Douglas K. Heilman

Quadriceps Weakness and Osteoarthritis of the Knee

Osteoarthritis of the knee is the most common cause of chronic disability among older persons in the United States [1]. In persons with symptomatic osteoarthritis of the knee, quadriceps muscle weakness is common and is widely believed to result from disuse atrophy secondary to joint pain. Although exercises to strengthen the quadriceps may relieve joint pain in persons with osteoarthritis of the knee [2-6], the role of periarticular muscle weakness in the pathogenesis of joint pain and disability in these persons is poorly understood. The basis for the beneficial effect of strengthening exercises is unclear, and the duration of the improvement has not been studied. Furthermore, the possibility that muscle weakness is an etiologic factor underlying the pathologic changes of osteoarthritis has seldom been considered. Elucidation of the role of muscle weakness in osteoarthritis is particularly important given our growing understanding of safe and effective methods for increasing strength in elderly persons [7, 8]. A substantial proportion of persons who have radiographic evidence of osteoarthritis of the knee have no joint pain [9]. Because asymptomatic persons with radiographic changes seldom seek medical attention for osteoarthritis, muscle weakness has not been studied previously in this group. Thus, it is not known whether quadriceps weakness precedes or follows joint pain or (if it follows joint pain) whether it is mediated by disuse atrophy or by physiologic mechanisms that may inhibit muscle contraction [10]. To address this issue, we studied the relation among lower-extremity muscle strength, lower-extremity lean tissue mass, and osteoarthritis of the knee in men and women 65 years of age and older. Methods Study Group To obtain a sample of elderly persons living in the community, we conducted brief telephone interviews with residents of households in central Indiana. Potential participants were selected through modified random-digit dialing to increase the sampled proportion of persons 65 years of age and older. Persons were eligible if they met the minimal criteria for participation: They were willing and able to provide informed consent and to undergo the necessary strength assessments and other evaluations. Persons were excluded if they had had amputations of both lower extremities, had undergone total knee arthroplasty, or had recently had a cerebrovascular accident or myocardial infarction. A total of 462 persons (approximately 55% of all who were eligible) agreed to participate and completed the following evaluations. Evaluations Radiography of the Knee Standing anteroposterior and lateral radiographs of both knees of each study participant were obtained, and the severity of osteoarthritis in the tibiofemoral compartment was graded by a musculoskeletal radiologist according to the criteria of Kellgren and Lawrence. Similar criteria, based on the presence of osteophytes and joint space narrowing, were used for the patellofemoral compartment [11]. The radiologist was blinded to the clinical status and characteristics of all patients. A participant had to have a Kellgren and Lawrence grade of 2 or more in either knee to be classified as having osteoarthritis. Knee Pain and Function The Western Ontario and McMaster Universities Arthritis Index was used to evaluate knee pain and function [12]. This index assesses the severity of knee pain during 5 activities or situations (walking on a flat surface, going up or down stairs, at night while in bed, sitting or lying, and standing upright) and the severity of impairment of lower-extremity function during 17 activities. Pain and functional impairment were assessed in each knee separately. Responses to each question about the severity of knee pain and level of impairment were recorded on a categorical scale as none, mild, moderate, severe, or extreme. Each category was assigned a corresponding numeric score from 1 to 5 (5 = extreme). Hence, the range on the pain scale was 5 to 25 and the range on the physical impairment scale was 17 to 85 (85 = greatest functional limitation). For the purposes of analysis, participants who rated the severity of their knee pain as moderate or greater (3) with any of the 5 activities on more than half of the days in the month preceding the evaluation were considered to have knee pain. Thus, pain in the more distant past that had resolved was not included. Participants were also questioned about current and previous regular (5 times per week) or occasional use of over-the-counter and prescription analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) in the past year. Lower-Extremity Muscle Strength The strength of each leg was evaluated by using an isokinetic dynamometer (KIN-COM 500H, Chattecx Corp., Hixson, Tennessee). Peak torque was recorded in both the concentric (contractions during muscle shortening) and eccentric (contractions during muscle lengthening) modes. Participants were allowed several submaximal or maximal practice efforts to familiarize themselves with the operation of the dynamometer. Once formal testing began, the best of three maximal efforts was recorded for flexion and extension at both 60 degrees per second and 120 degrees per second. Aborted efforts were repeated in order to obtain the best possible representation of strength for each participant. Concentric and eccentric testing yielded similar results, but because of greater variability in eccentric testing, only the concentric test results are shown. Lower-Extremity Lean Tissue Mass Total-body dual-energy x-ray absorptiometry was done in all participants by using a Lunar-DPX-L instrument (Lunar Corp., Madison, Wisconsin). Results were analyzed for total and regional body composition, including body fat, mineral, and lean components (lean components were components other than fat or mineral). The right and left lower extremities were analyzed separately. The lower extremity was defined as all tissue below a diagonal line drawn outward and upward from the groin area through the femoral neck. Statistical Analysis Participants were divided into four groups on the basis of presence or absence of radiographic evidence of osteoarthritis of the knee and presence or absence of knee pain, as defined above. Men and women were compared by using the t-test. Comparisons of Arthritis Index pain and functional impairment scores were done by using nonparametric approaches. For analyses of continuous data involving more than two groups of participants (for example, osteoarthritis with or without knee pain), analysis of variance was used to determine whether an overall difference was present. The Fisher protected least-significant-difference procedure was used for pairwise comparisons. Comparisons within participants (for example, comparison of the two legs in a person with unilateral osteoarthritis of the knee) were done by using paired t-tests. Regression models were constructed with the generalized estimating equations approach of Zeger and Liang [13]. This approach inflates the standard errors to adjust for correlations in both independent variables (such as strength) and dependent variables (such as radiographic grade) within participants. Statistically significant differences (P < 0.05) in the above analyses are specifically noted below. Results The characteristics of the 462 men and women in the cohort are shown in Table 1. As expected, men were taller, were heavier, and had greater lower-extremity strength and lean tissue mass in the lower extremities compared with women (P < 0.001 for all comparisons). Table 1. Age, Height, Weight, and Lower-Extremity Strength and Lean Tissue Mass* One hundred forty-five participants (31%; 33% of the women and 30% of the men) had radiographic evidence of osteoarthritis involving the tibiofemoral compartment, the patellofemoral compartment, or both. In 62 participants (43%), the radiographic changes were unilateral. Table 2 shows the association between osteoarthritis and obesity [14-16]. Women in the cohort who had osteoarthritis were approximately 15% heavier than women with normal radiographs and no knee pain. Men with osteoarthritis were also slightly heavier than men without osteoarthritis. Table 2. Body Weight and Summed Arthritis Index Scores for Recent Pain and Function in the Left Knee in Participants with and without Radiographic Evidence of Osteoarthritis* Among those with radiographic evidence of tibiofemoral osteoarthritis, women were slightly more likely than men to report knee pain (P = 0.10; Table 3). Table 3. Radiography and Recent Pain in the Left Knee Table 2 also shows the mean summed and the distribution of scores for left knee pain and functional impairment (data for the right knee were similar). Among men and women with radiographic evidence of osteoarthritis who reported having knee pain, the mean summed pain score for the knee with osteoarthritis was approximately 12 (median score, 2 of 5). In comparison, the mean pain score of participants who reported knee pain but did not have radiographic evidence of osteoarthritis in the painful knee was approximately 10 (median score, 2 of 5)-only slightly lower than the mean pain score of participants with radiographic changes. Consistent with their relatively low pain scores, these community-dwelling participants with osteoarthritis reported moderately low use of NSAIDs (Table 4). Table 4. Participants Reporting Regular Current or Previous Use of Analgesics and Nonsteroidal Anti-inflammatory Drugs Related to the Presence of Radiographic Evidence of Osteoarthritis of the Knee and Recent Knee Pain* Arthritis Index scores for functional impairment paralleled those for pain (Table 2). Participants with osteoarthritis had the greatest functional impairment (P < 0.001 for the comparison with patients who did not have pain or radiographic evidence of osteoarthritis). Functional impairment in participants who had pain but no radiographic evidence of osteoarthrit

Reduced quadriceps strength relative to body weight: A risk factor for knee osteoarthritis in women?

OBJECTIVE To determine whether baseline lower extremity muscle weakness is a risk factor for incident radiographic osteoarthritis (OA) of the knee. METHODS This prospective study involved 342 elderly community-dwelling subjects (178 women, 164 men) from central Indiana, for whom baseline and followup (mean interval 31.3 months) knee radiographs were available. Lower extremity muscle strength was measured by isokinetic dynamometry and lean tissue (i.e., muscle) mass in the lower extremities by dual x-ray absorptiometry. RESULTS Knee OA was associated with an increase in body weight in women (P = 0.0014), but not in men. In both sexes, lower extremity muscle mass exhibited a strong positive correlation with body weight. In women, after adjustment for body weight, knee extensor strength was 18% lower at baseline among subjects who developed incident knee OA than among the controls (P = 0.053), whereas after adjustment for lower extremity muscle mass, knee extensor strength was 15% lower than in the controls (P not significant). In men, in contrast, adjusted knee extensor strength at baseline was comparable to that in the controls. Among the 13 women who developed incident OA, there was a strong, highly significant negative correlation between body weight and extensor strength (r = -0.740, P = 0.003), that is, the more obese the subject, the greater the reduction of quadriceps strength. In contrast, among the 14 men who developed incident OA, a modest positive correlation existed between weight and quadriceps strength (r = 0.455, P = 0.058). No correlation between knee flexor (hamstring) strength and knee OA was seen in either sex. CONCLUSION Reduced quadriceps strength relative to body weight may be a risk factor for knee OA in women.

Decision analysis for avoiding postchemotherapy surgery in patients with disseminated nonseminomatous germ cell tumors.

PURPOSE This retrospective study was undertaken to assess the outcome of patients with disseminated nonseminomatous germ cell tumor (NSGCT) managed under a postchemotherapy strategy developed at Indiana University. PATIENTS AND METHODS This is a retrospective analysis of 295 consecutive patients with disseminated NSGCT treated with primary chemotherapy at Indiana University from 1987 to 1994. The patients were placed into five groups based on response to primary chemotherapy and the presence or absence of teratoma in the primary tumor. The 295 patients were divided as follows: group A (complete remission [CR]) n = 78; group B (unresectable), n = 50; group C (serologic CR, teratoma-positive primary tumor, resectable partial remission [PR]), n = 90; group D [serologic CR, teratoma-negative primary tumor, < 90% radiographic PR], n = 50; and group E (serologic CR, teratoma-negative primary tumor, > or = 90% radiographic PR), n = 27. Groups A, B, and E patients were routinely observed after chemotherapy, whereas groups C and D patients were routinely taken to postchemotherapy surgery. RESULTS The percent of patients who continuously had no evidence of disease (NED) were as follows: group A, 92%; group B, 40%; group C, 87%; group D, 86%; and group E, 74%. In assessing group A patients, the bulk of retroperitoneal disease at presentation had no influence on ultimate outcome. CONCLUSION Patients with NSGCT who achieve a serologic and radiographic CR with primary chemotherapy (group A) can be safely observed without surgical intervention, regardless of initial tumor bulk. Patients with a teratoma-negative primary tumor who achieve a serologic CR and a > or = 90% radiographic remission and are followed-up without surgical resection (group E) are at an increased risk of relapsed NSGCT. Decisions about postchemotherapy resection in this group remain complicated and controversial. Options include observation with serial radiologic evaluation or surgical resection of persistent mass or masses.

Results and Outcome of Retroperitoneal Lymph Node Dissection for Clinical Stage I Embryonal Carcinoma–Predominant Testis Cancer

PURPOSE To determine the incidence of metastatic disease and usage of chemotherapy (adjuvant or metastatic) after primary retroperitoneal lymph node dissection (RPLND) in patients with clinical stage (CS) I embryonal carcinoma (EC)-predominant testicular cancer. EC predominance was defined as the presence of EC at a level greater than that of any other histologic diagnosis. PATIENTS AND METHODS All CS I patients with nonseminomatous germ cell tumors who underwent RPLND at Indiana University from 1990 to 1995 were reviewed retrospectively. RESULTS Two-year follow-up was available for 292 of 320 patients. EC-predominant disease was found in 125 (42.8%) of 292. Eighty-five (68.0%) of 125 patients with EC-predominant disease had pathologic stage (PS) I, and 18 (21.2%) of this group of 85 relapsed. A significantly lower PS I relapse rate of 3% was found for patients who had non-EC-predominant disease (P <.0001). PS II disease was more frequent in patients with EC predominance, as 40 (32.0%) of 125 had retroperitoneal metastases, compared with 26 (15.6%) of 167 patients with a non-EC-predominant histologic diagnosis (P =.0024). Chemotherapy was administered to 48 (38.4%) of the 125 patients with CS I EC-predominant disease after RPLND. This included 25 CS I patients with PS II disease who received adjuvant chemotherapy in addition to 23 patients who subsequently required chemotherapy for relapse after RPLND. Ten (66. 6%) of 15 PS II EC-predominant patients were cured by surgery alone. Currently, all 125 EC-predominant patients are disease-free. CONCLUSION Patients with CS I EC-predominant disease are at a relatively high risk for metastatic disease.

Combined post-chemotherapy retroperitoneal lymph node dissection and resection of chest tumor under the same anesthetic is appropriate based on morbidity and tumor pathology

PURPOSE We determine if post-chemotherapy resection of residual retroperitoneal and chest tumor under the same anesthetic is reasonable based on tumor pathology and morbidity, and if the finding of necrosis in the abdomen allows observation of chest tumor. MATERIALS AND METHODS We retrospectively reviewed 143 post-chemotherapy patients who underwent resection of residual retroperitoneal and chest disease under the same anesthetic. RESULTS Retroperitoneal pathology was generally predictive of chest pathology. Concordance existed in 77.5% of patients with necrosis, 70% with teratoma and 69% with cancer of the abdomen. However, the correlation was much stronger (86%) in predicting necrosis/fibrosis if cases were categorized as uncomplicated by Indiana University criteria. Although the morbidity of the combined approach is higher than that of standard post-chemotherapy retroperitoneal lymph node dissection, it was acceptable. CONCLUSIONS The morbidity of post-chemotherapy retroperitoneal lymph node dissection and resection of chest disease under the same anesthetic is acceptable. Retroperitoneal pathology generally predicts chest pathology but this correlation is much stronger if the case is uncomplicated based on our criteria. In an uncomplicated case the discovery of necrosis of the abdomen allows observation of chest tumor.

Immunohistochemistry Can Be Used to Subtype Acute Myeloid Leukemia in Routinely Processed Bone Marrow Biopsy Specimens Comparison With Flow Cytometry

Flow cytometry (FC) is the preferred method of immunophenotyping acute myeloid leukemia (AML). However, there are situations in which FC is unavailable and in which immunohistologic staining of bone marrow biopsy specimens can be used to provide immunophenotypic information. To evaluate immunohistologic staining and to confirm its value, we selected 80 newly diagnosed cases of AML that were classified according to French-American-British (FAB) criteria and confirmed by flow cytometric analysis for this study. Paraffin-embedded bone marrow specimens were stained using a panel of antibodies that included CD34 (QBEND10), antimyeloperoxidase (anti-MPO), antihemoglobin, factor VIII-related antigen, and 3 epitopes of CD68 (HAM56, KP1, and PG-M1). Our findings suggest that with the use of the paraffin-reactive antibodies CD34 (QBEND10), MPO, CD68 (PG-M1), antihemoglobin, and factor VIII-related antigen, immunohistochemistry can be used to subclassify AML. Comparison of immunohistochemical results with FC immunophenotyping suggests that there is significant concordance in the results for markers that can be used with both techniques, indicating that the sensitivity and specificity of both methods is comparable (P > .53 in all cases).

A tailored intervention for mammography among low-income African-American women

Abstract This report describes a tailored intervention to increase compliance regarding mammography and the stage of its adoption among low-income African-American women aged 45 to 64 years. Two randomly assigned groups received either an in-person tailored intervention or routine care. The intervention was targeted toward perceived risk of breast cancer and perceived benefits of and barriers to breast cancer screening. Participants accrued from a community service center were followed for one year to identify the effect of the intervention on adoption of mammography.

Pancreatic enzyme supplementation in cystic fibrosis patients before and after fibrosing colonopathy.

BACKGROUND In 1994 we cared for nine cystic fibrosis patients with fibrosing colonopathy. To evaluate the relationship between fibrosing colonopathy and supplemental pancreatic enzymes we reviewed our dosing of enzymes prior to fibrosing colonopathy development and then evaluated the subsequent effect of drastically reducing pancreatic enzyme dose. METHODS We retrospectively reviewed pancreatic enzyme dosing for 267 cystic fibrosis patients with pancreatic insufficiency. The supplemental enzyme history of nine patients with fibrosing colonopathy was contrasted with the history of 258 nonaffected patients. The pancreatic enzyme doses of 75 patients taking at least 6,000 U lipase/kg/meal were systematically reduced to approximately 2,000 lipase units/kg/meal. We evaluated the effect of this dose reduction on change in height and weight z scores one year after achievement of stable enzyme dose. RESULTS In the year prior to diagnosis patients with fibrosing colonopathy took a significantly larger pancreatic enzyme dose, whether assessed by highest dose or cumulative dose, than did nonaffected patients. Similar results were observed after controlling for sex and age. All 75 patients on at least 6,000 U lipase/kg/meal were able to tolerate a significant reduction in dose while achieving clinically acceptable nutrient absorption, with no change over one year in height and weight z scores. CONCLUSIONS Our data demonstrate a strong relationship between very high doses of pancreatic enzyme supplementation and formation of fibrosing colonopathy. These very high doses do not appear to be needed for adequate nutrient absorption and growth.

Cyclo-oxygenase-2 expression in primary cancers of the lung and bladder compared to normal adjacent tissue.

Multiple observations in the laboratory and the clinical setting have linked expression of the enzyme cyclo-oxygenase-2 (COX-2) to carcinogenesis. The frequency and amount of COX-2 and Bcl-2 expression in primary lung and bladder cancer sites were detennined by immunoblot analysis of cell lysates prepared from frozen human tumor tissue and matched normal adjacent tissue. COX-2 protein was expressed statistically more frequently and at a higher level in primary adenocarcinomas and squamous cell carcinomas of the lung as well as transitional cell carcinomas of the bladder than in normal adjacent tissue. No correlation was observed between COX-2 and Bcl-2 expression in either the lung or bladder cancer specimens. Immunohistochemistry was also employed to localize COX-2 expression. In addition to expression in the malignant tissues, COX-2 was occasionally localized to the normal bronchial and transitional cell epithelia of the normal adjacent tissue. Detection of COX-2 in histologically normal appearing adjacent tissue suggests that COX-2 may be involved in early cellular changes leading to the development of lung and bladder cancer.

Dose-intensification of procarbazine, CCNU (lomustine), vincristine (PCV) with peripheral blood stem cell support in young patients with gliomas

BACKGROUND The regimen of procarbazine, CCNU, and vincristine is active against gliomas. Previous attempts at dose-intensification have been unsuccessful because of delayed and cumulative myelosuppression. We sought to determine whether peripheral blood stem cell (PBSC) infusions would allow dose-escalation and time compression. PROCEDURE Eleven patients, age 2.8-35.9 years, with newly diagnosed (n = 10) or recurrent (n = 1) gliomas underwent PBSC harvesting after mobilization with G-CSF. Chemotherapy consisted of CCNU 130 mg/m2 on day 0, vincristine 1.5 mg/m2 on days 0 and 7, and procarbazine 150 mg/m2 on days 1-7. PBSCs were reinfused on day 9 of each course. Four courses of chemotherapy were administered 28 days apart or when counts recovered. Involved field radiation was administered to newly diagnosed high-grade glioma patients following recovery from chemotherapy. RESULTS Compared to the standard PCV regimen given every 6 weeks, dose intensity received was 1.7- and 1.8-fold greater for CCNU and procarbazine. Chemotherapy was delivered on time in 33/41 (80.5%) courses. Four courses (9.8%) were complicated by absolute neutrophil counts < 200/microL; platelet nadirs < 50,000/microL occurred in two courses (4.9%). Fever with neutropenia complicated three courses. Eight of 9 patients with measurable disease had an objective decrease in tumor size and/or decreased enhancement. Median survival for patients with high-grade gliomas (n = 6) was 13 months. CONCLUSIONS Dose-intensification of PCV is possible using PBSCs.