Ralph S. Greco

Gemcitabine Chemotherapy and Single-Fraction Stereotactic Body Radiotherapy for Locally Advanced Pancreatic Cancer

PURPOSE Fractionated radiotherapy and chemotherapy for locally advanced pancreatic cancer achieves only modest local control. This prospective trial evaluated the efficacy of a single fraction of 25 Gy stereotactic body radiotherapy (SBRT) delivered between Cycle 1 and 2 of gemcitabine chemotherapy. METHODS AND MATERIALS A total of 16 patients with locally advanced, nonmetastatic, pancreatic adenocarcinoma received gemcitabine with SBRT delivered 2 weeks after completion of the first cycle. Gemcitabine was resumed 2 weeks after SBRT and was continued until progression or dose-limiting toxicity. The gross tumor volume, with a 2-3-mm margin, was treated in a single 25-Gy fraction by Cyberknife. Patients were evaluated at 4-6 weeks, 10-12 weeks, and every 3 months after SBRT. RESULTS All 16 patients completed SBRT. A median of four cycles (range one to nine) of chemotherapy was delivered. Three patients (19%) developed local disease progression at 14, 16, and 21 months after SBRT. The median survival was 11.4 months, with 50% of patients alive at 1 year. Patients with normal carbohydrate antigen (CA)19-9 levels either at diagnosis or after Cyberknife SBRT had longer survival (p <0.01). Acute gastrointestinal toxicity was mild, with 2 cases of Grade 2 (13%) and 1 of Grade 3 (6%) toxicity. Late gastrointestinal toxicity was more common, with five ulcers (Grade 2), one duodenal stenosis (Grade 3), and one duodenal perforation (Grade 4). A trend toward increased duodenal volumes radiated was observed in those experiencing late effects (p = 0.13). CONCLUSION SBRT with gemcitabine resulted in comparable survival to conventional chemoradiotherapy and good local control. However, the rate of duodenal ulcer development was significant.

The FcγRII Receptor Triggers pp125FAK Phosphorylation in Platelets

Platelets express a single low affinity receptor for immunoglobulin, FcγRII, that triggers multiple cellular responses upon interaction with multivalent immune complexes. In this study we show that immobilized IgG is also a potent stimulant of platelet activation triggering adhesion, aggregation, massive dense granule secretion, and thromboxane production. Platelet adhesion to IgG was blocked by the FcγRII receptor-specific monoclonal antibody, IV.3. Pretreatment of the platelets with cytochalasin D to inhibit actin polymerization similarly prevented cell binding to IgG having no effect on platelet binding to fibrinogen. Platelet adhesion to IgG also led to the induction of tyrosine phosphorylation of multiple proteins including pp125FAK and p72SYK. These proteins were also tyrosine-phosphorylated in αIIbβ3-deficient IgG-adherent platelets from patients with Glanzmanns thrombasthenia. These data demonstrate that FcγRII mediates pp125FAK phosphorylation and platelet adhesion to IgG independent of the integrin αIIbβ3. Treatment of the platelets with bisindolylmaleimide to inhibit protein kinase C prevented phosphorylation of pp125FAK as well as several other proteins, but not p72SYK phosphorylation. This study establishes that the FcγRII receptor mediates pp125FAK phosphorylation via protein kinase C.

The role of antibiotic bonding in the prevention of vascular prosthetic infections.

Oxacillin, a negatively charged antibiotic, was bonded to polytetrafluoroethylene (PTFE) grafts using the cationic surfactant, benzalkonium chloride. Control PTFE grafts and bonded grafts prepared at room temperature and at 90 C were placed in the infrarenal aorta of dogs and challenged by local contamination with Staphylococcus aureus. Bonded grafts were superior to controls in negative cultures, patency, and survival. The possible role of antibiotic bonding in the prevention of vascular prosthetic infection is discussed.

Subtle Differences in Quality of Life After Breast Cancer Surgery

Background: Lumpectomy with axillary dissection (LAD) has taken its place alongside mastectomy (M) as the treatment of choice for stage I and II breast cancer. Its appeal is based on lessening disfigurement and thus improving quality of life.Methods: We used the SF-36 Health Survey modified with ten questions relevant to breast cancer surgery to evaluate whether quality of life with LAD was better than with mastectomy in women with stage I and II disease. The additional questions addressed satisfaction with intimate relationships and sexuality, and explored impact on the way women dress, use bathing suits, hug people, are comfortable with nudity, and rate their sexual drive and sexual responsiveness.Results: LAD was not associated with statistically significant better quality-of-life scores on any SF-36 questions, except vitality (P = .02). No differences were noted in the areas of intimacy and sexual satisfaction. LAD patients reported significant differences in matters of dress, use of bathing suits, hugging, comfort with nudity, and sexual drive compared to patients undergoing mastectomy.Conclusions: The SF-36 health survey detected few differences in quality of life measures between patients with LAD and those with mastectomy. However, LAD impacts favorably on the way women dress, on comfort with nudity, and on sexual drive.

Prevention of vascular prosthetic infection with an antibiotic-bonded Dacron graft***★

Surfactant-mediated antibiotic bonding was used in an animal model of aortic prosthetic infection. Control grafts, control plus parenteral oxacillin, and oxacillin-bonded Dacron grafts were challenged by local inoculation with Staphylococcus aureus. Ninety percent of controls, 80% of parenteral antibiotic recipients, and only 30% of antibiotic-bonded Dacron grafts became infected (p less than 0.01, p less than 0.03). Antibiotic-bonded grafts were also superior in terms of suture line cultures and patency. In separate experiments in a subcutaneous pouch model, antibiotic bonding significantly improved the median infective dose of Dacron over that of controls and Dacron soaked in cephalosporin. These studies demonstrate that antibiotic-bonded Dacron implants are highly resistant to infection. A multicenter clinical trial is planned.

Three dimensional staging of breast cancer.

SummaryPurposeBreast cancers are three dimensional solids but very few are spherical. We hypothesized that calculations based on the greatest diameter would not accurately reflect tumor volume and that three dimensional measurements would affect tumor staging.Materials and methods: 165 invasive carcinomas measuring 2.5 cm or less and having three measured diameters (a ≥ b ≥ c) noted were evaluated. Tumor volume was calculated using four geometric models: the spherical 4/3π (a/2)3, prolate spheroid 4/3π (a/2) (c/2)2, oblate spheroid 4/3π (a/2)2 (b/2), and ellipsoid 4/3π (a/2 × b/2 × c/2). The ellipsoid correctly determined the volume for any tumor shape. All cases were stratified according to the TNM staging system. Differences in mean volume calculated as a sphere and ellipsoid for each tumor subclass were analyzed using Students T test. The reclassification of tumors by the ellipsoid formula was determined.Results: Seventy-six (46.1%) had tumors with three different diameters while only six (3.6%) were true spheres having three identical diameters. Mean tumor volume analysis of T1a, T1b, T1c, and T2 tumors demonstrated a statistically significant overestimation of volume when utilizing the sphere formula instead of the ellipsoid formula (p < 0.05). The differences in volume were more dramatic as the diameters increased. A total of 41 tumors were moved into smaller T subclasses including 10 node positive patients.Conclusions: Tumor volume analysis demonstrates that use of only the greatest diameter poorly reflects the true volume of a lesion and consistently overestimates volume. The ellipsoid formula accurately calculates volume for these three dimensional tumors and when utilized has significant relevance to staging small invasive breast cancers.

The noncovalent bonding of antibiotics to a polytetrafluoroethylene-benzalkonium graft.

This study evaluates the noncovalent bonding of anionic antibiotics to polytetrafluoroethylene grafts using hciual-konium chloride as u cationic anchor. The binding of radiolabeled surfactants and antibiotics was evaluated by liquid scintillation and in an in vitro microbiologic assay against Staphylococcus aureus. Significant quantities of antibiotic were bound when the grafts were pretreated with benzalkonium in ethanol or aqueous solution at elevated temperature. Bound antibiotic is stable in aqueous salt solutions, but slowly dissociates in the presence of blood or serum. The ionic nature of the bonding process is clarified by the use of a variety of antibiotics and surfactants with complementary charges. The ability of the bcn/.alkonium treated grafts to adsorb antibiotic from blood is, likewise, demonstrated and the possibility of concomitantly binding heparin and antibiotic simultaneously is evaluated. These studies support the ability to noncovalently bond antibiotics to polytetrafluoroethylene surfaces and form the basis for eventually utilizing these surfaces in the prevention of vascular prosthetic infections

Five year survival in patients with carcinoma of the rectum treated by electrocoagulation

Sixty-eight patients with rectal cancer treated by electrocoagulation are reviewed. All were followed up for a minimum of 5 years. The survival rate in patients with small exophytic cancers is greater than 70 percent. However, the recurrence rate after electrocoagulation is 40 percent. Electrocoagulation offers an alternative for the primary treatment of rectal cancer, particularly in older patients with small lesions.

Infection-Resistant Continuous Peritoneal Dialysis Catheters

The techniques of bonding of anionic antibiotics by treatment with cationic surfactants were applied to continuous ambulatory peritoneal dialysis (CAPD) catheters. The elution of 14C-penicillin from tridodecylmethylammonium chloride (TDMAC) treated silicone elastomer catheters in dialysis solution was biphasic, with 95% dissociated from the catheter by 48 h. Forty percent of the TDMAC left the catheter surface during the initial 2 days. The ability of the surfactant TDMAC to bind antibiotics after incubation in dialysis solution correlated directly with the amount of surfactant remaining. Rats with intraperitoneal dialysis catheters were inoculated with exit site and intraluminal bacterial challenges. Intraperitoneal catheter tips treated with TDMAC-penicillin were rendered more resistant to colonization after exit site and intraluminal bacterial challenges.

The Inverse Relationship Between Microvessel Counts and Tumor Volume in Breast Cancer

Abstract: Angiogenesis has emerged as an indicator of metastatic potential in invasive breast cancer. Exponential tumor growth and the appearance of metastasis are observed as new microvessels form. We postulated that the relevance of angiogenesis would be enhanced if analyzed as a function of tumor volume rather than greatest diameter alone and that microvessel counts would proportionately increase as does volume. Since tumors are three‐dimensional solids, volume was calculated using the formula for an ellipsoid, V = π/6 (a×b×c). Sixty‐four tumors 2.5 cm were studied and analyzed in 5 mm incremental ranges. Mean microvessel counts did not vary significantly among these tumor size groups. However, analysis of microvessel counts as a function of tumor volume decreased from 947.1/cm3 (0–0.5 cm) to 18.1/cm3 (2.1–2.5 cm), a greater than 50‐fold difference. High microvessel density in small cancers supports the notion of metastasis as an early event, making these small tumors perhaps ideal targets for antiangiogenic agents.