Epidermal growth factor in clinical practice – a review of its biological actions,clinical indications and safety implications

Chemotaxis, mitogenesis, motogenesis and cytoprotection are common cellular events involved in both tumourigenesis and tissue repair, which appear amplified upon growth factors exposure. Epidermal growth factor (EGF) promotes these events in epithelial and mesenchymal cells through the binding to a specific tyrosine kinase receptor. In experimental oncology settings, EGF does not initiate malignant transformation but exhibits ‘tumour promotion’. These observations have raised doubts on the clinical use of EGF despite solid demonstrations of efficacy in experimental conditions and clinical trials. The results of a Pubmed and Bioline investigation on EGF clinical uses and preclinical safety data are presented here. EGF topical administration has been used since 1989 to enhance the healing process of a variety of peripheral tissues wounds (16 clinical reports), as well as its intravenous, oral and rectal administration for gastrointestinal damages (11 clinical reports). EGF therapeutic efficacy and excellent tolerability seem demonstrated. Lack of long‐term adverse effects is highlighted in those studies with 6, 12 and 24 months of patients follow‐up. Although post‐treatment follow‐up may fall short for malignant growth, there are no reports on evidences linking EGF clinical use with cancer. A multicentre, nationwide survey in Cuba, 15 years after randomly using silver sulphadiazine with EGF or not in burn victims yielded that cancer incidence was comparable between EGF‐treated and control subjects and that such incidence rate does not differ from the age‐matched national incidence for those 15‐year period. All the animal species subjected to long‐term EGF systemic administration exhibit dose‐dependent and reversible epithelial organs hyperplasia with no changes in cells phenotypic differentiation. Histotypic pre‐malignant markers were not identified. The results emerged from co‐carcinogenesis studies and from transgenic mice over‐expressing EGF are conflicting and indicate that EGF overexposure, either innate or postnatal, may not be sufficient to transform cells. The ability of EGF to heal injured tissues in life‐threatening scenarios or to assist in preventing physical and social disability advocates for its clinical use under a rational medical risk/benefit balance.     

Recurrent Idiopathic Membranous Nephropathy: Early Diagnosis by Protocol Biopsies and Treatment with Anti‐CD20 Monoclonal Antibodies

Membranous nephropathy (MN) recurs posttransplant in 42% of patients. We compared MN recurrence rates in a historical cohort transplanted between 1990 and 1999 and in a current cohort diagnosed by protocol biopsies, we analyzed the progression of the disease and we assessed the effects of anti‐CD20 antibodies (Rituximab) on recurrent MN. The incidence of recurrent MN was similar in the historical (53%) and the current cohorts (41%), although in the later the diagnosis was made earlier (median, 4[2–21] months vs. 83[6–149], p = 0.002) and the disease was clinically milder. Twelve out of 14 patients (86%) with recurrent MN in the current cohort had progressive increases in proteinuria. Eight recipients were treated with Rituximab after their proteinuria increased from median, 211 mg/day (64–4898) at diagnosis to 4489 (898–13 855) (p = 0.038). Twelve months post‐Rituximab, 75% of patients had either partial (PR) or complete remission (CR). After 24 months 6/7 (86%) had PR/CR and one patient relapsed. Posttreatment biopsies showed resorption of electron dense immune deposits in 6/7 cases and were negative for C3 (4/7) and IgG (3/7). Protocol biopsies allow early diagnosis of subclinical recurrent MN, which is often progressive. Treatment of recurrent MN with Rituximab is promising and should be evaluated in a prospective randomized controlled trial.     

Artificial nucleus replacement: surgical and clinical experience

Objective: To assess long‐term clinical results of prosthetic disc nucleus (PDN) replacement for the treatment of lumbar disc herniation. Methods: Seventy‐two patients with lumbar disc herniation were implanted with a single PDN device from March 2002 to December 2003. Fifty‐eight (80.6%) patients attended clinical, functional, and radiographic follow‐up examinations for more than 48 months. Independent analysis was performed by careful review of the interviews, operative reports, preoperative and postoperative radiographs, and computed tomography scans or magnetic resonance imaging (MRI). Results: After implantation, a significant proportion of patients experienced pain relief. Improvements were noted in pain intensity, walking distance, neurological weakness, Oswestry and Prolo scores, intervertebral disc height and lumbar mobility. Intervertebral disc height was not well maintained, compared with the preoperative height it decreased 18% (P < 0.001). Several complications were associated with the implantation of PDN, including transient low‐back pain, implant dislocation, malposition of the implant, damage to the end plates and subsidence of implant. Conclusion: The clinical data show that PDN is preferred and can effectively increase the range of lumbar motion in patients with lumbar disc herniation. However, this study only represents cases in our centre.     

The effects of MRI signal intensity changes and clinical manifestations on prognosis after surgical intervention for cervical spondylotic myelopathy

Objective: To investigate whether the magnetic resonance (MR) T2 image signal intensity ratio and clinical manifestations can predict the prognosis in patients with cervical spondylotic myelopathy (CSM). Methods: A total of 73 patients treated with anterior, posterior, or posterior‐anterior combined surgery for compressive cervical myelopathy were enrolled retrospectively in this study. 1.5 T magnetic resonance imaging (MRI) was performed on all patients before surgery. T2‐weighted images (T2WI) of sagittal signal intensity were obtained of the cervical spinal cord, and the regions of interest (ROI) were taken by 0.05 cm². MR T2WI of sagittal normal cord signal at the C7‐T1 disc level were also obtained, and the ROI were taken by 0.3 cm². Signal value was measured by computer and the signal ratio between regions 0.05 cm² and 0.3 cm² calculated. Where no intramedullary high signal intensity was noted on MR T2WI, the ROI were taken by 0.05 cm² of the region of most severe spinal cord compression. The 73 patients were divided into three groups by hierarchical clustering analysis with signal intensity ratio (group 1: low signal intensity ratio; group 2: middle signal intensity ratio; group 3: high signal intensity ratio). Statistical analyses were performed with SPSS 11.0. Results: There were significant differences between the three groups according to the recovery rate (P < 0.001), age (P= 0.003), duration of disease (P= 0.001), Babinski sign (P < 0.001), pre‐ and postoperative Japanese Orthopaedic Association (JOA) score (P= 0.006). With increases in both signal intensity ratio grade and age, the recovery rate and pre‐ and postoperative JOA scores gradually decreased, and the incidence of Babinski sign increased. There was no significant difference in sex among the three groups (P= 0.387). Multiple comparison tests further supported the above‐mentioned results. Conclusion: Patients with light or no intramedullary signal changes on T2WI had a good surgical outcome. However, increase of signal intensity ratio and occurrence of the pyramidal sign were associated with a poor prognosis after surgery.     

Long term outcomes following surgical resection of myxopapillary ependymomas

Myxopapillary ependymomas, a specific tumor variant of spinal cord ependymomas, occur most commonly in the lumbosacral region. During the study period, 1,013 patients underwent surgery for spinal cord tumors. Fifty-two of the patients had a myxopapillary ependymoma. Forty-eight of these patients underwent surgery at our institutions. There were four patients who came for consultations only. Fourteen pediatric patients were diagnosed with myxopapillary ependymoma. The overall average age at which a patient was diagnosed was 31.8 years. The average age a child was diagnosed was 12.6 years. The adult mean age was 38.7 years. The clinical presentation was of a slow, indolent course, with average symptom duration of 20.8 months. Overall, the pediatric patients had a much more aggressive clinical course with a much higher rate of local recurrence and dissemination of the tumor within the neural axis (64% versus 32%). The median time to disease recurrence was 88 months for the entire group. The overall survival after 11.5 years of follow-up was 94%. The optimal management of patients harboring myxopapillary ependymomas remains somewhat controversial. Excellent outcomes may be obtained, however, with the use of aggressive surgical techniques. No clear benefit for adjunctive chemotherapy, and radiation therapy was demonstrated. Fred Epstein is deceased.     

Video-assisted thoracic surgery (VATS) for resection of metastatic adenocarcinoma as an acceptable alternative

Background  Adenocarcinomas commonly metastasize to the lungs and can be resected using open thoracotomy or video-assisted thoracic surgery (VATS). This study reviews metastatic resections in primary adenocarcinoma patients, using both thoracotomy and VATS. We aim to compare long-term prognoses to test the efficacy and viability of VATS. Methods  A retrospective review of primary adenocarcinoma patients who underwent resection of pulmonary metastases from 1990 to 2006 was carried out. Information was obtained by chart review. Endpoints analyzed were disease-free interval (DFI), survival time, and recurrence-free survival (RFS). Results  In a total of 42 (16 male, 26 female; median age 58.5 years) primary adenocarcinoma patients, 21 patients underwent first pulmonary metastatic resection using VATS (7 male, 14 female; median age 57 years) and 21 using thoracotomy (9 male, 12 female; median age 59 years). Primary adenocarcinomas were mainly 27 colorectal (64%) and 11 breast (26%). Two VATS (10%) and three open patients (14%) had local recurrences of the original cancer. Median postoperative follow was 13.3 months [interquartile range (IQR) 4.5–32.8 months] for VATS and 36.9 months (IQR 19.3–48.6 months) after thoracotomy. Median DFI–1 was 22.3 months (IQR 13.5–40.6 months) for VATS patients and 35.6 months (IQR 26.7–61.3 months) for open patients. Second thoracic occurrences were noted in six VATS patients (median DFI–2 9.2 months), and in seven open patients (median DFI-2 21.5 months). Third thoracic occurrences were noted in one VATS patient (DFI-3 18.7 months) and in one thoracotomy patient (DFI-3 21.8 months). Odds ratio of recurrence showed 12.5% less chance of developing recurrence in VATS patients. Five-year RFS was 53% in VATS and 57% in thoracotomy patients. Conclusions  VATS has become a viable alternative to open thoracotomy for resection of pulmonary metastases. In cases of primary adenocarcinoma, VATS showed no increase in number of thoracic recurrences, and comparable RFS. Short-term follow-up is encouraging; long-term follow-up will be needed to confirm these results.     

The aluminum content of bone increases with age, but is not higher in hip fracture cases with and without dementia compared to controls

Aluminum is considered a potentially toxic metal, and aluminum poisoning may lead to three types of disorders: aluminum-induced bone disease, microcytic anemia and encephalopathy. This is well known in patients with chronic renal failure, but since healthy subjects with normal renal function retain 4% of the aluminum consumed, they are also at risk of long-term low-grade aluminum intoxication. Included in this study were a total of 172 patients (age range 16–98 years) with the aim of examining whether aluminum accumulates in bone with increasing age. Additionally, we aimed to investigate whether the aluminum content of bone differs between controls and hip fracture cases with and without dementia, in particular in those with Alzheimers disease. During operations for all cases, bone biopsies were taken with an aluminum-free instrument from the trabecular bone. The samples were measured for their content of aluminum using an inductively coupled mass spectrometer. We found an exponential increase in aluminum content of bone with age. The average aluminum values, adjusted for age, were similar in men and women (P=0.46). No significant differences in sex- and age-adjusted mean aluminum values between the controls and the hip fracture cases with (P=0.72) and without (P=0.33) dementia could be detected. The average aluminum concentration among cases with Alzheimers disease was also similar to the values of hip fracture patients with other types of dementia (P=0.47). Odds ratios of hip fracture for each quartile of aluminum content in bone were also estimated to detect non-linear effects, but we did not find any statistically significant association remaining after age and sex adjustment. Thus, our results indicate that we accumulate aluminum in bone over our life span, but this does not seem to be of major pathogenetic significance for the occurrence of hip fracture or dementia.