Usefulness of serial pulmonary function testing as an indicator of amiodarone toxicity.

A prospective study was conducted of 189 patients treated with amiodarone, maintained at doses of 400 to 800 mg/day and followed for up to 6 years. Only patients who had life-threatening ventricular arrhythmias unresponsive to conventional therapy were enrolled, and they underwent baseline pretreatment pulmonary function tests, with follow-up testing every 6 months. Morbidity and mortality statistics were confirmed by chart review and patient telephone interview. Of the 189 enrolled patients, 101 are alive, 84 are dead and 4 are lost to follow-up. Amiodarone-induced toxicity to the neurologic system, lungs, thyroid or liver was the primary or complicating cause of death in 12 of the 84 patients who died. The overall prevalence of all these forms of toxicity was 15%. Sixty-nine percent of the patients with amiodarone toxicity had pulmonary toxicity alone or combined with other forms of toxicity. Pulmonary function test abnormalities were noted at baseline in 75% of patients who had amiodarone-induced toxicity. The proportion of abnormal baseline pulmonary function tests was not significantly different among all toxic patients, pulmonary toxic patients and nontoxic patients. An evaluation of the decrease in pulmonary function over time could not distinguish patients who developed toxicity from those who did not. The observed incidence of pulmonary toxicity is consistent with published values; however, contrary to the findings of others, no statistically significant differences in pulmonary function at baseline or in changes over time were found between toxic and nontoxic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Manufacture of porous biodegradable polymer conduits by an extrusion process for guided tissue regeneration.

We have fabricated porous, biodegradable tubular conduits for guided tissue regeneration using a combined solvent casting and extrusion technique. The biodegradable polymers used in this study were poly(DL-lactic-co-glycolic acid) (PLGA) and poly(L-lactic acid) (PLLA). A polymer/salt composite was first prepared by a solvent casting process. After drying, the composite was extruded to form a tubular construct. The salt particles in the construct were then leached out leaving a conduit with an open-pore structure. PLGA was studied as a model polymer to analyze the effects of salt weight fraction, salt particle size, and processing temperature on porosity and pore size of the extruded conduits. The porosity and pore size were found to increase with increasing salt weight fraction. Increasing the salt particle size increased the pore diameter but did not affect the porosity. High extrusion temperatures decreased the pore diameter without altering the porosity. Greater decrease in molecular weight was observed for conduits manufactured at higher temperatures. The mechanical properties of both PLGA and PLLA conduits were tested after degradation in vitro for up to 8 weeks. The modulus and failure strength of PLLA conduits were approximately 10 times higher than those of PLGA conduits. Failure strain was similar for both conduits. After degradation for 8 weeks, the molecular weights of the PLGA and PLLA conduits decreased to 38% and 43% of the initial values, respectively. However, both conduits maintained their shape and did not collapse. The PLGA also remained amorphous throughout the time course, while the crystallinity of PLLA increased from 5.2% to 11.5%. The potential of seeding the conduits with cells for transplantation or with biodegradable polymer microparticles for drug delivery was also tested with dyed microspheres. These porous tubular structures hold great promise for the regeneration of tissues which require tubular scaffolds such as peripheral nerve, long bone, intestine, or blood vessel.

In vivo evaluation of poly(L-lactic acid) porous conduits for peripheral nerve regeneration.

The present study provides in vivo trials of poly(L-lactic acid) (PLLA) as a porous biodegradable nerve conduit using a 10 mm sciatic nerve defect model in rats. The PLLA conduits, fabricated by an extrusion technique, had an inner diameter of 1.6 mm, an outer diameter of 3.2 mm, and a length of 12 mm. They were highly porous with an interconnected pore structure (of 83.5% porosity and 12.1 microm mean pore size). The conduits were interposed into the right sciatic nerve defect of Sprague Dawley rats using microsurgical techniques; nerve isografts served as controls. Walking track analysis was performed after conduit placement monthly through 16 weeks. At the conclusion of 6 and 16 weeks, sections from the isograft/conduit and distal nerve were harvested for histomorphometric analysis. The right gastrocnemius muscle was also harvested and its weight was determined. All conduits remained intact without breakage. Moreover, no conduit elongated during the 16 weeks of placement. Walking track analysis and gastrocnemius muscle weight demonstrated increasing regeneration over the 16 weeks in both the conduit and isograft control groups, with control values significantly greater. The nerve fiber density in the distal sciatic nerve for the PLLA conduits (0.16+/-0.07) was similar to that for the control isografts (0.19+/-0.05) at 16 weeks. The number of axons/mm2 in the distal sciatic nerve for the PLLA conduits was lower than that for the isografts (13 800+/-2500 vs. 10700+/-4700) at 16 weeks. The results for PLLA were significantly improved over those for 75:25 poly(DL-lactic-co-glycolic acid) of a previous study and suggest that PLLA porous conduits may serve as a scaffold for peripheral nerve regeneration.

Muristerone A-induced nerve growth factor release from genetically engineered human dermal fibroblasts for peripheral nerve tissue engineering.

In this study, human dermal fibroblasts (hDFBs) were genetically modified to release human nerve growth factor (NGF) using an ecdysone-inducible system. NGF cDNA was inserted into the pIND vector and then hDFBs were cotransfected with pIND-NGF and pVgRXR. Muristerone A, an analog of ecdysone, was used as the inducing agent. NGF release from transfected hDFBs was assessed in vitro and in vivo. Transfected hDFBs in the presence of Muristerone A possessed a maximal in vitro release of 8.5 +/- 0.4 pg of NGF/mL per 10(3) cells, demonstrating significantly higher NGF levels compared to control hDFBs. The in vitro release rate curve for transfected hDFBs in the presence of Muristerone A exhibited a maximum of 5.1 +/- 0.2 ng NGF/10(6) cells/day. A PC-12 bioassay demonstrated that the in vitro NGF released is bioactive. When transfected hDFBs in the presence of Muristerone A were placed in vivo in nude rats, NGF levels reach 2074 +/- 257 pg/mL and 1620 +/- 132 pg/mL at 24 and 48 h, respectively. These levels were significantly higher than negative control and wound fluid levels. Results support further in vivo investigation of this molecular "on" switch for peripheral nerve regeneration.

Postirradiation sarcomas in Sprague-Dawley rats.

A series of radiation-induced neoplasms occurred in Sprague-Dawley rats 4-8 months after irradiation of a single hind leg with 60Co gamma rays. The rats were exposed to fractionated cumulative doses that ranged from 0 to 106 Gy. Osteosarcomas, malignant fibrous histiocytomas and fibrosarcomas developed in the radiation fields of a number of the rats in the higher-dose groups. Tumors did not develop throughout an 8-month observation period in rats that received doses of only 0 or 46 Gy. The most common postirradiation sarcomas in humans are osteosarcoma, malignant fibrous histiocytoma and fibrosarcoma. The Sprague-Dawley rat may serve as a good animal model in studying the development of sarcoma in humans after regional radiotherapy.

Endotoxaemia as a cause of fever in immunosuppressed patients.

Using a recently developed chromogenic substrate assay sensitive to 10 pg/ml Escherichia coli endotoxin in plasma, systemic endotoxaemia was found in 52% of 21 episodes of fever in patients with a haematological malignancy who were infected. Endotoxaemia was also found in 27% of 22 episodes of fever of unknown origin. In 45 afebrile patients neither neutropenia nor cytotoxic chemotherapy was a cause of endotoxaemia. Passage of endotoxin from portal blood into the systemic circulation can contribute to unexplained fever in immunosuppressed patients.

Calcitonin gene-related peptide improves skin flap survival and tissue inflammation.

The effects of systemic administration of calcitonin gene-related peptide (CGRP) on survival and inflammation of experimental skin flaps subjected to prolonged arterial ischemia were studied. An island groin flap was elevated in the rat. The femoral artery was occluded for 8, 10, 12 or 14 h in four groups of 10 rats. In a group of 10 sham-operated control animals, the femoral artery was not occluded. After ischemia, blood flow was restored and flap survival evaluated at day 7. Following 12 h of ischemia, three flaps (30%) survived, compared with 100% survival of the control group. In the second part of the study the effects of CGRP on flap survival were assessed. Eighty flaps were rendered ischemic for 12 h, and received systemic CGRP (10(-7), 10(-8), 10(-9), 10(-10) M) or saline (control) at the end of the ischemia period. Administration of CGRP (10(-7) M) significantly increased the number of flaps surviving compared with the control. The effect of systemic pretreatment of the animals with the CGRP receptor antagonist CGRP8(-37), followed by CGRP (10(-7) M) treatment was also evaluated in 10 flaps. Flap survival in this group was 10%. In the third part of the study the anti-inflammatory effects of CGRP were evaluated. Forty rats were subjected to arterial ischemia for 12 h, and received systemic CGRP (10(-7) M), or saline at the end of the period of ischemia. The animals were sacrificed at 24 h and flap tissue samples were obtained. Myeloperoxidase (MPO) analysis was used as marker of neutrophil accumulation. CGRP (10(-7) M) significantly reduced the 24 h MPO accumulation in the flap, compared with saline treatment. A group of animals was pretreated with CGRP8(-37), followed by CGRP (10(-7) M), and a significant increase of MPO accumulation was seen, compared with the group treated only with CGRP. This study suggests that CGRP has a beneficial effect on survival of the rat ischemic groin flap, and diminishes the inflammatory response to the ischemic insult.

Histologic changes of intraoral free skin flaps.

BACKGROUND: It was the purpose of this study to assess the histologic skin changes of free tissue transfers used to reconstruct intraoral defects. METHODS: Patients who were at least 12 months after intraoral free tissue reconstruction were selected for study. A 3-mm punch biopsy of the intraoral portion of the flap was performed and submitted for routine histologic analysis and periodic acid-Schiff (PAS) staining. The adjacent native oral mucosa was also biopsied and served as control. RESULTS: Eight patients (42 to 71 years old) were studied. A variety of skin flaps were employed and included free rectus abdominis (4), radial forearm (2), scapula (1), and osteocutaneous fibula flaps (1). Histologic examination demonstrated that all specimens maintained normal skin architecture and maturation. Adnexal structures were demonstrated in all but one. Acute inflammation in conjunction with diffuse parakeratosis and spongiosis were seen with 4 cases. Fungal forms consistent with Candida species were identified in the stratum corneum by PAS stain in these 4 cases. CONCLUSION: The histologic integrity of skin appears to be maintained in cutaneous free flaps placed intraorally. Previous studies have noted an inflammatory infiltrate in the epithelial tissues of intraorally placed flaps, yet have not commented on the significance of this finding even when it was noted in a chronic setting. Our study is the first to correlate these changes with the presence of fungi. The effect of the acute inflammation and associated fungal forms may suggest the need for chronic therapy and merits further study.

The radial forearm free flap for head and neck reconstruction: a review.

BACKGROUND: The radial forearm free flap has become a workhorse flap in head and neck reconstruction. Its lack of bulk, ease of dissection, vascularity, and malleability are among its many advantages. PATIENTS AND METHODS: A review of 157 radial forearm free flaps performed in 155 patients between March 1988 and June 1994 at The University of Texas M.D. Anderson Cancer Center was undertaken to determine outcome. Patient age ranged from 22 to 80 years (mean 56). There were 79 men and 76 women. Follow-up ranged from 2 to 75 months. The most prevalent neoplasm was squamous cell carcinoma (n = 129). RESULTS: The most frequent tumor staging was T3, N0, M0. Various defects were observed; however, those requiring floor-of-mouth coverage were most common (n = 95). Partial or segmental mandibular resection was seen in 42. An osseous component was included in the radial forearm flap in 9 patients, and 64 patients had undergone some form of previous tumor resection. Fifty-seven patients received preoperative irradiation and 52, postoperative. The internal jugular vein (n = 131) and the external carotid artery (n = 134) were the most frequent recipient sites for microvascular anastomosis. Vein grafts were needed in 4 cases, and end-to-side anastomoses were most commonly performed. Total flap loss occurred in 7 cases (4.5%) and partial flap loss in 1 (0.6%). For total flap loss, salvage was accomplished by a second radial forearm free flap in 2 cases and alternative rotational flaps in 5. Other complications (infection, hematoma, fistula formation, etc.) were seen in 34%. Donor-site difficulties were seen in 21 cases. CONCLUSION: The radial forearm free flap offers a variety of reconstructive options for the head and neck. Its low flap loss and complication rates offer the best choice for oral lining restoration if bulk is not required.

Soft tissue reconstruction following hemipelvectomy.

BACKGROUND: Resection of primary and metastatic pelvic bone disease may result in large soft tissue deficits. Guidelines for soft tissue reconstruction following pelvic bone resection were evaluated in a retrospective study. METHODS: Over a 5-year period 21 patients (31%) required soft tissue reconstruction following pelvic bone resection. Data on these patients were retrieved from case records. RESULTS: Twelve patients underwent immediate, planned reconstruction, 1 a two-stage reconstruction, and 8 patients required a delayed procedure for complications after bone resection and primary closure. Soft tissue reconstruction was usually accomplished with muscle-based flaps; (25 flaps in 20 patients: 20 pedicled, 5 free), or with skin grafts alone (1 patient). Specific postreconstruction complications occurred in 9 patients, 5 in flaps based on the ipsilateral rectus muscle. CONCLUSION: Flap closure is indicated to achieve primary closure and eliminate deadspace. The ipsilateral rectus muscle should be used with caution and contralateral-based rectus flaps considered. Indications for free flaps include the size and location of the defect and availability of tissue from an amputated limb.

Reconstruction of the lower extremity after ablative resection for cancer.

Limb-sparing surgery for cancer of the lower extremity has ushered the development of composite, one-stage reconstructions that employ a combination of autologous tissues, bone allografts, and endoprosthetic devices. The success of these efforts in preserving limb function has been generally good, yet the ultimate level of function is less than normal. Microsurgery has assumed a progressively greater role in the reconstruction of composite defects and allows much latitude in the surgical planning and in the management of delayed complications. Although patients who opt for limb salvage reconstructions frequently require more operative procedures and have longer hospitalizations than patients undergoing primary amputation, their functional outcome surpasses that of the amputation group and thus justifies the surgical effort.

Sinistral (left-sided) portal hypertension.

Between 1953 and 1988, 21 patients with splenic vein thrombosis (SVT), 12 of whom had sinistral portal hypertension (SPH) were treated at our institution. SVT was identified at autopsy in nine patients. Twelve additional patients presented with SPH: bleeding esophageal varices, SVT and normal hepatic function. SVT was caused by pancreatic neoplasm (5), chronic pancreatitis (5), and pancreatic pseudocyst (2). SVT was diagnosed by splanchnic angiography, splenoportography, computerized tomography, and ultrasonography. Gastric varices were diagnosed by endoscopy (10) and barium swallow (2). Splenectomy was performed as primary therapy in 10 patients. Three of these 10 had en block distal pancreatectomy. Two high-risk patients had splenic artery embolization, one as a prelude to splenectomy performed 48 hours later and the other as definitive therapy. One splenectomized patient continued to bleed. No further bleeding occurred in 10 splenectomized patients in follow-up from 1 week to 14 years. Sinistral portal hypertension is a clinical syndrome of splenic vein thrombosis caused by pancreatic pathology and manifests as bleeding gastric varices in patients with a patent portal vein and normal hepatic function. Splanchnic arteriography is necessary for accurate diagnosis. Splenectomy is the effective treatment of choice.

Choice of technique for reconstruction.

This article discusses the complex set of issues that go into choosing a technique for breast reconstruction. These factors include not only the technical aspects of breast restoration, but oncologic care, psychologic factors, and patient preference. The various flap options and indications for them are described.

Multidisciplinary care in head and neck cancer.

Head and neck cancer treatment is uniquely suited to multidisciplinary care. A comprehensive list of essential participants consists of a broad spectrum of health care professionals. A spirit of cooperation and mutual respect is the foundation for the synergy that results in the best possible patient care. Reconstructive surgery has emerged as a sophisticated subspecialty that fills a critical role restoring the head and neck patient to maximal health and well-being. The concept of multidisciplinary care, pioneered at the nation's comprehensive cancer centers, should be adopted universally by clinicians seeking to offer the patient with head and neck cancer the best care.

Engineering strategies for peripheral nerve repair.

Tissue engineering in the peripheral nervous system unites efforts by physicians, engineers, and biologists toward a common goal to create either natural or synthetic tubular nerve guidance channels as alternatives to nerve autografts for the repair of peripheral nerve defects. Guidance channels help direct axons sprouting from the regenerating nerve end, provide a conduit for diffusion of neurotropic and neurotrophic factors secreted by the damaged nerve stumps, and minimize infiltration of fibrous tissue. In addition to efforts to control these physical characteristics of nerve guidance channels, researchers are optimizing the incorporation of biologic factors and engineering interactive biomaterial that can specifically stimulate the regeneration process. It is believed that current and future research will ultimately result in biologically active and interactive nerve guidance channels that can support and enhance peripheral nerve regeneration over longer, more clinically relevant defect lengths.

Advances in head and neck reconstruction.

Head and neck deformities, which can be caused by trauma, congenital defects, infections, or neoplasms, produce a stereotypical constellation of functional and aesthetic deficits, depending on the specific anatomic region. These deformities can be classified into six major anatomic categories: intraoral, mandibular, midfacial, cranial base, cutaneous, and scalp. This article presents a reliable approach to the reconstruction of these six areas that is used at the University of Texas M. D. Anderson Cancer Center. The emphasis is on an analysis of the unique functional and aesthetic problems presented by each of these specific anatomic lesions, and the reconstructive options are selected to maximize outcomes. The problems and limitations of current methods are discussed, and areas of potential development are explored.

A variation in the appearance of melanoma-in-situ (Clark's level I malignant melanoma).

Recently two cases of atypical melanoma-in-situ have been treated. The role of assessing this lesion, its clinical presentation, and margins of resection is reviewed. Early diagnosis and biopsy are essential.

Lower back reconstruction: an approach to wound closure in the cancer patient.

Repair of the lower back wound in the patient with cancer presents the surgeon with a plethora of challenges. Frequently, the wide range of the surgeon's armamentarium of flaps must be used to provide stable wound coverage. We present the reconstruction techniques used in five patients with cancer who had lower back wounds below T10 and of at least 100 cm2. The approach we used to evaluate the lower back wound and to determine surgical techniques and options for reconstruction is discussed.

Silicon tissue assay: a measurement of capsular levels from chemotherapeutic port-a-catheter devices.

A plethora of data has been used to condemn and defend the role of silicone and its association with "adjuvant disease." In the ongoing attempt to enhance our knowledge, we have chosen to identify tissue silicon levels (n = 15) in capsules that form around chemotherapeutic port-a-catheter devices, which consist of a metal dome encapsuled by silicone. We have compared these levels with previously established silicon levels in augmented breast capsules, distant tissue sites in these same augmented women, and nonaugmented cadaveric tissues from various geographic locations in the United States. All specimens were harvested by a "no touch" technique, not formalin fixed, frozen, and shipped to an independent toxicology laboratory for analysis. Inductively coupled plasma atomic emission spectroscopy was employed to obtain the tissue silicon measurements. Results demonstrated silicon values ranging from nondetectable in 9 patients to as high as 41 micrograms/gm. These values fell in between our cadaveric (0.5 to 6.8 micrograms/gm) and augmented tissue silicon levels (18 to 8700 micrograms/gm). Although the sample size is small and the power of statistical analysis is low, there was no correlation between the patient's silicon level and age, type of cancer, type of chemotherapeutic agent, radiation therapy, or length of time the port-a-catheters were in place. Although detectable levels of silicon identified around port-a-catheter devices were higher than expected, it is impossible to make any conclusions about these levels and the role of a potential collagen-vascular disease. What we have shown, however, is that silicone breast implants may not be the only medical device that can elevate tissue silicon levels. Our data seem to suggest that there may be a progression of measurable tissue silicon levels based on the amount of environmental or device-related silicon exposure a person has had at a particular time in his or her life. It is our belief that as we identify these tissue silicon levels, they will serve as a baseline and reference for further scientific studies.

From cadavers to implants: silicon tissue assays of medical devices.

A plethora of data has been used to condemn and defend the role of silicone and its association with "adjuvant disease." In the ongoing attempt to enhance our knowledge, we have chosen to identify tissue silicon levels in patients with saline implants or tissue expanders. We have compared these levels with tissue samples from a variety of patients with and without medicinal silicone devices from both the northeast and southwest United States over a 4-year period. All specimens were harvested by a "no touch" technique, non-formalin fixed, frozen, and shipped to an independent toxicology laboratory for analysis. Inductively coupled plasma atomic emission spectroscopy was used to obtain the tissue silicon measurements. Silicon tissue values in cadaveric tissue (n = 20 cadavers; n = 120 specimens) averaged 2.2 mcg/gm of tissue with undetectable silicon levels in over 50 percent of the specimens (range 0 to 45 mcg/gm; median = 0). Silicon levels surrounding port-a-catheter devices (n = 15 patients; n = 15 specimens) averaged 8.04 mcg/gm of tissue (range 0 to 41 mcg/gm; median = 0). Tissue levels in the capsules surrounding saline (n = 10 patients; n = 22 specimens) and silicone implants (n = 31 patients; n = 58 specimens) averaged 292 mcg/gm (range 0 to 1380 mcg/gm; median = 110) and 1439 mcg/gm (range 0 to 9800 mcg/gm, median = 490), respectively. Tissue levels, however, from distant sites (n = 22 specimens) in these same patients were equivalent to the cadaveric nonaugmented values (average = 3.2 mcg/gm; range 0 to 5.8 mcg/gm; median = 2.7). The results imply that there is a continuum of exposure to silicone medical devices based on the mechanical properties of silicone. The data seem to suggest that there may be a progression of measurable tissue silicon levels based on the amount of environmental or device-related silicone exposure a person has over his or her lifetime. It is our hope that these levels will serve as a baseline for our continuing knowledge of implantable medical devices.