for nonsystemic preoperative drug delivery.

The recent literature documents the growing interest in local intratumoral chemotherapy as well as systemic preoperative chemotherapy with evidence for improved outcomes using these therapeutic modalities. Nevertheless, with few exceptions, the conventional wisdom and standard of care for clinical and surgical oncology remains surgery followed by radiation and/or systemic chemotherapy, as deemed appropriate based on clinical findings. This, in spite of the fact that the toxicity of conventional systemic chemotherapy and immunotherapy affords limited effectiveness and frequently compromises the quality of life for patients. Indeed, with systemic chemotherapy, the oncologist (and the patient) often walks a fine line between attempting tumour remission with prolonged survival and damaging the patients vital functions to the point of death. In this context, it has probably been obvious for more than 100 years, due in part to the pioneering work of Ehrlich (1878), that targeted or localized drug delivery should be a major goal of chemotherapy. However, there is still only limited clinical use of nonsystemic intratumoral chemotherapy for even those high mortality cancers which are characterized by well defined primary lesions i.e. breast, colorectal, lung, prostate, and skin. There has been a proliferation of intratumoral chemotherapy and immunotherapy research during the past two to three years. It is therefore the objective of this review to focus much more attention upon intratumoral therapeutic concepts which could limit adverse systemic events and which might combine clinically feasible methods for localized preoperative chemotherapy and/or immunotherapy with surgery. Since our review of intratumoral chemo‐immunotherapy almost 20 years ago (McLaughlin & Goldberg 1983), there have been few comprehensive reviews of this field; only one of broad scope (Brincker 1993), three devoted specifically to gliomas (Tomita 1991; Walter et al. 1995; Haroun & Brem 2000), one on hepatomas (Venook 2000), one concerning veterinary applications (Theon 1998), and one older review of dermatological applications (Goette 1981). However, none have shed light on practical opportunities for combining intratumoral therapy with subsequent surgical resection. Given the state‐of‐the‐art in clinical and surgical oncology, and the advances that have been made in intratumoral drug delivery, minimally invasive tumour access i.e. fine needle biopsy, new drugs and drug delivery systems, and preoperative chemotherapy, it is timely to present a review of studies which may suggest future opportunities for safer, more effective, and clinically practical non‐systemic therapy.

Silicone gel breast implant failure: evaluation of properties of shells and gels for explanted prostheses and meta-analysis of literature rupture data.

After 30 years of clinical use, the 1992 Food and Drug Administration moratorium on silicone gel breast implants (SGBIs) resulted from a paucity of scientific data concerning their safety. The frequency of rupture and reoperative procedures was not known, nor were reliable data available for changes in the physical properties of shells and the composition of gels that might lead to SGBI failure. For this reason the authors conducted large-cohort meta-analyses of failure data for SGBIs based on numerous literature reports and also investigated systematically shell and gel properties from explanted SGBIs. They report their failure analysis data for more than 9,770 SGBIs (an update of an earlier study of more than 8,000 implants) as well an examination of the properties of shells and gels for 74 explanted SGBIs that ranged in age from 2 to 19 years (mean implanted age, 9.9 years). The explants tested were from several different manufacturers. For the modest-size explant cohort that was tested, 31 of 74 implants (42%) were found to be ruptured (some extensively). Even many intact shells were so weakened that only 51 shells had sufficient strength to enable preparation of samples for testing of mechanical properties and for analysis of composition by solvent extraction. Shells were found to contain 15 to 25% of extractable silicone. Exhaustive extraction of gels showed that they actually contained very little crosslinked silicone—85 to 95% being extractable soluble silicone fluid. Tensile and tear strengths of explanted silicone elastomer shells were lower than unimplanted prostheses and were generally well below reported manufacturers’ values. This updated large-cohort failure analysis continues to show that shell rupture is related directly to implant duration (e.g., from analysis of variance statistics, 26% failure at 3.9 years, 47% at 10.3 years, 69% at 17.8 years;p ≤ 0.001). However, for the relatively small series of explants for which physical property data are reported, no significant correlation was observed between implant duration and the degradation of implant strength. It therefore appears most reasonable to conclude that after early weakening of shells as a result of swelling of the shell elastomer by diffusion of silicone oil from the gel, SGBI failure can occur in a time-dependent manner as a result of continuing implant motion and cyclic stresses that are exacerbated by stress concentration at thin areas, defects, and folds in the shells.

In vitro measurement of silicone bleed from breast implants.

&NA; A method to measure gel bleed from intact silicone gel‐filled breast implants was developed. This nondestructive technique permits accurate and reproducible serial measurements of silicone bleed from smooth wall breast implants (n = 10) under simulated physiologic conditions in vitro. Gel bleed rates from new low bleed gel‐filled implants and intact explants (unbarriered, low bleed, double lumen) were determined. These results demonstrate the reliability of this method to quantify silicone gel bleed and may permit a meaningful comparison of bleed rates from implants in the future. (Plast. Reconstr. Surg. 97; 756, 1995.)

Silicone Degradation Reactions

Silicone (polydimethylsiloxane, PDMS) is generally a very stable polymer. Because of this, it is used in a wide variety of adverse environments such as those with high temperature or as electrical insulation. However, a great deal of this stability derives from the fact that hydrolysis reactions which occur are reversible and the polymer essentially heals itself. It is likely that such reversibility would not occur in the surface region where high concentrations of other components, such as water, can exist. Because of the significant concern about the fate of silicone released from breast implants in particular, it is important to understand the types of chemical changes which may occur in silicone upon exposure to physiological environments so that the data on various silicon-containing species can be correlated with other physiological studies on known compounds. Accordingly, this chapter will focus on the known silicone degradation reactions which occur within normal physiological ranges (37° and mixed aqueous environment). Various other studies will be drawn upon to evaluate the possible changes since the literature on silicone modification under physiological situations is sparse at this time. Three main reactions discussed are hydrolysis, oxidation, and addition.

Properties of gel-silica optical matrices with 4.5-nm and 9.0-nm pores

Sol-gel processing of tetramethyl orthosilicate with HNO3 as a catalyst has been used to make optically transparent silica matrices with interconnected porosity of 1.2 to 1.4 nm radii. However, large pores are often needed for impregnation of the matrices with optically active organics. Larger pore volumes are also desirable for many applications of these optical composites. Two methods for producing larger pore matrices are compared: (1) Catalysis with dilute HF, and (2) aging in a basic NH4OH solution. Pore radii of matrices made by the HF method are 5.0 nm after thermal stabilization at 900 degree(s)C and 4.4 nm after 1000 degree(s)C. Pore volumes are 0.9 cm3/g at 900 degree(s)C and 0.7 cm3/g at 1000 degree(s)C. The ammonia aging process yields 9.0 nm radius pores at 900 degree(s)C and 8.7 nm pores at 1000 degree(s)C. Pore volumes are 1.0 cm3/g at 1000 degree(s)C. Optical properties (including UV cut-off, UV-vis-NIR transmission, IR absorption, index of refraction), bulk and structural densities of the matrices made by both methods (900 degree(s)C and 1000 degree(s)C stabilization) are compared with the 1.4 nm pore radius matrices.