Pharmacodynamics and pharmacokinetics of a 72-hour infusion of 9-aminocamptothecin in adult cancer patients.

PURPOSE: To investigate the pharmacokinetics and pharmacodynamics of 9-aminocamptothecin (9-AC) infused over 72 hours at doses of 5 to 74 micrograms/m2/h. PATIENTS AND METHODS: 9-AC lactone and total (lactone plus carboxylate) plasma concentrations were measured in 44 patients with solid tumors using a high-performance liquid chromatography (HPLC) assay. Fifteen patients underwent extended pharmacokinetic sampling to determine the distribution and elimination kinetics of 9-AC. RESULTS: At steady-state, 8.7% +/- 4.7% (mean +/- SD) of the total drug circulated in plasma as the active 9-AC lactone. Clearance of 9-AC lactone was uniform (24.5 +/- 7.3 L/h/m2) over the entire dose range examined; however, total 9-AC clearance was nonlinear and increased at higher dose levels. In 15 patients treated at dose levels > or = 47 micrograms/m2/h, the volume of distribution at steady-state for 9-AC lactone was 195 +/- 114 L/m2 and for total 9-AC it was 23.6 +/- 10.6 L/m2. The elimination half-life was 4.47 +/- 0.53 hours for 9-AC lactone and 8.38 +/- 2.10 hours for total 9-AC. In pharmacodynamic studies, dose-limiting neutropenia correlated with steady-state lactone concentrations (Css) R2 = .77) and drug dose (R2 = .71). CONCLUSION: Plasma 9-AC concentrations rapidly declined to low levels following the end of a 72-hour infusion and the mean fraction of total 9-AC circulating in plasma as the active lactone was less than 10%. The pharmacokinetics of 9-AC may have a great impact on its clinical activity and should be considered in the design of future clinical trials of this topoisomerase I inhibitor.

Severe neurotoxicity following 5-fluorouracil-based chemotherapy in a patient with dihydropyrimidine dehydrogenase deficiency.

Patients with decreased dihydropyrimidine dehydrogenase (DPD) activity are at increased risk for experiencing serious adverse reactions following 5-fluorouracil (5-FU)-based chemotherapy. Symptoms include severe and potentially life-threatening gastrointestinal toxicity, myelosuppression, and neurological toxicity. In the present study, we describe a 50-year-old Caucasian man who developed severe encephalopathy during his second cycle of 5-FU chemotherapy. The patient remained in a comatose state for 4 days but then showed dramatic improvement in his neurological status following continuous i.v. infusion of thymidine at 8 g/m2/day. Laboratory studies revealed the patient to be severely DPD deficient, as demonstrated by DPD enzyme activity from peripheral blood mononuclear cells being below the lower limit of the 95th percentile of a control population and by Western immunoblot analysis showing undetectable levels of DPD protein. Additional studies revealed a significant defect in pyrimidine catabolism with a 3.3- and 365-fold increase in the levels of uracil in plasma and urine, respectively, compared to normal subjects. Family studies suggest that the inheritance pattern of this syndrome is complex and most consistent with an autosomal recessive trait. This study demonstrates that cancer patients with DPD deficiency are at increased risk for developing severe neurological toxicity secondary to 5-FU chemotherapy, and that infusional thymidine should be considered as a potential rescue agent against this particular host toxicity.

Closure of large postradiation vesicovaginal fistula with rectus abdominis myofascial flap.

We report the case of a patient who developed a large radiation-induced vesicovaginal fistula. She also had a paucity of the omentum due to previous laparotomy and adhesions. We were able to treat this patient successfully with a pedicled myofascial rectus abdominis flap.

Magnetic ports in tissue expanders--a caution for MRI.

Although a great deal is known about the potential hazards of ferromagnetic materials relative to MRI, little has been written about the safety of tissue panders. Recently a new modification of the existing ports has been made available by incorporating a magnet for ease of identification of the injection site. Despite its low mass, the intrinsic magnetic field presents a contra-indicating factor due to the potential for torque and movement in the presence of the strong magnetic field found in the clinical MR imagers. With any evidence of tissue expander prosthesis obtained in the history, a careful questioning about the possibility of a magnetic port should be carried out.

Successful cryopreservation of microvenous allografts.

Vein grafts are used in approximately 20% of microsurgical cases. Although autogenous veins currently form the major source, they are associated with increased operating time and donor site scars. Cryopreserved allograft veins may serve as an alternative source. To our knowledge, cryopreservation of veins (1 mm or less) has not been reported. In this article we have described the process of cryopreserving rat veins (less than 1 mm in diameter) and their preliminary use as interpositional vein grafts.

The quadriceps musculocutaneous flap: a reliable, sensate flap for the hemipelvectomy defect.

We have presented a detailed account of the anatomy, technique, and indications for the use of the quadriceps musculocutaneous flap. Our experience thus far has proved this flap to be a desirable alternative to the traditional hemipelvectomy closure technique in that it provides a more durable and reliable pelvic coverage for these patients.

A case of multiple pilar tumors and pilar cysts involving the scalp and back.

The case of a patient with multiple proliferating trichilemmal tumors and trichilemmal cysts of the scalp and back is discussed. The multicentric presentation of this tumor is unusual and, to our knowledge, has not been described previously. The appearance of trichilemmal cysts in association with multiple proliferating trichilemmal tumors suggests a common histogenesis of these two neoplasms. The typical presenting features, histologic description, and recommended treatment for these tumors are reviewed.

Local full-thickness skin-graft coverage for the radial forearm flap donor site.

Closure of the radial forearm flap donor site has been achieved by triangulating the defect and using a full-thickness skin graft from the adjacent volar forearm. Coverage of the flexor carpi radialis tendon has been more robust, and the aesthetic results have been superior to split-thickness skin-graft coverage of the forearm flap donor site.

Presuturing--a new technique for closing large skin defects: clinical and experimental studies.

We have developed a new technique termed presuturing for aiding in the closure of large skin defects which may have otherwise required a skin graft or flap. This technique is based on biomechanical properties of skin (creep, stress relaxation) which allow skin to stretch beyond its inherent extensibility. Presuturing is performed under local anesthesia and consists of plicating intact skin over the area of planned excision the night prior to operation. Experimental studies in a pig model showed the decrease in force required to close a standard-sized wound to be 40.1 percent less than control (p less than 0.001). Fourteen patients who underwent wide excision of skin lesions had their wounds presutured. All but one wound could be closed primarily without undermining. Presuturing seems to be an easy and clinically useful technique in aiding the primary closure of large defects.

The permeability of tissue expanders to bacteria: an experimental study.

Infection is an occasional but serious complication of tissue expansion. Bacteria in many cases are found both inside and outside the expander. The mechanism of how they spread inside and out is not fully understood. In the current study, we have assessed both the expander membranes (n = 28) and the port (n = 42) in terms of leakage and transmission of Staphylococcus aureus in normal expansion (100 percent) and overexpansion (400 percent) in an in vitro model. Our results indicate that the membrane was impermeable to S. aureus, whereas the bacteria were able to migrate freely through the puncture sites in the ports.

Measurement of capsular contracture: the conventional breast implant and the Pittsburgh implant.

At present, there is no accurate, reliable method of experimentally measuring capsular contracture. This study had four goals: (1) to define the parameters of capsular contracture employing principles of biomechanics of soft tissues, (2) to develop laboratory techniques to measure the parameters, (3) to design an implant that mechanically impedes the process of encapsulation, and, (4) to test this implant against a conventional one. We have developed a breast implant (the Pittsburgh implant) with an altered surface topography. Its silicone shell is punctuated by projections 1 mm in height and 1 mm in diameter. Two techniques were devised to measure contracture. The first involved measuring the force deformation along a coronal axis. The second involved measuring hydrostatic pressures within the implant resulting from the injection of known quantities of saline. Measurements were performed in vivo on 36 animals. By both force and pressure measurements, the Pittsburgh implant showed less capsular contracture (p = 0.12 and 0.012, respectively). Histology revealed that the prototype surface alters the linear arrangement of myofibroblasts and redirects the laminar collagen into a waveform pattern. We conclude from this experimental study that an altered surface topography may serve as a means of rendering a capsule less mechanically effective. We feel that the proposed methods can be used in the laboratory to characterize the extent of capsular contracture.

[Establishment of a human lung alveolar cancer cell strain and its characteristics].

A human lung alveolar cancer cell strain (HAC-84), isolated from lung adenocarcinoma cell line in Gejiu (GLC-82) by colony selecting method, has been continuously propagated in vitro for more than 2 years through 164 passages till May 1 st 1986. HAC has the typical malignant characteristics as GLC. There are plenty of phospholipid and osmiophilic multilamellar bodies in the cytoplasm of all cells and the membrane-like material in most of the nuclei, which differentiate HAC from GLC and the other types of lung cancers. The cytoplasmic inclusions are the same as those found in type II alveolar epithelial cells of the lung. So, HAC, originated from the type II alveolar cells, is identified as human lung alveolar cancer cell strain. It is significant in the research of the properties and origin of the alveolar cancer, the action and formation of the alveolar surfactants.

[Establishment and characteristics of a human synovial sarcoma cell line].

A human synovial sarcoma cell line (HSS-84), from a painful mass excised locally near the left sternoclavicular joint, was established and has been continuously propagated in vitro for more than one year through 54 passages till the end of 1985. Doubling time was 65 hr. The index of mitosis was 28.8%. The chromosome number for most of the cells was hypertriploid. The cells, stored in liquid nitrogen, had a good revival. Cytologically, some cells, showing elongated, spindle, stellate or spidery shape with prominent processes, were arranged in loose or bundled pattern, similar to sarcoma cells; some cells showed ovoid and polygonal in mosaic arrangement, similar to epithelioid cells. Both features indicated biphasic differentiation of the cells. By electron microscopy, the cells consisted of light and dark cells with microvilli and obvious abnormality. Histopathologically, the tumor, from which HSS-84 originated, was a biphasic differentiation synovial sarcoma. It was composed of malignant spindle interstitial cells and malignant epithelioid cells lining the clefts or spaces. The latter was similar to cultured cells by electron microscopy. HSS-84 was identical with the donor. HSS-84 establishment will be useful for research on diagnosis, therapy, origin and biphasic differentiation of the synovial sarcoma.

Cryopreserved microvascular conduits: current applications and future prospects.

Modern cryopreservation techniques have resulted in the clinical use of cryopreserved allograft heart valves and large diameter veins. In addition to these large vascular tissues, there is a need for small-diameter vascular allografts. We review our studies of cryopreserved rat microvenous allografts (1 mm diameter) in both the arterial and venous systems. The clinical utilization of cryopreserved allografts in reconstructive microsurgery and the potential problems associated with the use of allogeneic tissues will be addressed. Further applications for vascular cryopreservation in reconstructive surgery include small-diameter arteries, vascularized tissue flaps, and limbs.