Ototoxicity prognostic models in adult and pediatric cancer patients: a rapid review.

PURPOSE: A cornerstone of treatment for many cancers is the administration of platinum-based chemotherapies and/or ionizing radiation, which can be ototoxic. An accurate ototoxicity risk assessment would be useful for counseling, treatment planning, and survivorship follow-up in patients with cancer. METHODS: This systematic review evaluated the literature on predictive models for estimating a patient's risk for chemotherapy-related auditory injury to accelerate development of computational approaches for the clinical management of ototoxicity in cancer patients. Of the 1195 articles identified in a PubMed search from 2010 forward, 15 studies met inclusion for the review. CONCLUSIONS: All but 1 study used an abstraction of the audiogram as a modeled outcome; however, specific outcome measures varied. Consistently used predictors were age, baseline hearing, cumulative cisplatin dose, and radiation dose to the cochlea. Just 5 studies were judged to have an overall low risk of bias. Future studies should attempt to minimize bias by following statistical best practices including not selecting multivariate predictors based on univariate analysis, validation in independent cohorts, and clearly reporting the management of missing and censored data. Future modeling efforts should adopt a transdisciplinary approach to define a unified set of clinical, treatment, and/or genetic risk factors. Creating a flexible model that uses a common set of predictors to forecast the full post-treatment audiogram may accelerate work in this area. Such a model could be adapted for use in counseling, treatment planning, and follow-up by audiologists and oncologists and could be incorporated into ototoxicity genetic association studies as well as clinical trials investigating otoprotective agents. IMPLICATIONS FOR CANCER SURVIVORS: Improvements in the ability to model post-treatment hearing loss can help to improve patient quality of life following cancer care. The improvements advocated for in this review should allow for the acceleration of advancements in modeling the auditory impact of these treatments to support treatment planning and patient counseling during and after care.

Surface replacement hemiarthroplasty for the treatment of osteonecrosis of the femoral head.

We reviewed the results of thirty-three femoral resurfacing procedures in twenty-five patients who had stage-III or early stage-IV osteonecrosis of the femoral head according to the classification system of Ficat and Arlet. There were no perioperative complications. Thirty hip prostheses (91 percent) survived for a minimum of five years. At a mean of 10.5 years (range, four to fourteen years) postoperatively, sixteen (62 percent) of the twenty-six hips with stage-III disease had a good or excellent Harris hip score. Four of the seven hips with stage-IV disease did not have or need a total hip arthroplasty. Overall, twenty hips (61 percent) had a good or excellent result according to the scoring system of Harris, and thirteen (39 percent) had a fair or poor result and subsequently had or needed a total hip arthroplasty. The mean interval between the hemiarthroplasty and the total hip arthroplasty was sixty months (range, thirty-six to 136 months). These thirteen hips all had a successful clinical result (a Harris hip score of at least 80 points) at a mean of thirty months (range, twenty-four to seventy-two months) after the total hip arthroplasty. The results of the present study suggest that resurfacing of the femoral head can be a successful interim procedure for the management of patients who have Ficat and Arlet stage-III or early stage-IV disease with a large lesion that is not amenable to other treatment options except total hip arthroplasty.

The operative treatment of peroneal nerve palsy.

We retrospectively reviewed the results of operative decompression for peroneal nerve palsy in thirty-one patients who had been managed between 1980 and 1990. All patients had been managed non-operatively for at least two months after they had initially been seen. Intraoperatively, we found epineurial fibrosis and bands of fibrous tissue constricting the peroneal nerve at the level of the fibular head and at the proximal origin of the peroneus longus muscle. At a mean of thirty-six months (range, twelve to seventy-two months) postoperatively, thirty (97 per cent) of the thirty-one patients reported subjective and functional improvement and were able to discontinue the use of the ankle-foot orthosis. In contrast, only three of nine patients who had been managed non-operatively reported subjective and functional improvement (p < 0.01). Peroneal nerve palsy does not always resolve spontaneously; if it is left untreated, the loss of dorsiflexion of the ankle and persistent paresthesias can result in severe functional disability. Therefore, if non-operative measures do not lead to improvement within two months, we believe that operative decompression should be considered.

Deep wound infections after neuromuscular scoliosis surgery: a multicenter study of risk factors and treatment outcomes.

STUDY DESIGN: A retrospective case-control study evaluating risk factors for infection, causative organisms, and results of treatment in patients with cerebral palsy or myelomeningocele who underwent fusion for scoliosis was performed. OBJECTIVES: To identify risk factors for infection, and to characterize the infections in terms of infecting organisms and response to treatment. SUMMARY OF BACKGROUND DATA: No previous studies have analyzed risk factors or causative organisms, nor have they indicated results of treatment for infections in this group of patients. METHODS: After a 10-year retrospective review of 210 surgically treated patients, deep wound infections developed in 16 patients with myelomeningocele and 9 patients with cerebral palsy. These patients were studied extensively for possible risk factors, along with 50 uninfected patients matched for age, diagnosis, and year of surgery. Statistical testing was performed to identify risk factors. The courses of the infections were characterized in terms of organisms isolated and response to treatment. Treatment was performed in a stepwise fashion and classified in terms of the most successful step: debridement and closure, granulation over rods, or instrumentation removal. RESULTS: Of the 10 risk factors tested, 2 were found to be significant: degree of cognitive impairment and use of allograft. Findings showed that 52% of the infections were polymicrobial. Gram-negative organisms were isolated as commonly as gram-positive organisms. The most common organisms were coagulase-negative Staphylococcus, Enterobacter, Enterococcus, and Escherichia coli.- Debridement and closure were successful in 11 of 25 patients with deep wound infection. Of the 14 patients with infection not resolved by serial debridements and closure, 2 were managed successfully by allowing the wound to granulate over rods, and 7 required rod removal for persistent wound drainage. There were three symptomatic pseudarthroses. Infections resulting from gram-positive organisms were most often managed successfully with debridement and closure (P = 0.012). CONCLUSIONS: Patients with cerebral palsy or myelomeningocele who have severe cognitive impairment, and those who received allograft may be at increased risk for infection. Infections are more often polymicrobial and caused by gram-negative organisms than is typical for elective orthopedic procedures. This suggests an enteric source. Treatment with debridement and closure was not always successful. Patients in whom infection develops are then at increased risk for pseudarthrosis.

Proximal femoral bone loss and increased rate of fracture with a proximally hydroxyapatite-coated femoral component.

We performed a retrospective analysis of the clinical and radiological outcomes of total hip replacement using an uncemented femoral component proximally coated with hydroxyapatite. Of 136 patients, 118 who had undergone 124 primary total hip replacements were available for study. Their mean age was 66.5 years (19 to 90) and the mean follow-up was 5.6 years (4.25 to 7.25). At the final follow-up the mean Harris hip score was 92 (47.7 to 100). Periprosthetic femoral fractures, which occurred in seven patients (5.6%), were treated by osteosynthesis in six and conservatively in one. We had to revise five femoral components, one because of aseptic loosening, one because of septic loosening and three because of periprosthetic fracture. At the final follow-up there were definite signs of aseptic loosening in two patients. Radiologically, proximal femoral bone loss in Gruen zones I and VI was evident in 96.8% of hips, while bone hypertrophy in zones III and V was seen in 64.7%. In 24 hips (20.2%) the mean subsidence of the stem was 3.7 mm which occurred within the first 12 postoperative weeks. This indicated poor initial stability, which might have been aggravated by early weight-bearing. The high rate of failure in our study suggests that proximal femoral bone loss affects the long-term survival of the replacement.

Avascular necrosis of the talus treated by core decompression.

We reviewed 11 patients (17 ankles) who had had core decompression for symptomatic avascular necrosis of the talus before collapse. The Mazur grading system was used to assess function preoperatively and at final follow-up, and radiographs were graded according to the Ficat and Arlet (1980) classification modified for the ankle. At a mean follow-up of seven years (2 to 14) 14 ankles (82%) had an excellent or good outcome (Mazur scores > 80 points; pain scores > 40 points (41 to 50). The other three ankles required tibiotalar fusion at a mean of 13 months (5 to 20) after core decompression. We conclude that core decompression is a viable method of treatment for symptomatic avascular necrosis of the talus before collapse.

Acquired hallux varus and clinical tolerability.

This retrospective study was undertaken to determine the long-term clinical problems, residual disability, and need for further surgery in patients with iatrogenic hallux varus. Between 1975 and 1985, in 16 (19 feet) of 83 patients who underwent foot surgery for hallux valgus or metatarsus primus varus, hallux varus deformity was noted at 1-year follow-up on dorsoplantar roentgenograms obtained with the patients bearing weight. Thirteen of those patients (16 feet) were reexamined at an average of 18.3 years (220 months) after surgery. The average hallux varus deformity in this group was 10.1 degrees. Eleven patients (12 feet) rated their results as excellent. The average hallux metatarsophalangeal interphalangeal score for all patients was 91.5 points. Only those with extreme hallux varus deformity were dissatisfied or required further surgery.

Modified Austin procedure for correction of hallux valgus.

The Austin osteotomy is a widely accepted method for correction of mild and moderate hallux valgus. In view of publications by Kitaoka et al. in 1991 and by Mann and colleagues, a more radical lateral soft tissue procedure was added to the originally described procedure. From September 1992 to January 1994, 85 patients underwent an Austin osteotomy combined with a lateral soft tissue procedure to correct their hallux valgus deformities. Seventy-nine patients (94 feet) were available for follow-up. The average patient age at the time of the operation was 47.1 years, and the average follow-up was 16.2 months. The average preoperative intermetatarsal angle was 13.9 degrees, and the average hallux valgus angle was 29.7 degrees. After surgery, the feet were corrected to an average intermetatarsal angle of 5.8 degrees and an average hallux valgus angle of 11.9 degrees. Sesamoid position was corrected from 2.1 before surgery to 0.5 after surgery. The results were also graded according to the Hallux Metatarsophalangeal Interphalangeal Score, and the functional and cosmetic outcomes were graded by the patient. Dissection of the plantar transverse ligament and release of the lateral capsule repositioned the tibial sesamoid and restored the biomechanics around the first metatarsophalangeal joint. There was no increased incidence of avascular necrosis of the first metatarsal head compared with the original technique.

Basal closing wedge osteotomy for correction of hallux valgus and metatarsus primus varus: 10- to 22-year follow-up.

Between 1974 and 1985, 59 patients (83 feet) underwent basal closing wedge osteotomy in combination with a bunionectomy and a lateral soft tissue release for correction of hallux valgus and metatarsus primus varus at this institution. Of the original 59 patients, 42 patients (60 feet) with at least 10 years of follow-up (average, 194 months; range, 144-266 months) were available for this study. Results were analyzed by review of the medical records and plain radiographs, a standardized clinical questionnaire, and physical examination. Of the 60 feet, patients rated outcomes as excellent or good in 51 feet (85%) and rated cosmesis as excellent or good in 44 feet (73%). Radiographically at final follow-up, hallux valgus and intermetatarsal angles averaged 19.9 degrees (range, 0-40 degrees) and 6.7 degrees (range, 0-18 degrees), respectively. The sesamoid position was corrected from an average preoperative grade of 2.6 to a grade of 0.9 at final follow-up. The average shortening of the first metatarsal was 5 mm. The disadvantages of the closing wedge osteotomy are that it is technically demanding and it entails the risk of shortening, dorsal malalignment, and metatarsalgia. In the current study, long-term complications included hallux varus deformity (16 feet), dorsal malalignment (15 feet), and metatarsalgia (14 feet). Despite good correction of the intermetatarsal angle and sesamoid position, the clinical results and the incidence of complications after basal closing wedge osteotomy were not as favorable as those reported for other procedures in the literature. Therefore, alternative procedures, such as the basal crescentic osteotomy or the basal chevron osteotomy, should be used.

Seventy cases of injuries of the small intestine caused by blunt abdominal trauma: a retrospective study from 1970 to 1994.

BACKGROUND: Injuries of the hollow viscera are far less common in blunt abdominal trauma than in penetrating abdominal trauma. This article is a 25-year retrospective study of 70 patients with injuries of the small intestine caused by blunt trauma. All patients were treated surgically at the trauma hospital (Unfallkrankenhaus) in Graz. In our series, blunt abdominal trauma causing hollow viscus injuries occurred in conjunction with multiple trauma in 68.8% of cases. The overall mortality rate was 25.7%. METHODS: The following methods were used for evaluating the intestinal injury: detailed history of the accident and examination of the patients (e.g., transverse abdominal bruise) diagnostic peritoneal lavage before 1984, abdominal sonography since 1984, computed tomography, and laboratory tests. RESULTS: Prognosis and results depended partly on the general condition of the patient, as well as the timeliness of diagnosis and surgical management of the small bowel injury. Delays in diagnosis were common because of the overall condition of the patient, as well as the difficulty in establishing a definitive diagnosis by using current radiologic and serologic modalities. CONCLUSION: It should be stated that the high mortality of small bowel injuries after blunt abdominal trauma justifies an aggressive approach to diagnosis and surgical treatment of these injuries. This article focuses on injury mechanisms and current concepts in diagnosis and the therapy of small intestine lacerations in blunt abdominal trauma.

[Potential uses of cytokines and growth factors in treatment of osteonecrosis]. / Die potentiellen Anwendungen von Zytokinen und Wachstumsfaktoren bei der Behandlung der Osteonekrose.

Osteonecrosis of the femoral head remains a devastating disease for young patients. As the normal process of bone formation, bone destruction, and fracture healing becomes more clearly understood, molecular agents--including cytokines, bone morphogenetic proteins, and angiogenic factors--will be identified as potential therapeutic agents for the treatment of osteonecrosis. As the pathology of osteonecrosis and repair of osteonecrotic lesions becomes clear, the potential combination of these molecular factors to influence the outcome of the disease in its repair process should become evident. With the myriad of agents and combinations of agents which may be beneficial in the treatment of osteonecrosis, a reproducible animal model is urgently needed to determine which of these combinations is most effective. Despite the lack of an animal model, progress in the use of cytokines for osteonecrosis treatment in conjunction with traditional treatment methods is possible in human subjects. This is due to the extremely low incidence of adverse reactions when these cytokines are used locally in nanogram to microgram quantities.

[Therapy of osteonecrosis. Basic principles and decision aids]. / Therapie der Osteonekrose. Grundlagen und Entscheidungshilfen.

The treatment of osteonecrosis of the femoral head involves a continuum based on a radiographic spectrum of disease. Core decompression or pharmacological agents can be utilized for the earliest small or medium-sized pre-collapsed lesions. For these types of lesions, osteotomy has been tried by various authors with moderate success. For small or medium lesions that are post-collapse, various bone grafting procedures have been used. This approach should be tempered with a look at the articular cartilage if this is damaged or the lesion is large. Limited femoral resurfacing can be used for hips that do not have acetabular involvement. If there is acetabular involvement, total hip replacement remains the treatment of choice. There are present innovations in total hip arthroplasty that hopefully will lead to increased longevity of these prostheses with newer polyethylenes as well as the use of ceramic and other types of interfaces. Another possible advance for this disease would be the use of metal on metal standard prostheses, as well as metal on metal resurfacing arthroplasties. In terms of a salvage of the femoral head, all of the different procedures--core decompression, osteotomy, bone grafting--can be enhanced by new advances in the development of the utilization of bioactive factors. These range from osteoinductive agents such as cytokines, angiogenic stimulating factors, and bone morphogenetic proteins. In addition, osteoconductive substances may be helpful and can be combined with osteoinductive substances. These bioactive factors are described in detail in another chapter of this issue. With the ushering in of the millennium, there is hope for better results with this disease.

The interrelations between high- and low-molecular weight forms of normal and mutant (Krabbe-disease) galactocerebrosidase.

Galactocerebrosidase (beta-d-galactosyl-N-acylsphingosine galactohydrolase; EC 3.2.1.46) activity of brain and liver preparations from normal individuals and patients with Krabbe disease (globoid-cell leukodystrophy) have been separated by gel filtration into four different molecular-weight forms. The apparent mol.wts. were 760000+/-34000 and 121000+/-10000 for the high- and low-molecular-weight forms (peaks I and IV respectively) and 499000+/-22000 (mean+/-s.d.) and 256000+/-12000 for the intermediate forms (peaks II and III respectively). On examination by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis, the high- and low-molecular-weight forms revealed a single protein band with a similar mobility corresponding to a mol.wt. of about 125000. Antigenic identity was demonstrated between the various molecular-weight forms of the normal and the mutant galactocerebrosidases by using antisera against either the high- or the low-molecular-weight enzymes. The high-molecular-weight form of galactocerebrosidase was found to possess higher specific activity toward natural substrates when compared with the low-molecular-weight form. It is suggested that the high-molecular-weight enzyme is the active form in vivo and an aggregation process that proceeds from a monomer (mol.wt. approx. 125000) to a dimer (mol.wt. approx. 250000) and from the dimer to either a tetramer (mol.wt. approx. 500000) or a hexamer (mol.wt. approx. 750000) takes place in normal as well as in Krabbe-disease tissues.

The nature of mutation in Krabbe disease.

Galactosylceramide beta-galactosidase cross reacting material was demonstrated in brain, liver, and skin fibroblasts from patients with Krabbe disease. The mutant enzyme was antigenically identical to the normal enzyme and exhibited similar electrophoretic mobility. Normal quantities of the catalytically deficient enzyme were measured in the patients' tissues by a sensitive single radial immunodiffusion assay, indicating that the mutation is in structural gene for the enzyme protein.