Numerous studies have demonstrated that liposomal encapsulation decreases the life-threatening chronic and acute toxicities of doxorubicin in the face of unaltered or improved antitumor activity. Minimal attention has been paid to the encapsulation effect on the lesser toxicities of the drug, specifically the vesicant properties. In this report we assess the effect of the encapsulation of doxorubicin in an egg-yolk phosphatidylcholine (EPC) cholesterol liposome on the drug's topical toxicity. In addition, to ensure acceptable activity and reduction in toxicity comparable with those of previously assessed formulations, the cardiac and acute toxicities and antitumor activity of the liposomal doxorubicin complex were also investigated. Antitumor efficacy was assessed using the metastatic murine P815 mastocytoma model. Equivalent doses of free and encapsulated doxorubicin possessed the same antitumor activity in the prolongation of animal survival in 14-day survival studies conducted to assess the effect of liposomal encapsulation on the acute toxicity of this drug. The LD50 of liposomal doxorubicin was found to be 40 mg/kg, 53% higher than that of free doxorubicin (26 mg/kg). Histologic examination of cardiac sections taken from DBA/2J mice 7 days after a single i.v. injection of free or liposomal doxorubicin (25 mg/kg) revealed that the liposomal preparation was much less cardiotoxic. In animals receiving the free drug, edema, monocytic infiltration, and cell necrosis were evident. In contrast, those receiving the liposomal preparation demonstrated slight cellular edema but showed no evidence of cellular necrosis. To assess vesicant properties, DBA/2J mice were given a single s.c. injection (0.2 ml) of free or liposomal doxorubicin (2 mg/ml). Those receiving the free drug immediately developed erythema and edema at the injection site, which progressed to ulceration. Those receiving the liposomal complex developed slight erythema and edema but did not ulcerate at any time. All signs of irritation in this group had subsided 3 weeks postinjection. In summary, the liposomal complex used eliminated the vesicant properties of doxorubicin as well as significantly decreasing its cardiac and acute toxicities in the face of unaltered antitumor activity.

Background. Local failure after curative surgery for colorectal adenocarcinoma remains a major source of morbidity and mortality. This retrospective analysis reviews the authors' experience with pelvic exenteration in the setting of recurrent and locally advanced colorectal cancer. Methods. Between 1979 and 1986, 50 pelvic exenterations were performed for recurrent (43) and primary (7) colorectal pelvic malignancies. Of these, 30 patients were operated on with curative intent, whereas 20 underwent operation for palliation of intractable pain, sepsis, fistula, bleeding, or bowel obstruction. Twenty‐six patients had received radiation to 4000 cGy or more. Of the recurrent tumors, the median time from primary treatment to exenteration was 39.7 months. Results. Postoperative mortality included 7 in‐hospital deaths (14%): 5 of 20 in the palliative group and 2 of 30 in the curative group. Complications were common (a total of 71 occurrences), but there has been a significant decrease with experience. The median survival was 19 months for the curative group and 10 months for the palliative group, excluding perioperative mortality. The 5‐year survival was 6% overall, and 10% for the curative group. Eighty‐nine percent of patients in the curative group had significant pain relief (71% complete, 18% partial), whereas 67% of those in the palliative group had complete or partial pain control. Conclusions. Long‐term survival after pelvic exenteration for recurrent colorectal carcinoma is uncommon (2/43), but sustained palliation and local control can be achieved with acceptable morbidity and mortality in most patients with intractable pelvic symptoms.

The leukocyte CD44 and CD45 cell surface receptors are associated via the linker proteins ankyrin and fodrin with the cytoskeleton, which itself is important in immune cell functions such as adherence, chemotaxis, and phagocytosis. The effects of rat antihuman CD44 and CD45 monoclonal antibodies on phagocytosis of fluoresceinated heat-killed Staphylococcus aureus 502A by normal human neutrophils (PMNs) during 2 hr incubation in RPMI-1640 was studied via flow cytometry and confocal microscopy. Flow cytometry was performed using an excitation wavelength of 488 nm, fluorescence being measured at 515-560 nm on 50,000 PMNs per sample. Confocal microscopy was performed on samples after further incubation with rhodamine-conjugated antiankyrin. Anti-CD44 resulted in an increase of 27-31% compared to control (P = 0.004) in the proportion of PMNs fluorescing, an increase of 17-24% (P = 0.001) in mean intracellular fluorescence per PMN, and an increase in total PMN fluorescence of 50-58% compared to control (P < 0.001). In contrast, anti-CD45 had little effect on phagocytosis. Colchicine (a microtubule-disrupting agent) enhanced, whereas cytochalasin-D (a microfilament inhibitor) inhibited bacterial phagocytosis; cytochalasin-D completely abrogated the effect of anti-CD44 on this PMN function. Hyaluronic acid augmented phagocytosis by an increment similar to that observed with anti-CD44. Two-color flow cytometry and confocal microscopy demonstrated that ankyrin always colocalized with ingested fluorescein isothiocyanate (FITC)-labeled bacteria. These data strongly suggest that CD44 is involved in bacterial phagocytosis, provide further evidence of CD44 receptor linkage to cytoskeletal elements in human leukocytes, and suggest that ankyrin has a significant role in the transport of phagosomes.

A B S T R A C T The question of whether hypersensitivity to streptococcal antigens plays a role in the pathogenesis of the nonsuppurative sequelae of streptococcal infections remains at present unclear. As a first step in the approach to this question, the degree of cellular reactivity of peripheral blood leucocytes to streptococcal antigens was investigated in a number of rheumatic fever patients, patients with uncomplicated streptococcal infections, as well as normal healthy subjects.Using the in vitro technique for the inhibition of capillary migration of peripheral blood leucocytes as an index of the degree of sensitivity to streptococcal antigens, the results indicate that patients with acute rheumatic fever exhibit an exaggerated cellular reactivity to these antigens and in particular to streptococcal cell membrane antigens. This abnormal response to streptococcal membrane antigens appears to persist in rheumatic subjects for at least 5 yr after the initial 'attack of rheumatic fever. Only Group A streptococcal membrane antigens elicited this unusual response in rheumatic subjects, since the cellular reactivity to Group C and D streptococcal membranes was the same in all groups. Patients with evidence of valvular disease exhibited the same degree of cellular reactivity to these antigens as did patients without clinical evidence of rheumatic heart disease.The nature of the antigens responsible for the observed cellular response remains unknown. Enzymatic treatment of streptococcal cell walls and membranes designed to remove type-specific M proteins did not alter the observed cellular reactivity to the streptococcal antigens. The finding that an abnormal cellular response to certain streptococcal antigens is present only in rheuReceived for publication 17 July 1972 and in revised form 14 January 1974. matic patients suggests that cell-mediated factors may play an important role in the disease process. INTRODUCTICNThe question of whether hypersensitivity to hemolytic streptococci and their products might play a role in the pathogenesis of the nonsuppurative sequelae of streptococcal infections has been the subject of investigation for many years. Starting with the early work of Swift and Derick and Derick, Hitchcock, and Swift in animals (1-3), it was apparent that delayed hypersensitivity to streptococci behaved in a manner similar to that observed for tuberculin sensitivity (4). Initiation of sensitivity by prolonged focal contact between the intact bacteria and tissues of the host, inability to passively transfer streptococcal-delayed hypersensitivity with serum alone, and the lack of correlation between circulating antibodies to streptococcal products and delayed allergy were all characteristics of the streptococcal hypersensitive state (5). Apropos of these studies, several intriguing observations concerning the streptococcal hypersensitive state were made. First, repeated small inoculations of heat-killed streptococci were more effective in inducing the hypersensitive state than a single inoculation of ...