Cellular transplantation in the treatment of experimental hepatic failure.

The survival of Lewis rats with D-galactosamine-induced fulminant hepatic failure was prolonged if they were given intraperitoneal injections of single-cell suspensions of liver or bone marrow cells from normal rats. Suspensions of liver cells were also effective in prolonging the survival of rats with ischemia-induced hepatic necrosis. The liver cells did not act by repopulating the recipient liver.

Selective immune stimulation during induction of allograft tolerance in the rat by radical immunosuppression.

Recent investigation of a biologically active synthetic polymer, NED 137, has demonstrated its ability to induce a B cell differentiation response to certain antigens, even in the presence of T cell depletion. In this report, the effect of T cell depletion combined with NED 137, on skin allografting, is explored in the Lewis strain rat. Animals were T cell-depleted by thymectomy, total body irradiation, and syngeneic marrow repopulation. They were then challenged with skin allografts +/- NED 137 treatment. Graft survival was significantly prolonged in the T-depleted rats regardless of treatment with NED 137. The drug did not increase the immune response to donor antigen as measured by in vivo lysis of 51Cr-labeled cells. Immunization with heterologous erythrocytes produced a low level of differentiation of IgM-producing cells in the T cell-depleted skin allografted group, but in contrast the T-depleted NED 137-treated rats had a normal response to immunization. These data suggest that selective stimulation of the humoral component of the immune response is feasible at a time when T cell-mediated function has been radically suppressed, without producing adverse effects on allograft survival.

Reversal of cyclosporine-induced mortality with a synthetic polymeric immunostimulant in a murine model of fecal peritonitis.

We have been investigating the effects of a synthetic immunostimulative polymer known as copovithane (Cpv). This agent appears to enhance humoral immunity in untreated and cyclosporine-immunosuppressed mice and is nontoxic in rodents and man. The purpose of this study was to determine whether cyclosporine (CsA) is deleterious to survival in a murine cecal ligation, puncture, and excision (CLPE) model of fecal peritonitis, and--if so--whether this effect could be ameliorated by Cpv without interfering with skin allograft acceptance. Cpv significantly prolongs survival in the CLPE model; the optimal dose for this effect was found to be 100 mg/kg. CsA was found to have a significant and deleterious effect on survival at several dosage levels when administrated 48 and 24 hr before cecal ligation, and immediately before and 16 hr after cecal ligation. Using a dose of CsA sufficient for skin allograft acceptance and the same schedule of administration outlined above, Cpv 100 mg/kg was administered 48 hr prior to cecal ligation. Mice treated with CsA plus Cpv had significantly longer survival than mice treated with CsA alone; furthermore, the survival of CsA-plus-Cpv-treated animals was not significantly different from that of saline-treated controls. Acceptance and survival of H-2 incompatible skin allografts in mice treated with CsA were not affected by Cpv 100 mg/kg/week. We conclude that CsA-induced mortality in the CLPE model can be abrogated by Cpv without adversely affecting skin allograft survival. It may eventually be possible to reduce the incidence of septic complications in clinical allotransplantation by prophylactically administering Cpv to patients on CsA immunosuppression.

Allogeneic and xenogeneic hepatocyte transplantation in experimental hepatic failure.

Previous studies have demonstrated the efficacy of syngeneic hepatocyte transplantation in the treatment of D-galactosamine-induced acute hepatic failure in Lewis strain rats. This report describes the efficacy and immunological consequences of allogeneic and xenogeneic hepatocyte transplantation in the same model. The i.p. administration of allogeneic (minor and major histoincompatibility) hepatocytes or xenogeneic (rabbit or porcine) hepatocytes at a dose of 4 x 10(7) cells/rat given at 48 hr after toxin all resulted in significant improvement in survival compared to that of controls, and also comparable to the results obtained with syngeneic hepatocyte transplantation. Sensitization to i.p. allogeneic (WF) hepatocyte administration was demonstrated by in vivo 51Cr release, indirect immunofluorescent technique, and accelerated skin allograft rejection. Similarly, the in vivo 51Cr release assay was able to detect sensitization to porcine hepatocytes. Despite evidence of immunogenicity, redosing with either WF or porcine hepatocytes resulted in no overt toxicity. Furthermore, presensitization by either WF hepatocytes or skin allografts did not adversely affect survival after WF hepatocyte treatment in D-galactosamine-induced hepatic failure in Lewis strain rats. These data demonstrate that histocompatibility is not a constraint to successful hepatocyte transplantation and that repeated treatments are potentially safe and efficacious despite sensitization.

Lithiumogenic disorders of the thyroid and parathyroid glands as surgical disease.

Little notice has been paid in the surgical literature to problems with psychoeffective lithium, which by interfering with adenylate cyclase affects thyroid and parathyroid function, causing hypercalcemia, hyperparathyroidism, and hypothyroidism. Seven patients with lithiumogenic hyperparathyroidism occurring after years of lithium therapy underwent treatment and manifested osteoporosis (n = 2), hypertension (n = 2), nephrolithiasis (n = 1), coma (n = 1), rising hypercalcemia (n = 1), goitrous myxedema (n = 4), nephrogenic diabetes insipidus (n = 2), renal failure (n = 2), and hyperlipidemia (n = 1). Disease-directed parathyroidectomy (without morbidity) was curative. Unique laboratory findings included normal serum phosphorus and reduced urinary calcium and cyclic adenosine monophosphate values. Three separate cases of thyroid carcinoma after long-term lithium therapy were also treated, being preceded by myxedema (n = 2) and concurrent with hyperparathyroidism (n = 1). There has been only one previous report of lithium-associated thyroid carcinoma. All patients taking lithium should undergo surveillance for thyroid and parathyroid dysfunction and neoplasia, and appropriate surgical and medical treatment should be considered in each situation. Although hyperparathyroidism may be reversible with lithium discontinuance, such therapy may be obligatory for patient well-being, thus dictating parathyroidectomy.

Comparison of the antitumor effects of a synthetic biopolymer and standard adjuvants.

The synthetic biopolymer NED 137 is capable of stimulating an immune response to tumor antigen. This article compares the efficacy of NED 137 to bacille Calmette-Guerin, Corynebacterium parvum, pyran, levamisole, and Freund's complete adjuvant in a rat tumor model where adjuvant treatment is administered after excision of subcutaneous tumor implants. A single intraperitoneal injection of NED 137 at 30 mg/kg body weight prolonged survival beyond 60 days with no evidence of recurrent or metastatic disease, whereas with the other adjuvants, animals survived a mean of 30 to 40 days with 100% local recurrence and a 60% to 90% incidence of pulmonary metastases. Use of NED 137 resulted in a greater lysis of tumor cells compared to other adjuvants when assessed in an in vivo 51Cr release assay. A phase I clinical study of high-risk gastrointestinal cancer patients treated with NED 137 is reported at a median survival time of 23 weeks (103 patients). This group is compared to a historical control group from the same institution. No NED 137-related toxicity has been noted to date.

Effect of radiofrequency hyperthermia and chemotherapy on primary and secondary hepatic malignancies when used with metronidazole.

Hyperthermia is selectively toxic to neoplastic tissue. Since August 1981, 357 patients with incurable tumors in various body areas have been treated with chemotherapy and radiofrequency hyperthermia (RFHT) with adjuvant metronidazole at this center. Of this group, the cases of 102 patients with hepatic tumors are reported here. Patients received one to ten treatment courses, each course consisting of two to five daily RFHT sessions. Systemic temperature rose 0.6 +/- 0.3 degrees C during treatment, and tumor core temperature (measured by percutaneous transhepatic thermistor) reached 39.5 +/- 1.2 degrees C in 38 monitored patients. Results have been encouraging; in particular, among 15 patients with newly diagnosed colorectal metastases limited to the liver (and as yet untreated for their secondary disease), there has been objective partial tumor regression in 66.7%. Side effects have been few. Skin burns and subcutaneous fat necrosis were seen in 3.9% and 13.7% of patients, respectively. Tumor temperature is difficult to measure reliably and does not correlate with machine power or tumor response. A phase III trial is currently underway to determine the efficacy of RFHT and chemotherapy for patients with hepatic metastases from colorectal adenocarcinoma.

Reversal of toxic and anoxic induced hepatic failure by syngeneic, allogeneic, and xenogeneic hepatocyte transplantation.

This report describes the efficacy of syngeneic hepatocyte transplantation in an anoxic model and of xenogeneic (rabbit and porcine) hepatocyte transplantation in a toxic model of fulminant hepatic failure in the rat. Lewis strain rats that received 4 X 10(7) hepatocytes intraperitoneally at 48 hours after hepatic artery ligation had a significantly improved survival rate (79%, n = 14) when compared with control animals (38%, n = 21, P less than 0.05). Xenogeneic hepatocytes (4 X 10(7) cells/rat) given intraperitoneally to D-galactosamine-poisoned Lewis rats at 48 hours after toxin administration were able to significantly improve survival rate as compared with controls (71% versus 14%, n = 14, P less than 0.01 for rabbit; and 75%, n = 14 versus 12.5%, n = 16, P less than 0.001 for porcine). Although an increase in in vivo cytotoxicity could be demonstrated after procine hepatocyte transplantation, no adverse clinical effects were observed. The methodology for the harvest and storage of large numbers of hepatocytes from a large animal liver has been developed, and it is now feasible to proceed to the clinical application of hepatocyte transplantation for human fulminant hepatic failure.

Do we really need another localizing technique for parathyroid glands?

To evaluate magnetic resonance imaging (MRI) in the preoperative localization of abnormal parathyroid glands, we examined 16 patients with primary hyperparathyroidism at initial presentation with MRI and ultrasound of the neck. These studies were analyzed prospectively and compared with the findings at bilateral neck exploration. The surgeon was intentionally blinded to the imaging studies. MRI was accurate in the lateralizing of an abnormal gland in 21 of 32 sides (66 percent). Sensitivity was 65 percent and specificity was 66 percent. Ultrasound was accurate in 19 of 32 sides (59 percent). Sensitivity was 50 percent and specificity was 75 percent. The difference was not statistically significant. We do not believe that MRI is indicated prior to initial exploration in patients with primary hyperparathyroidism.

A retrospective comparison of the morbidity and cost of different reconstructive strategies in oral and oropharyngeal carcinoma.

PURPOSE: Evaluate and compare the morbidity and costs of different reconstructive strategies in oral and oropharyngeal carcinoma. STUDY DESIGN: Retrospective cross-sectional. PATIENTS AND METHODS: One hundred twenty-seven consecutive patients treated surgically for oral and oropharyngeal carcinoma between 1990 and 1996 were evaluated. Sixty-three patients had segmental mandibulectomies with 30 plate-soft tissue reconstructions and 33 bone-soft tissue flaps. Sixty-four patients had soft-tissue-only reconstructions. The following outcome parameters were analyzed: operative time, intraoperative blood loss, postoperative admission length, ICU and coronary care unit admission length, surgical interventions for complications, re-admissions, and prolonged (>6 mo) gastrostomy tube feeding, and all costs within the disease-free interval. Means and standard deviations were calculated for continuous parameters. Differences among the three groups were analyzed using one-way analysis of variance. For discontinuous parameters, the chi-square test was applied. RESULTS: Longer operative time (1.8 h) and more blood loss (150 mL) for bone-soft tissue flaps were the only statistically significant findings (P<.05) between the three groups. CONCLUSION: There is no rationale for allowing presumed factors of morbidity or cost select for type of reconstruction in patients with oral and oropharyngeal carcinoma.

Oromandibular reconstruction with the fibular free flap. Analysis of 50 consecutive flaps.

OBJECTIVE: To evaluate the results and functional outcome associated with fibular free flap reconstruction of orofacial and mandibular defects. DESIGN: We conducted a retrospective analysis of 50 consecutive fibular free flaps during a 3-year period. Forty patients were available for follow-up, which ranged from 4 to 39 months. SETTING: Academic tertiary care referral medical center. PATIENTS: Fifty consecutive mandibular reconstructions using the fibular free flap were performed on 47 patients. Thirty-five patients (74%) underwent primary reconstruction. Sixty-six percent of the mandibular defects were anterior or combined anterolateral types; the remainder were pure lateral defects. In 38 patients (81%), a skin paddle was included with the flap to provide either a mucosal lining or skin cover, whereas in only 9 patients (19%), bone was used alone. MAIN OUTCOME MEASURES: Factors reflecting functional properties and processes as well as complications of the upper aerodigestive tract were evaluated clinically and radiographically. RESULTS: Four flaps required reexploration as emergencies, and none were successfully salvaged (8.5% failure). Three patients underwent further free vascularized fibula transfer with 1 failure. During follow-up, swallowing was normal in 25 patients (64%), oral continence was normal or almost normal in 26 patients (67%), and speech was normal or easily intelligible in 35 patients (90%). Aesthetic results were excellent or acceptable in 37 patients (95%). CONCLUSIONS: Our results reveal that the vascularized fibular free flap is very suitable with an excellent success rate for reconstructing both the composite or simple long-spanned mandibular defect. The overlying skin island is reliable and provides lining or coverage for intraoral and extraoral defects. Superior functional cosmetic results are expected in the majority of patients, while donor site morbidity is minimal.

Recurrence of hyperparathyroidism after total parathyroidectomy and autotransplantation in peritoneal dialysis patients.

OBJECTIVE: To evaluate the effectiveness of total parathyroidectomy (PTX) with autotransplantation in the treatment of secondary hyperparathyroidism (HPT), and to assess recurrence rate of HPT in this peritoneal dialysis (PD) population. DESIGN: A retrospective study in a single home PD unit. PATIENTS: Between 1994 and 1998, 19 of 574 patients on PD underwent PTX for treatment of secondary HPT. MAIN OUTCOME MEASURES: Clinical and biochemical improvement, recurrence of HPT, improvement in anemia post-PTX. RESULTS: Nineteen (3.3%) patients required PTX between 1994 and 1998. These 5 men and 14 women ranged in age from 22 to 66 years; they had been on maintenance PD pre-PTX for 47.5 +/- 38.1 months, and were followed for 26.1 +/- 15.5 months post-PTX. Sixteen patients had temporary hypocalcemia that was managed by oral (n = 10) or intravenous (n = 6) calcium supplements and calcitriol, while 3 patients had severe "hungry bone" syndrome postoperatively. One patient had recurrent laryngeal nerve palsy post-PTX. Bone pain disappeared in all 12 patients. Pruritus improved in 12/13 patients; fatigue improved in 15/16 patients. Comparison showed significant differences between hemoglobin and hematocrit values 1 month pre-PTX and 12 months post-PTX (p < 0.05). Parathyroid hormone (PTH) level in 15 (79%) patients returned to normal (< or = 7.6 pmol/L) during the first month post-PTX. In 5/12 (42%) patients, PTH level was < or = 7.6 pmol/L 2 years post-PTX, while in 2/12 (17%), PTH was > 22.8 pmol/L (three times normal) 2 years post-PTX, and 3/5 (60%) patients had a PTH > 22.8 pmol/L 3 years post-PTX. CONCLUSIONS: Total PTX with autotransplantation is associated with a tendency for recurrence of HPT. Our findings suggest that total PTX with autotransplantation may be an ineffective procedure in controlling HPT over the long term.

Classification of mandibular defects.

A classification of mandibular defects based on functional as well as aesthetic factors is presented. By taking into account the difficulties in restoring form and function and not simply relying on traditional anatomic landmarks, it is hoped that this method will allow different types of reconstructions to be fairly evaluated. It also should help surgeons to tailor individual reconstructive techniques to specific clinical situations. Major difficulties in mandibular reconstruction arise when a condyle requires replacement, when there is a mucosal and/or skin component to the defect, and when the area to be reconstructed involves the anterior arch. The classification is based on three upper-case and three lower-case characters: H, C, L and o, m, s. H defects are lateral defects of any length, including the condyle but not significantly crossing the midline; L defects are the same only without the condyle; C defects consist of the entire central segment containing the four incisors and the two canines. Combinations of these letters are possible (an angle-to-angle defect, for example, is represented as LCL). Thus H and L defects may reach or even extend slightly beyond the midline but are not referred to as LC or HC unless they contain the entire central segment. The letters o (neither a skin nor a mucosal component), s (skin), m (mucosa), and sm (skin plus mucosa) are added to denote the epithelial requirement.

Orofacial and mandibular reconstruction with the iliac crest free flap: a review of 60 cases and a new method of classification.

Sixty vascularized iliac crest free-tissue transfers were used for oromandibular reconstruction, 46 as osteocutaneous and 14 as osseous flaps. Forty-one patients had preoperative radiotherapy, and 8 had failed previous attempts at reconstruction. Forty-nine of the 60 reconstructions were carried out primarily, most commonly following ablative surgery for radiorecurrent squamous carcinoma. Ages ranged from 19 to 85 years, and follow-up ranged from 2 months to 5 years. Flap survival was 95 percent. Eight-six percent of patients returned to their previous activities. There were 2 perioperative deaths, and 31 patients were alive at follow-up. Horizontal defects from 5 to 16 cm were reconstructed, and in 22 patients, both oral lining and skin coverage were replaced. Radiographic evidence of bone union was noted in 96 percent of synostoses, and clinical union was seen in all but one patient. One patient required bilateral hemimandibular reconstructions for sequential primaries at different operative sittings. Functional and cosmetic results were generally satisfactory and were excellent in bone-only reconstructions. Several surgical principles evolved to minimize bulk and eliminate the need for intermaxillary fixation or external fixation postoperatively. To improve results in large or more lateral through-and-through defects, an accessory pectoralis musculocutaneous flap proved advantageous. Cosmetic and functional results depend largely on three factors: the extent of the surgery, the leanness of the patient, and his or her position on the surgical learning curve.

The free flap and plate in oromandibular reconstruction: long-term review and indications.

The purpose of this study was to define the role of reconstruction plates as bone replacement in oromandibular reconstruction. From 1987 through 1991, 71 consecutive oral cancer patients underwent composite resection and reconstruction and were entered into one of two studies. In the first study of 31 patients, 15 underwent oromandibular reconstruction using a radial forearm osteocutaneous flap, while the remainder (16) received a radial forearm fasciocutaneous flap together with a mandibular reconstruction plate. The second study involved 40 subsequent patients, all receiving the latter form of reconstruction. Twenty-one of the plates were stainless steel, and the remaining 19 were of the titanium hollow screw (THORP) type. We followed the patients prospectively. We defined success as a reconstruction that we did not have to remove. Additionally, since the patients had limited life expectancy, we developed the idea of days of life lost and incorporated it into our definition of a successful outcome. Vascularized autogenous bone proved to be more successful than metallic plates used alone in terms both of reconstruction survival and of minimizing days of life lost. The overall success rate of mandibular plate reconstruction was 78.9 percent, but analysis by defect type revealed a failure rate of 35 percent when the defects were anterior and only 5 percent when they were lateral. THORP plates demonstrated a trend towards more durability. We would now recommend plate reconstruction only in lateral defects in patients with a poor prognosis.

Elimination of 51Cr-labelled target cells as a method of in vivo assessment of immune reactions.

This report describes the use of an in vivo 51Cr release assay which is able to monitor various immune reactions in the rat. This assay is able to quantitate the immune response to tumour and also to assess the relative efficacy of different immunostimulants in this tumour model. These data correlate well with survival studies in tumour-bearing rats. This assay can also measure the sensitizing effect of antigens from animals differing at both the major and minor histocompatibility locus using various routes of sensitization and various donor tissues. Allograft survival can also be correlated to in vivo 51Cr release. This method is both reproducible and specific. The in vivo 51Cr release assay is a useful and versatile means of monitoring the development of antitumour responses and the degree of sensitization to histocompatibility antigens in a variety of situations in the rat. It may therefore prove useful as a rapid method for screening new antitumour and immunosuppressive regimens to be used in various studies.