Eugene P. Goldberg

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.

Inhaled chemotherapy in lung cancer: future concept of nanomedicine.

Regional chemotherapy was first used for lung cancer 30 years ago. Since then, new methods of drug delivery and pharmaceuticals have been investigated in vitro, and in animals and humans. An extensive review of drug delivery systems, pharmaceuticals, patient monitoring, methods of enhancing inhaled drug deposition, safety and efficacy, and also additional applications of inhaled chemotherapy and its advantages and disadvantages are presented. Regional chemotherapy to the lung parenchyma for lung cancer is feasible and efficient. Safety depends on the chemotherapy agent delivered to the lungs and is dose-dependent and time-dependent. Further evaluation is needed to provide data regarding early lung cancer stages, and whether regional chemotherapy can be used as neoadjuvant or adjuvant treatment. Finally, inhaled chemotherapy could one day be administered at home with fewer systemic adverse effects.

Management of malignant pleural effusion by suicide gene therapy in advanced stage lung cancer: a case series and literature review

Gene therapy can be defined as the transfer of genetic material into a cell for therapeutic purposes. Cytosine deaminase (CD) transferred into tumor cells by an adenoviral vector (Ad.CD), can convert the antifungal drug fluorocytosine (5-FC) to the antimetabolite 5-fluorouracil (5-FU), which kills not only the transfected tumor cells but also their neighbors by the so-called ‘bystander effect’. After testing a protocol for Ad.CD transfer and lung tumor burden control in a Lewis mouse model, we used this technique in the management of lung cancer patients with malignant pleural effusion (MPE): two cases are presented investigating the possible enhancement of anticancer effect in both non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) by local activation of the pro-drug 5-FC. Results were discussed in parallel to a literature review on the topic. 5-FC and Ad.CD were administered intratumorally to Lewis mouse lung carcinoma and the effect was monitored by tumor size and electromicroscopy. Two patients with advanced stage lung cancer (1SCLC, 1NSCLC), which developed MPE during first-line treatment were administered 1012 plaque-forming unit (pfu) Ad.CD by intrapleural instillation, in two doses (day1 and day7). Instillation was performed when the pleural fluid was ⩽200 ml. In addition, they received 5-FC 500 mg four times daily for 14 days. Lung tumor regression and successful transfer of adenoviral particles were observed in treated animals. Patients presented complete regression of pleural effusion as monitored by computerized tomography scan. Neutrapenia and anemia were the most severe adverse effect presented (grade III/grade IV 100%). The increased toxicity followed by the intrapleural gene therapy indicates the augmentation of anticancer effect of transformed pro-drug 5-FC to active 5-FU. The obtained data indicate that intrapleural gene therapy may be a useful tool, adjunct to chemotherapy, in the management of MPE related to lung cancer.

Prevention of postoperative pericardial adhesions with hydrophilic polymer solutions

Pericardial adhesions subject patients requiring cardiac reoperation to potential injuries of the heart, great vessels, and extracardiac grafts during resternotomy. We evaluated polyvinylpyrrolidone (PVP) and a methlycellulose derivative (MCD) as intraoperative irrigating solutions in the prevention of postoperative pericardial adhesions. Fifteen dogs weighing 15 to 20 kg were divided into three equal cohorts and subjected to left thoracotomy with pericardiotomy. Prior to surgical manipulation, the pericardial cavity was irrigated with either PVP, MCD, or Ringers lactate (RL). Serosal injury stimulating intraoperative trauma was induced by gauze sponge abrasion of the epicardium and inner surface of the pericardium and by allowing desiccation of serosal surfaces for 30 min. The pericardial cavity was evaluated for adhesion formation 6 weeks postoperatively by reoperation. Two independent observers, unaware of the study solution, evaluated the extent and severity of pericardial adhesions on a 0-4 scale. All dogs in the RL control group had surgically significant adhesions and a mean adhesion score of 3.2 +/- 1.1. In contrast, no PVP- or MCD-treated dog had surgically significant adhesions. The mean adhesion scores were 0.2 +/- 0.4 for PVP and 0.5 +/- 0.7 for MCD. Our results indicate that PVP (P less than 0.004) and MCD (P less than 0.024) significantly reduce pericardial adhesion formation when compared to RL. Clinical application of PVP or MCD for the prevention of pericardial adhesions should reduce morbidity and mortality of cardiac reoperation.

Distribution of organic matrix in calcium oxalate renal calculi

SummaryThe quantity of protein and carbohydrate comprising the matrix of calcium oxalate monohydrate (COM) renal stones was found to decrease with distance from the surface of the stone. The average organic concentration of stones 3 to 30 mm in diameter ranged from 5.7% at the surface to 2.7% at the core. This concentration gradient suggests matrix involvement in a “growth front” on stone surfaces with migration of organic material from the “older” interior. The matrix distribution was not readily correlated with density variations or with the presence of hydroxyapatite or calcium oxalate dihydrate. Surface matrix concentrations were greater than amounts predicted by physical adsorption. Electron microscopy confirmed the presence of the organic-rich surface layer and also suggested that increase in stone size occurs predominantly by crystal growth with microcrystal aggregates as growth centers.

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.

Synthesis, Properties, and Intratumoral Evaluation of Mitoxantrone-loaded Casein Microspheres in Lewis Lung Carcinoma

Abstract— Smooth, round, uniform bovine casein microspheres of 1–5 and 10–20 μm size were readily prepared by a steric stabilization technique previously developed in this laboratory for synthesis of albumin microspheres. The avid phagocytic uptake of casein and albumin microspheres was demonstrated with fluorescein‐labelled microspheres using a macrophage‐like mouse myelomonocytic leukaemia cell line. Post‐synthesis loading of 25% mitoxantrone was achieved for casein microspheres containing 20% polyglutamic acid. Preliminary intratumoural chemotherapy experiments with a mouse Lewis lung carcinoma indicated that mitoxantrone and mitoxantrone‐loaded casein‐polyglutamic acid microspheres exhibited lower toxicity when administered intratumorally.

Myringotomy Tube Materials: Bacterial Adhesion and Infection

Postoperative infection after placement of myringotomy tubes is common. Surgeons and manufacturers of surgical devices have frequently substituted one material for another in middle ear prostheses without analyzing the interaction of material and infection. Implant material attributes are reviewed. Scanning electron micrographs are presented that demonstrate characteristic surface differences between materials and between the same material of different manufacturers. A preliminary clinical controlled study of the covariance of purulence with silicone vs fluorocarbon tubes demonstrates statistically significant differences. The implications of this information are discussed.

Efficacy of mitoxantrone-loaded albumin microspheres for intratumoral chemotherapy of breast cancer.

Systemic toxicity of intravenously delivered chemotherapy is a limiting factor in the treatment of many cancers. We have shown that intratumoral injection of antineoplastic drugs can provide high localized drug concentrations with greatly reduced systemic toxicity. Using albumin microspheres as a drug carrier, localized and sustained release of chemotherapeutic drugs has been achieved by intratumoral injection, thus increasing the intratumoral dose and antitumor efficacy. Microspheres provide the advantages of localized, prolonged drug release. The efficacy and toxicity of intratumoral free mitoxantrone or mitoxantrone-loaded albumin microspheres were evaluated in a murine breast cancer model. In the same model, a combination of these two therapies was also evaluated. Results indicated that intratumoral mitoxantrone, especially in microsphere preparations, significantly improved survival and decreased systemic toxicity.

Hydrophilic surface modification of metallic endoluminal stents.

PURPOSE Stainless steel endovascular stents are inherently thrombogenic so that thrombus accumulates on these devices, leading to acute vessel occlusion. A potential solution to this problem is stent surface modification with hydrophilic polymers, which might limit platelet adhesion and reactivity. METHODS N-vinylpyrrolidone (NVP) and potassium sulfopropyl acrylate (KSPA) hydrophilic monomers were gamma graft polymerized onto 1 cm2 stainless steel slabs and 4 mm Palmaz stainless steel stents. Surface characteristics of modified and plain stainless steel stents were then investigated with contact angle and x-ray photoelectron spectroscopy measurements, and in vitro and in vivo platelet reactivity was assessed as 111Indium platelet accumulation expressed as counts/min/cm2. RESULTS Surface modification of stainless steel slabs and stents with both NVP and KSPA hydrophilic polymers significantly reduced in vitro platelet adhesion (plain = 2249 +/- 723 counts/min/cm2, NVP = 428 +/- 156 counts/min/cm2, KSPA = 958 +/- 223 counts/min/cm2) and in vivo platelet accumulation after 1 hour of blood flow exposure (plain = 1407 +/- 796 counts/min/cm2, NVP = 426 +/- 175 counts/min/cm2, KSPA = 399 +/- 124 counts/min/cm2. In addition, platelet accumulation on modified stents indexed to plain stents was lowest in KSPA-modified stents (NVP = 79.3% +/- 31.7% of plain, KSPA = 51.2% +/- 36.2% of plain). Surface analysis confirmed surface grafting with both monomers, and SEM documented smoothing of the irregular surfaces of the stainless steel stents after grafting. CONCLUSION Hydrophilic polymer surface modification of stainless steel stents decreases initial stent surface platelet accumulation, which may decrease the risk of vessel thrombosis associated with the use of these devices.