Improved axonal regeneration of transected spinal cord mediated by multichannel collagen conduits functionalized with neurotrophin-3 gene.

Functionalized biomaterial scaffolds targeted at improving axonal regeneration by enhancing guided axonal growth provide a promising approach for the repair of spinal cord injury. Collagen neural conduits provide structural guidance for neural tissue regeneration, and in this study it is shown that these conduits can also act as a reservoir for sustained gene delivery. Either a G-luciferase marker gene or a neurotrophin-3-encoding gene, complexed to a non-viral, cyclized, PEGylated transfection vector, was loaded within a multichannel collagen conduit. The complexed genes were then released in a controlled fashion using a dual release system both in vitro and in vivo. For evaluation of their biological performance, the loaded conduits were implanted into the completely transected rat thoracic spinal cord (T8-T10). Aligned axon regeneration through the channels of conduits was observed one month post-surgery. The conduits delivering neurotrophin-3 polyplexes resulted in significantly increased neurotrophin-3 levels in the surrounding tissue and a statistically higher number of regenerated axons versus the control conduits (P<0.05). This study suggests that collagen neural conduits delivering a highly effective non-viral therapeutic gene may hold promise for repair of the injured spinal cord.

Do Greek healthcare users and healthcare providers share cancer care priorities? Analysing the results from two Delphi studies.

Traditionally healthcare providers have determined how healthcare resources should be allocated. However, in recent years, healthcare users have increasingly been invited to identify those priorities important to them. Yet, healthcare users' priorities do not always match the priorities set by healthcare providers. In Greece, there has not been any research to measure the extent of agreement between healthcare providers and users on cancer care priorities. This project aimed to identify the priorities of healthcare users and providers with regards to the areas of cancer care that needed to be developed or improved in Greece and to examine the extent of agreement between the two groups. Two parallel Delphi surveys were conducted to identify the priorities and arrive at a consensus. Thirty participants formed the panel of healthcare providers and 30 participants the panel of healthcare users. The participants identified 18 key cancer care areas that require development or improvement; however, there were significant differences on the prioritisation between the two panels. It is encouraging that 18 key areas were shared by both panels. These areas can form an agenda for further exploration. Healthcare users can participate in developing priorities for cancer care; however, education is required so that they are better able to make informed choices.

Physiologic studies of the pulmonary capillary bed after barium sulfate embolization.

22 anesthetized dogs were given a barium sulfate suspension intravenously in a dose sufficient to double mean pulmonary artery pressure. 10 sec breath-holding carbon monoxide diffusing capacity (D(LCO10)) was measured before and after this standard embolization in each dog. No post-embolic decrease in D(LCO10) was observed. In the study of this apparent paradox, it was found that the potential for further increase in D(LCO10) during exercise remained after embolization. During rest prolongation of breath holding to 60 sec decreased CO absorption significantly more in the embolized than in the nonembolized dogs. While D(LCO10) was not affected by standard barium embolization, oxygen diffusing capacity was clearly decreased. The bronchial collateral circulation did not participate in preventing a D(LCO10) decrease after embolization since surgical interruption of the bronchial circulation did not alter the response to barium. Microscopic examination of lung sections taken after standard embolization showed plugging of precapillary vessels in the 40-50 mu range. These studies suggest that acute precapillary embolic obstruction of vessels of this size interferes remarkably little with CO absorption over short periods of time, probably because of continued CO absorption in portions of the capillary net distal to the sites of impaction. The remarkable anastomotic nature of this capillary network with multiple sources of access possibly provides the anatomic basis for this observation. This study demonstrates a clear dissociation between acute changes in pulmonary vascular resistance and D(LCO10)-both during rest and exercise.

Potential impact on survival of improved tumor downstaging and resection rate by preoperative twice-daily radiation and concurrent chemotherapy in stage IIIA non-small-cell lung cancer.

PURPOSE: The main objectives of this study were (a) to ascertain the feasibility and toxicity of preoperative twice-daily radiation therapy and concurrent chemotherapy, surgery, and postoperative therapy in stage IIIA (N2) non-small-cell lung cancer (NSCLC), and (b) to evaluate tumor response, resection rate, pathologic tumor downstaging, and survival. METHODS: Eligibility included biopsy-proven N2 lesion (stage IIIA) by mediastinoscopy, Karnofsky performance score > or = 70, and weight loss less than 5% in the 3 months before diagnosis. The treatment program consisted of two courses of preoperative cisplatin, vinblastine, and fluorouracil (5-FU); 42 Gy concurrent radiation at 1.5 Gy per fraction in two fractions per day; surgery on day 57; and one more course of postoperative chemotherapy and 12 to 18 Gy of concurrent twice-daily radiation. RESULTS: Forty-two patients with stage IIIA (N2) NSCLC (27 men and 15 women, age 38 to 77 years) were enrolled onto this prospective study. Forty of 42 patients tolerated the intended dose (42 Gy) of preoperative radiation and 37 of 39 resected patients received prescribed postoperative radiation. The intended dose of chemotherapy was given in 100%, 70%, and 60% of patients for the first, second, and third courses of chemotherapy. Marked dysphagia that required intravenous hydration was noted in 14% of patients (six of 42). Myelotoxicities included grade > or = 3 granulocytopenia in 23% and thrombocytopenia in 6% of 113 chemotherapy courses. Febrile neutropenia that required hospital admission was noted in 9% of 113 chemotherapy courses. Surgical resection was performed in 93% of patients. Treatment-related mortality was noted in 7% of patients. The overall survival rates by the Kaplan-Meier method were 66%, 37%, and 37% at 2,3, and 5 years, respectively, with a median follow-up time of 48 months. Pathologic examination of the surgical specimen showed a downward shift in tumor extent from stage IIIA (N2) to stage II (N1) in 33%, to stage I (NO) in 24% (10 of 42), and to stage 0 (TONO) in 9.5%, for a total of 67%. The degree of tumor downstaging was also translated into a survival benefit: 5-year survival rates from the time of surgery were 79%, 42%, and 18% for postoperative tumor stages 0 and I, II, and III, respectively (P = .04). CONCLUSION: Concurrent chemoradiotherapy using twice-daily radiation is an effective induction regimen that resulted in 67% tumor downstaging, and an encouraging 37% 5-year survival rate. The degree of tumor downstaging may be a useful intermediate end point for survival benefit in stage IIIA (N2) NSCLC.

Tumor proliferation in rectal cancer following preoperative irradiation.

PURPOSE: This study examines the effect of preoperative irradiation on tumor proliferation in rectal cancer. PATIENTS AND METHODS: One hundred twenty-two patients with locally advanced rectal cancer received 45 to 50 Gy of preoperative irradiation followed by surgery. Pretreatment tumor biopsies and postirradiation surgical specimens were scored for proliferative activity by assaying the extent of Ki-67 and proliferating-cell nuclear antigen (PCNA) immunostaining and the number of mitoses per 10 high-power fields (hpf). Preirradiation and postirradiation proliferative activity was determined and correlated to clinical outcome. RESULTS: There was an overall reduction in the tumor proliferative activity of rectal cancer after irradiation compared with its preirradiation state. Decreases in the activity of all three markers of tumor proliferation (Ki-67 and PCNA immunostaining, and mitotic counts) were observed in irradiated tumors compared with pretreatment biopsies. Postirradiation tumor proliferative activity was associated with pathologic tumor stage. A high level of proliferative activity was observed in tumors downstaged to the rectal wall (T1-2) compared with tumors that retained transmural penetration (T3-4). Multivariate analysis indicated that postirradiation proliferative activity and stage were independently associated with survival following surgery. Patients with tumors that exhibited elevated proliferative activity postirradiation had improved survival compared with patients with tumors that showed less proliferative activity. CONCLUSION: Moderate- to high-dose preoperative irradiation decreases both the tumor size and proliferative activity of rectal cancers. Elevated postirradiation tumor proliferative activity correlates strongly with improved survival. This may aid in identifying high-risk patients following preoperative irradiation and surgery.

IS EXERCISE CORTISOL RESPONSE OF ENDURANCE ATHLETES SIMILAR TO LEVELS OF CUSHING'S SYNDROME?

Several theories exist as to the mechanism causing the development of the Overtraining Syndrome in athletes. One theory proposes hypercortisolemic states (e.g., "pseudo" Cushing's Syndrome type-condition) brought on by intensive exercise training and the stress of sporting competitions results in neuroendocrine dysfunctions and subsequent physiological compromise. We wondered whether stressful exercise could provoke changes in cortisol to the magnitude of that seen in Cushing's Syndrome patients. Therefore we conducted a study to determine if the cortisol levels in highly trained endurance athletes in response to a stressful exercise bout compared to that found in Cushing Syndrome patients. Cortisol levels were examined in physically active men at rest, and after intensive, prolonged exercise (~85 min at 75% VO2max) and compared to that of Cushing's patients at rest. Results showed exercise does significantly (p<0.001) and substantially elevate cortisol to near Cushing's Syndrome levels. However, the cortisol response to exercise in athletes is highly transient and abates rapidly. The present findings support that cortisol responses to exercise such as what endurance athletes might encounter in their sporting competition (or during an intensive exercise training session) can elevate cortisol to the levels seen in Cushing Syndrome patients (i.e., for only a short period of time).

Radiation therapy for chordomas of the base of skull and cervical spine: patterns of failure and outcome after relapse.

PURPOSE: To determine the patterns of failure and outcome following relapse of chordomas of the base of skull and cervical spine. METHODS AND MATERIALS: Between November 1975 and October 1993, 204 patients were treated for chordoma of the base of skull or cervical spine, of which 63 have developed relapse. These 63 patients constitute the main focus of this study. Forty-five patients presented with base of skull and 18 with cervical spine tumors. All patients received combined proton and photon beam radiation. The median prescribed dose was 70.1 cobalt-Gray equivalent (CGE) (range 66.6-77.4). There were 25 males and 38 females, with a median age of 41 years (range 7-66). Median follow-up was 54 months (range 8-158). RESULTS: Sixty-three of the 204 patients treated (31%) had treatment failure. Among the 63 patients who relapsed, 60 (95%) experienced local recurrence, and in 49 patients (78%), this was the only site of failure. Two of 63 patients (3%) developed regional lymph node relapse and 3 of 63 (5%) developed surgical pathway recurrence (1 left neck, 1 palate and 1 nasal cavity). Thirteen of 204 patients relapsed in distant sites, accounting for 20% (13 of 63) of all patients with recurrence in this series. The most common metastatic sites were lungs and bones presenting in 7 of 13 and 6 of 13 patients, respectively. Only 2 of 13 patients failed with isolated distant metastasis. The actuarial 3- and 5-year survival rates after local relapse (60 patients) were 44 and 5%, respectively. Following distant failure (13 patients), the 3- and 5-year survival rates were 25 and 12%, respectively. After any relapse (63 patients) the corresponding survival rates were 43 and 7%. Following local relapse, 49 of 60 patients underwent salvage therapy consisting of subtotal resection in most patients (46 of 49). The remaining 11 of 60 patients received supportive care only. Salvage therapy resulted in stable or improved status without subsequent disease progression in 26 of 49 (53%), and progressive disease in 16 of 49 patients (33%). The actuarial 2- and 5-year overall survival rates following relapse for the 49 patients who underwent salvage treatment were 63 and 6%, which favorably compared to the 2-year survival rate of 21% for those who received supportive care only (p = 0.001). CONCLUSION: Local relapse is the predominant type of treatment failure for chordomas of the base of skull and cervical spine. Salvage treatment may relieve symptoms; however, most patients will ultimately succumb to their disease. Poor long-term survival rates following relapse emphasize the importance of a combined treatment approach with experienced surgeons and radiation oncologists at the time of primary treatment. For most patients, only permanent local tumor control will offer a chance of cure.

Time-dose considerations in the treatment of anal cancer.

PURPOSE: To analyze the impact of patient and treatment parameters in concurrent chemoradiation treatment for anal carcinoma. METHODS AND MATERIALS: Retrospective review of 50 MO anal cancer patients treated from 1984-1994. Most patients received concurrent 5-FU, mitomycin, and radiation. Local control and disease-free/overall survival were determined and analyzed according to patient and treatment parameters. RESULTS: With 43 month median follow-up, projected overall survival is 66% at 5 and 8 years. Disease-free survival is 67% at 5 years and 59% at 8 years. Local control is 70% at 5 and 8 years. Doses of > or =54 Gy are associated with improved 5-year survival (84 vs. 47%, p = 0.02), disease-free survival (74 v. 56%, p = 0.09), and local control (77 vs. 61%, p = 0.04). Although local control, disease-free survival, and overall survival were improved in patients whose overall treatment time was <40 days, this was not statistically significant. Outcome in the four patients with pretreatment hemoglobin (Hgb) <10 appeared worse with 3-year overall survival 50 vs. 68% (p = 0.07), disease-free survival 0 vs. 67% (p = 0.11), and local control 0 vs. 74% (p = 0.05). Projected 5-year overall survival, relapse-free survival, and local control in 4 HIV(+) patients is 0, 75, and 75%. Multivariate analysis reveals that dose (p = 0.02) and Hgb (p = 0.05) independently affect local control, dose (p = 0.02) affects disease-free survival, and dose (p = 0.01), Hgb (p = 0.03), T-stage (p = 0.03), and HIV-status (0.07) independently influence overall survival. CONCLUSION: Radiation doses of > or =54 Gy are associated with significantly improved survival and local control in anal cancer patients treated with chemoradiation. Overall treatment times of less than 40 days are associated with a trend towards improved outcome, but this is not significant. Pretreatment hemoglobin <10 is associated with worse treatment outcome. Survival of HIV (+) patient is poor, but the majority of such patients in this series died of intercurrent disease with their anal carcinomas controlled by chemoradiation.

Primary squamous cell carcinoma of the ovary. Report of 37 cases.

A total of 37 cases of ovarian primary squamous cell carcinoma (SCC)-19 associated with a dermoid cyst (SCCD), seven associated with endometriosis (SCCE), and 11 pure (SCCP)-are described. The last 18 cases belong within the new World Health Organization category of SCC in the surface epithelial-stromal category. The 19 patients with SCCD were 21-75 (mean, 52) years old; three of the carcinomas were in situ and seven, six, and three tumors were stages I, II, and III, respectively. The tumors and associated dermoid cysts were 6-35 cm in greatest dimension, usually forming mural nodules with intracavitary protrusion and focal necrosis and hemorrhage; two, seven, and seven tumors were grades 1, 2, and 3, respectively. SCCD was focally associated with a columnar epithelial cyst lining in 13 cases, suggesting an origin therein. One patient with stage I, grade 1 SCCD also had squamous cell carcinoma in situ (CIS) of the cervix. The seven patients with SCCE were 29-70 (mean, 49) years old, and one, three, one, and two tumors were stages I, II, III, and IV, respectively; all of the tumors were grade 3. One was associated with squamous cell carcinoma in situ of the cervix. The 11 patients with SCCP were 27-73 (mean, 56) years old, and one, four, five, and one tumors were stages I, II, III, and IV, respectively. The tumors were 6-26 cm in greatest diameter, usually solid with focal necrosis; one and 10 tumors were grades 2 and 3, respectively. Three patients with SCCP also had cervical squamous cell carcinoma in situ. The patients with SCCE had a poorer overall survival than those with SCCD. Five of the six patients with SCCE for whom adequate follow-up information was available died of their disease (mean survival, 5 months); also, in all five cases of SCCE reported in the literature, the patients died of their disease (mean survival, 4 months). The stage of the tumor and its grade correlated best with overall survival for all three types of SCC.

Incidence of Cell-Saver contamination during cardiopulmonary bypass.

During regular bacteriological surveillance of cardiac surgical equipment and patients, the Cell Saver apparatus (CSA) was prospectively evaluated to determine if it represented an additional risk for infection. Nineteen patients were studied. After each operation, the effluent from the CSA was sterilely sealed for subsequent culture. A total of 42 aerobic and 42 anaerobic cultures were made. Postoperatively all patients were evaluated daily for four days and before discharge for clinical evidence of infection. Four patients had positive CSA cultures without evidence of postoperative clinical infection. Five patients in whom postoperative infectious complications developed had negative CSA cultures. Ten patients had negative CSA cultures and no evidence of postoperative infection. We conclude that the CSA does not appear to contribute to the risk of infection in cardiac surgical patients and that it is a safe adjunct to cardiac surgery.

CA 19-9 is an index of response to neoadjunctive chemoradiation therapy in pancreatic cancer.

PURPOSE: This study examines the changes of serum levels of CA 19-9 in patients with pancreatic cancer following neoadjuvant irradiation and chemotherapy to define the potential role of this tumor marker in preoperative management of these patients. MATERIALS AND METHODS: Serum CA 19-9 levels were measured in 42 patients before receiving external beam irradiation with concurrent 5-fluorouracil in preparation for laparotomy and Whipple procedure or intraoperative irradiation (IORT). The CA 19-9 levels were determined again after irradiation, and changes were correlated with findings of restaging computed tomography (CT) scan and laparotomy. RESULTS: Following preoperative irradiation, 10 patients (24%) experienced an increase in CA 19-9 levels whereas 29 patients (69%) showed a decrease in CA 19-9. There was no change in the CA 19-9 levels of 3 patients (7%) after treatment. Of the 10 patients with increased CA 19-9 levels after irradiation, 9 (90%) had developed distant metastases or local tumor progression as determined by restaging CT scan or at laparotomy. In contrast, only 6 of 29 patients (21%) with declining CA 19-9 levels after irradiation demonstrated metastases or local tumor progression on restaging CT scan or at laparotomy. The correlation of CA 19-9 increase or decrease with disease progression or control, respectively, was statistically significant (P = 0.009). CONCLUSIONS: Serum CA 19-9 levels may rise or fall during neoadjuvant therapy. A rising CA 19-9 reliably indicates cancer progression while a falling CA 19-9 connotes disease control in the majority of patients. In developing strategies for application of neoadjuvant therapy for pancreatic cancer, monitoring of CA 19-9 appears most useful for the identification of patients who manifest progressive tumor growth and metastasis in spite of this treatment.

Effects of isometric muscle training on residual limb volume, strength, and gait of below-knee amputees.

This study was undertaken to determine if prosthetic suspension capabilities of below-knee amputees could be improved by using biofeedback in a controlled exercise program. Improvements in muscle bulk of four amputees were assessed. Changes in transverse cross-sectional areas and suspension ability of the residual limb were measured. The effect of muscle training on gait and on muscle-use patterns during gait was observed. Marked increases in muscle bulk below the knee and improvement in suspension capabilities were seen in two of the subjects, and somewhat lesser improvements were seen in the remaining two subjects. From these changes, one could modify prosthetic designs to take advantage of the residual limb muscles for suspension. For this reason, training the below-knee amputee to exercise the residual limb musculature should become part of routine physical therapy management. In this study, biofeedback was proven to be a useful tool for the reeducation of the residual limb musculature.

Sleep disorders in children after burn injury.

Eighty-two children and adolescents between the ages of 30 months and 20 years (mean, 11.8 years) who were admitted to one of two pediatric burn units with a mean initial burn injury of 43.8% total body surface area and a mean age at time of injury of 4.2 years were studied 1 year or more after burn injury (mean, 7.3 years). Subjects were found to have profound at-home sleep disorders, which were manifested as nightmares in 30 subjects (37%), bed-wetting in 20 (24%), and sleep-walking in 6 (18%). Dream content related to normal childhood topics in 45 patients (55%), burn injury in 6 (7%), and burn treatment in 5 (6%). No relationship exists between age at time of burn, length of time after burn injury, cause of burn injury, family history of nightmares, or patient history of bed-wetting and the incidence of nightmares. Daytime naps were reported in 50 subjects (63%), although 46 (mean age, 11.7 years) were well beyond the normal age for napping.

Upper extremity socket design options.

A careful evaluation of the amputee's physical situation is necessary to determine the best available prosthetic options. Evaluation of the psychologic and vocational needs are needed to determine the most appropriate designs. Other factors, such as hobby and sport activities, need to be determined to complete the prescription. Because the function of a prosthesis cannot restore all of the lost capability of the missing limb, every effort should be taken to provide the best available substitute by careful prescription, design, and construction.

Skin transplantation.

Transplantation of skin has been recognized as a method to increase the survival of patients who have suffered a massive skin deficit. Until about 30 years ago, a patient who suffered a 60% BSA skin deficit usually died from the effects of overwhelming sepsis. Great strides have since been made in the techniques and technology of skin transplantation. Many different methods are now used to enhance wound closure and to maximize the functioning and cosmesis of the grafted areas. Current methods of permanent wound closure include autografting, Integra with epidermal autografting, cultured epithelial cells, and microskin grafting. Other methods of temporary wound closure include allografts, xenografts, and synthetic materials. These temporary wound coverings act as a "second skin" and keep the wound free from infection while preventing the loss of fluid from the granulation bed. Research continues to strive toward faster wound closure with minimal functional and cosmetic deficits.

The use of portfolios in the assessment of learning and competence.

BACKGROUND: Portfolios have been used to incorporate accreditation of prior learning into nursing and midwifery assessment. This article aims to review the available literature on the use of portfolios. CONCLUSION: There needs to be a thorough evaluation of portfolios to determine their effectiveness as assessment tools in relation to the curriculum.

Patient accounts: getting it from all sides and PPS, UB-82, and DRGs. Roundtable on patient accounts management.

Patient accounts management today is facing new challenges. And the patient accounts manager is beseiged by a multitude of threats and opportunities, forcing the manager to seek ways to improve productivity, maintain cash flow, and enhance working relationships. In response, HFMA conducted a roundtable discussion with patient accounts managers from the American Guild of Patient Account Management and HFMA to determine some of these threats and opportunities confronting the manager. This article presents the highlights of that discussion.

A biomaterials approach to peripheral nerve regeneration: bridging the peripheral nerve gap and enhancing functional recovery.

Microsurgical techniques for the treatment of large peripheral nerve injuries (such as the gold standard autograft) and its main clinically approved alternative--hollow nerve guidance conduits (NGCs)--have a number of limitations that need to be addressed. NGCs, in particular, are limited to treating a relatively short nerve gap (4 cm in length) and are often associated with poor functional recovery. Recent advances in biomaterials and tissue engineering approaches are seeking to overcome the limitations associated with these treatment methods. This review critically discusses the advances in biomaterial-based NGCs, their limitations and where future improvements may be required. Recent developments include the incorporation of topographical guidance features and/or intraluminal structures, which attempt to guide Schwann cell (SC) migration and axonal regrowth towards their distal targets. The use of such strategies requires consideration of the size and distribution of these topographical features, as well as a suitable surface for cell-material interactions. Likewise, cellular and molecular-based therapies are being considered for the creation of a more conductive nerve microenvironment. For example, hurdles associated with the short half-lives and low stability of molecular therapies are being surmounted through the use of controlled delivery systems. Similarly, cells (SCs, stem cells and genetically modified cells) are being delivered with biomaterial matrices in attempts to control their dispersion and to facilitate their incorporation within the host regeneration process. Despite recent advances in peripheral nerve repair, there are a number of key factors that need to be considered in order for these new technologies to reach the clinic.