Sustained pyridoxine response in primary hyperoxaluria type 1 recipients of kidney alone transplant.

Combined liver kidney transplant is the preferred transplant option for most patients with primary hyperoxaluria type 1 (PH1) given that it removes the hepatic source of oxalate production and improves renal allograft survival. However, PH1 patients homozygous for the G170R mutation can develop normal urine oxalate levels with pyridoxine therapy and may be candidates for kidney alone transplant (KTx). We examined the efficacy of pyridoxine therapy following KTx in five patients homozygous for G170R transplanted between September 1999 and July 2013. All patients were maintained on pyridoxine posttransplant. Median age at transplant was 39 years (range 33-67 years). Median follow-up posttransplant was 8.5 years (range 0.2-13.9 years). At the end of follow-up, four grafts were functioning. One graft failed 13.9 years posttransplant due to recurrent oxalate nephropathy following an acute medical illness. After tissue oxalate stores had cleared, posttransplant urine oxalate levels were <0.5 mmol/24 h the majority of times checked. Calcium oxalate crystals were noted in only 3/13 allograft biopsies. This series suggests that a subgroup of PH1 patients demonstrate sustained response to pyridoxine therapy following KTx. Therefore, pyridoxine combined with KTx should be considered for PH1 patients with a homozygous G170R mutation.

Use of tumor dynamics to clarify the observed variability among biochemical recurrence nomograms for prostate cancer.

BACKGROUND: Nomograms for biochemical recurrence (BCR) of prostate cancer (PC) after radical prostatectomy can yield very different prognoses for individual patients. Since the nomograms are optimized on different cohorts, the variations may be due to differences in patient risk-factor distributions. In addition, the nomograms assign different relative scores to the same PC risk factors and rarely stratify for tumor growth rate. METHODS: We compared BCR-free probabilities from the GPSM model with a cell kinetics (CK) model that uses the individual's tumor state and growth rate. We first created a cohort of 143 patients that reproduced the GPSM patient distribution in Gleason score, Prostate specific antigen (PSA), Seminal vesicle involvement and Margin status since they form the GPSM score. We then performed 143 CK calculations to determine BCR-free probabilities for comparison with the GPSM results for all scores and with four other prominent nomograms for a high-risk patient. RESULTS: The BCR-free probabilities from the CK model agree within 10% with those from the GPSM study for all scores once the CK model parameters are stratified in terms of the GPSM risk factors and the PSA doubling time (PSADT). However, the probabilities from widely used nomograms vary significantly. CONCLUSIONS: The CK model reproduces the observed GPSM BCR-free probabilities with a broad stratification of model parameters for PC risk factors and can thus be used to describe PC progression for individual patients. The analysis suggests that nomograms should stratify for PSADT to be predictive.

Transplantation outcomes in primary hyperoxaluria.

Optimal transplantation strategies are uncertain in primary hyperoxaluria (PH) due to potential for recurrent oxalosis. Outcomes of different transplantation approaches were compared using life-table methods to determine kidney graft survival among 203 patients in the International Primary Hyperoxaluria Registry. From 1976-2009, 84 kidney alone (K) and combined kidney and liver (K + L) transplants were performed in 58 patients. Among 58 first kidney transplants (32 K, 26 K + L), 1-, 3- and 5-year kidney graft survival was 82%, 68% and 49%. Renal graft loss occurred in 26 first transplants due to oxalosis in ten, chronic allograft nephropathy in six, rejection in five and other causes in five. Delay in PH diagnosis until after transplant favored early graft loss (p = 0.07). K + L had better kidney graft outcomes than K with death-censored graft survival 95% versus 56% at 3 years (p = 0.011). Among 29 year 2000-09 first transplants (24 K + L), 84% were functioning at 3 years compared to 55% of earlier transplants (p = 0.05). At 6.8 years after transplantation, 46 of 58 patients are living (43 with functioning grafts). Outcomes of transplantation in PH have improved over time, with recent K + L transplantation highly successful. Recurrent oxalosis accounted for a minority of kidney graft losses.

Referral and ascertainment bias in patients with synchronous and metachronous endometrial malignancy.

The purpose of this study was to evaluate the frequency in patients with endometrial cancer of other malignancies and the influence of referral and ascertainment biases on these associations. Analysis of 1,028 local and referred patients who had a hysterectomy for endometrial cancer was based on residence at the time of diagnosis. Altogether, 208 patients had a history of another malignancy, most frequently breast, colon, and ovary. At the time of surgery for endometrial cancer, the prevalence of lymphoma and breast and ovarian cancers was greater than expected although the higher prevalence of lymphoma was limited to referred patients. During follow-up after hysterectomy, the incidence of lung cancer was lower than expected, whereas the incidence of lymphoma was higher. Breast, colorectal, and bladder cancers were more common than expected although this finding was limited to local patients. We concluded that results of epidemiologic studies from tertiary care centers may be misleading if they do not account for referral and ascertainment biases.

Clinical significance of alterations of chromosome 8 in high-grade, advanced, nonmetastatic prostate carcinoma.

BACKGROUND: Chromosome 8 alterations, including loss of 8p21-22 and gain of 8q24, are commonly observed in prostate carcinoma. We examined whether these alterations are associated with poor prognosis in prostate cancer. METHODS: We used dual-probe fluorescence in situ hybridization and DNA probes for 8p22 (lipoprotein lipase gene), centromere 8 (8cen), and 8q24 (c-myc gene) to determine the corresponding copy numbers in tumor samples from 144 patients with high-grade, advanced (stage III) prostate carcinoma. Cox models were used for multivariate analysis of systemic progression or patient death from prostate cancer. All statistical tests are two-sided. RESULTS: We classified the 8p22, 8cen, and c-myc copy number as normal, loss, and gain. An additional increase (AI) category of c-myc relative to the centromere copy number (i.e., overrepresentation and amplification of c-myc) was also used. Alterations of 8p22 were not statistically significantly associated with either systemic progression or patient death. Alterations of c-myc were associated with both systemic progression (P =.024) and patient death (P =.039); AI of c-myc showed the poorest outcome. We also evaluated the prognostic relevance of the combined 8p22-8cen-c-myc loci anomaly pattern for the following six patterns: normal-normal-normal, loss-any 8cen-normal, loss-gain-gain, gain-gain-gain, non-loss-any 8cen-AI, and loss-any 8cen-AI, where any 8cen is normal, loss, or gain of the chromosome 8 centromere. Patients with the loss-any 8cen-AI pattern had earlier systemic progression (P =.009) and earlier cause-specific death (P =.013) than did patients with other patterns. Multivariate analyses demonstrated that the loss-any 8cen-AI pattern was an independent risk factor for systemic progression (P<.001) and cause-specific death (P =.002). CONCLUSIONS: Genetic alterations of chromosome 8 appear to accumulate in parallel with the progression of prostate carcinomas. AI of the c-myc gene, especially with loss of 8p22, appears to be associated with poor patient prognosis.

Lung cancer mortality in the Mayo Lung Project: impact of extended follow-up.

BACKGROUND: The Mayo Lung Project (MLP) was a randomized, controlled clinical trial of lung cancer screening that was conducted in 9211 male smokers between 1971 and 1983. The intervention arm was offered chest x-ray and sputum cytology every 4 months for 6 years; the usual-care arm was advised at trial entry to receive the same tests annually. No lung cancer mortality benefit was evident at the end of the study. We have extended follow-up through 1996. METHODS: A National Death Index-PLUS search was used to assign vital status and date and cause of death for 6523 participants with unknown information. The median survival for lung cancer patients diagnosed before July 1, 1983, was calculated by use of Kaplan-Meier estimates. Survival curves were compared with the log-rank test. RESULTS: The median follow-up time was 20.5 years. Lung cancer mortality was 4.4 (95% confidence interval [CI] = 3.9-4.9) deaths per 1000 person-years in the intervention arm and 3.9 (95% CI = 3.5-4.4) in the usual-care arm (two-sided P: for difference =.09). For participants diagnosed with lung cancer before July 1, 1983, survival was better in the intervention arm (two-sided P: =.0039). The median survival for patients with resected early-stage disease was 16.0 years in the intervention arm versus 5.0 years in the usual-care arm. CONCLUSIONS: Extended follow-up of MLP participants did not reveal a lung cancer mortality reduction for the intervention arm. Similar mortality but better survival for individuals in the intervention arm indicates that some lesions with limited clinical relevance may have been identified in the intervention arm.

Fifty-year trend in incidence rates of bronchogenic carcinoma by cell type in Olmsted County, Minnesota.

An earlier report suggested that incidence rates of primary bronchogenic carcinoma had leveled off for men in Olmsted County, MN. Extension of that study to cover 50 years in this midwestern community now shows that lung cancer incidence continues to increase in both sexes, with rates in women approaching those found in men 20 years ago. This increase was seen for all cell types of bronchogenic carcinoma. Because one pathologist reevaluated tissues, changing histologic classifications were not responsible for secular trends; nor were the results influenced by referral bias inasmuch as the study was population based.

Aneuploidy and aneusomy of chromosome 7 detected by fluorescence in situ hybridization are markers of poor prognosis in prostate cancer.

Fluorescence in situ hybridization is a new methodology which can be used to detect cytogenetic anomalies within interphase tumor cells. We used this technique to identify nonrandom numeric chromosomal alterations in tumor specimens from the poorest prognosis patients with pathological stages T2N0M0 and T3N0M0 prostate carcinomas. Among 1368 patients treated by radical prostatectomy, 25 study patients were ascertained who died most quickly from progressive prostate carcinoma within 3 years of diagnosis and surgery. Tumors from 25 control patients who survival for more than 5 years and who were matched for age, tumor histological grade, and pathological stage also were evaluated. The tumors from all 25 (100%) poor prognosis patients and from 11 of 25 (44%) control patients were found to be aneuploid by fluorescence in situ hybridization (P < 0.0001). Alterations of chromosome 7 were observed in 24 of the tumors (96%) from the poor prognosis patients versus 3 tumors (12%) from the control group (P < 0.0001). Moreover, a characteristic aneuploidy pattern with multiple abnormal chromosomes and a hypertetrasomic population was generally found in tumors from the poor prognosis patients. This preliminary study suggests that fluorescence in situ hybridization studies of prostate cancer specimens may help to identify those patients at highest risk for early cancer death.

Preoperative prediction of surgical margin status in patients with prostate cancer treated by radical prostatectomy.

PURPOSE: We sought to determine the preoperative factors associated with surgical margin status in patients who underwent radical prostatectomy for prostate cancer. PATIENTS AND METHODS: The study group consisted of 339 patients who were treated by radical retropubic prostatectomy and bilateral pelvic lymphadenectomy at the Mayo Clinic. None received preoperative adjuvant therapy. The mean age at the time of surgery was 66 years (range, 45 to 79 years). All specimens were totally embedded and whole-mounted. Positive surgical margin was defined as the presence of cancer cells at the inked margins. Numerous pathologic characteristics in needle biopsies and preoperative clinical findings were analyzed. RESULTS: The overall margin positivity rate was 24%. In univariate analysis, preoperative serum prostate-specific antigen (PSA) level, Gleason score, perineural invasion, percentage of cancer in the biopsy specimens, and number and percentage of biopsy cores involved by cancer were all associated with positive surgical margins. In multivariate analysis, preoperative serum PSA level (odds ratio for a doubling of PSA levels, 1.9; 95% confidence interval, 1.5 to 2.4; P <.001) and percentage of cancer in the biopsy specimens (odds ratio for a 10% increase, 1.3; 95% confidence interval, 1.2 to 1.4; P <.001) were predictive of margin status in radical prostatectomy. With use of preoperative serum PSA level and percentage of cancer in the biopsy as predictors of surgical margins, the overall accuracy as measured by the area under the receiver operating characteristic curve was 0.74. CONCLUSION: Preoperative serum PSA level and percentage of cancer in the biopsy specimens were independently associated with surgical margin status in patients who underwent radical prostatectomy for prostate cancer. The combination of these two factors provides a high level of predictive accuracy for margin status.

Radical prostatectomy for clinically localized prostate cancer: long-term results of 1,143 patients from a single institution.

PURPOSE: To determine the efficacy and complication rate of radical prostatectomy (RP) as a treatment option for clinically localized prostate cancer (clinical stage < or = T2c). METHODS: The study was a retrospective analysis of 1,143 consecutive patients (median age, 64 years; range, 38 to 79 y) who underwent RP at one institution (mean follow-up time, 9.7 years). Complications for this study population were compared with those of a contemporary group of 1,000 consecutive patients. RESULTS: Of 1,143 patients, 83 (7%) had a low clinical stage (T1) and 160 (14%) had a low histologic grade (Gleason score < or = 3); 648 (57%) had a high clinical stage (T2b or T2c) and 204 (18%) had a high histologic grade (Gleason score > or = 7). Only 113 (10%) died of prostate cancer, and 177 (15%) developed metastasis. Adjuvant treatment (androgen deprivation or radiation therapy) was given in 197 (17%) patients (> or = pT3) and provided virtually identical results as without adjuvant treatment. The 10- and 15-year crude survival rates for 1,143 patients were 75% +/- 1.5% (SE) and 60% +/- 2.2%, respectively; the cause-specific survival rates were 90% +/- 1.1% and 83% +/- 1.9%, respectively; and the metastasis-free survival rates were 83% +/- 1.3% and 77% +/- 1.9%, respectively (398 men at risk at 10 years and 138 men at risk at 15 years). The 10-year survival rate for patients with Gleason score > or = 7 was 74% +/- 3.9%. Only tumor grade was a significant predictor for disease outcome. The hospital mortality rate decreased from 0.7% for the 1,143 study patients to 0% for the more recent 1,000 patients. Severe incontinence declined to 1.4% for the more recent 1,000 patients. Most patients who underwent RP were healthy (Charlson comorbidity index). CONCLUSION: Survival at 15 years was similar to the expected survival rate. Current morbidity and mortality rates associated with RP were extremely low. Thus, RP has been a viable management option for men with clinically localized prostate cancer who have a life expectancy of more than 10 years.

Aneusomies of chromosomes 8 and Y detected by fluorescence in situ hybridization are prognostic markers for pathological stage C (pt3N0M0) prostate carcinoma.

In an attempt to identify new prognostic markers, we performed fluorescence in situ hybridization (FISH) ploidy analysis of tumor tissue from patients with a targeted stage and histological grade of prostate carcinoma. We identified all 227 patients from the Mayo Clinic radical prostatectomy data base who had a high histological grade pathological stage C (pT3N0M0) tumor removed between 1966 and 1987. After histological review of the paraffin-embedded specimen blocks, 181 cases were suitable for FISH analysis using chromosome enumeration probes for chromosomes 7, 8, 10, 12, X, and Y. FISH detected 80 (44%) diploid, 22 (12%) tetraploid, and 79 (44%) aneuploid tumors. The common aneusomies were of chromosomes 7 and 8, which were present in 51 (28%) and 46 (25%) tumors, respectively. Aneusomies of chromosomes 10, 12, X, and Y were observed in 11 (6%), 15 (8%) 12 (7%) and 16 (9%) tumors, respectively. FISH aneuploid tumors showed a trend of more frequent systemic prostate cancer progression than nonaneuploid tumors (P = 0.060). For individual chromosome anomalies, gains of chromosome 8, aneusomy of chromosome 8, and aneusomy of chromosome Y correlated highly with systemic cancer progression (P = 0.006, 0.013, and 0.021, respectively). Gains of chromosome Y and aneusomy of chromosome Y were associated with an increased prostate cancer death rate (P < 0.001 for both). Multivariate analysis showed that gains of chromosome 8 and aneusomy of chromosome Y were significant independent "predictors" of systemic cancer progression (P = 0.008) and cancer death (P < 0.001), respectively. These results demonstrate that aneuploidy and specific aneusomies detected by FISH are potential markers for a poor prognosis in histological high-grade pathological stage C (pT3N0M0) prostate carcinoma.

Predictive properties of serum-prostate-specific antigen testing in a community-based setting.

BACKGROUND: Most studies that have described the sensitivity and specificity of prostate-specific antigen (PSA) as a screening test have been conducted in urology practice settings or in media-based screening programs. The control patients from these settings may have a higher prevalence of urologic disorders that increase serum PSA levels than that of the general population in which screening efforts might take place, leading to biased estimates of sensitivity and specificity. OBJECTIVE: To determine the sensitivity and specificity of serum PSA levels for the early detection of prostate cancer in a population-based setting. PATIENTS AND METHODS: This population-based case-control study was conducted in Olmsted County, Minnesota, where the Rochester Epidemiology Project could identify all incident cases of prostate cancer through passive surveillance of medical care provided to local residents. Case patients were all 177 men (age range, 50-79 years) who were newly diagnosed as having prostate cancer from 1990 through 1992 and had a prediagnostic serum PSA determination (90% of all incident cases). Control patients were randomly selected from the Olmsted County population and had undergone a clinical examination to exclude prostate cancer. RESULTS: The median (25th and 75th percentiles) of serum PSA levels was 9.4 ng/mL (5.4 and 18.6 ng/mL, respectively) for case patients and 1.2 ng/mL (0.7 and 2.1 ng/mL, respectively) for control patients (P < .001). When sensitivity was plotted against 1-specificity, the area under the receiver operating characteristic curve was 0.94 (SE, 0.01). The predictive power declined somewhat with age, with areas under the curve of 0.96, 0.94, and 0.90 for men in their 50s, 60s, and 70s, respectively. When cases were restricted to the 155 men with clinically localized disease, the area under the curve was essentially unchanged (0.94; SE, 0.01) and still much greater than the estimates of 0.75 that were reported from urology practice- and media-based settings. CONCLUSIONS: In a community-based setting, serum PSA levels provide better discrimination between men with and without clinically localized prostate cancer than has been observed in studies that were conducted in urologic practices. These results suggest that previous decision analyses may have underestimated the predictive value of PSA for the detection of prostate cancer in a primary care or community-wide screening program.

Effect of season on physical activity score, back extensor muscle strength, and lumbar bone mineral density.

Seasonal variation in physical activity, back extensor muscle strength (BES), and bone mineral density (BMD) of the lumbar spine was studied in 65 healthy postmenopausal women. Physical activity score (PAS) was assessed with an ordinal scale (0-18); this score and the BES were obtained monthly for 2 years (25 readings). BMD values were obtained semiannually (5 readings). A periodic (cosine) regression model was fit to each subject's PAS and BES data to obtain individual estimates of the annual peak day d and the average annual range due to seasonality. There was a strong (P less than 0.001) seasonal pattern in physical activity; August 3 was the average peak day, and the seasonal range was 2.0 PAS units. There was modest (P = 0.047) seasonality in BES; June 6 was the estimated peak day, and the seasonal range was 8.22 pounds (about 7% of the 0.002), and the highest monthly average BMD was in August. This seasonal range of 1.4% is larger than the average annual decline with age in BMD observed in longitudinal studies of postmenopausal women. The results of this study have important implications for the planning of longitudinal studies involving changes in physical activity or bone mass in geographic areas with diverse seasons.

Circadian variation in ionized calcium and intact parathyroid hormone: evidence for sex differences in calcium homeostasis.

The rate of bone loss with age and the incidence of osteoporosis are greater in women than men, which led us to question whether subtle sex differences may occur in the circadian variation of serum ionized calcium (iCa) and PTH. We measured iCa hourly and intact PTH every 2 h for 26 h in 25 women (21-69 yr) and 24 men (20-67 yr) consuming self-selected diets. Urine was collected at 0800-1600, 1600-2400, and 2400-0800 h. Serum iCa levels followed a circadian rhythm in both sexes (P less than or equal to 0.01), and the patterns differed between sexes, notably during early morning, when serum iCa levels were lower in women (P = 0.02). Urinary calcium excretion and fractional excretion of calcium declined in both sexes at night (2400-0800 h), but the decline in men was significantly greater (P = 0.02). Similarly, the percent reduction in urinary calcium excretion at night was greater in men than in women (34% vs. 17%; P less than or equal to 0.05). In women, 26-h mean serum iCa values correlated significantly with total daily calcium intake (r = 0.44; P = 0.03). Serum intact PTH levels showed a significant circadian pattern in both sexes (P less than or equal to 0.001). The patterns of serum intact PTH differed between the sexes (P = 0.05), with an earlier and greater increase at night in men. This blunted nocturnal rise in PTH in women may explain the poor nocturnal adaptation to fasting found in women who, despite lower calcium intake, did not reduce urinary calcium loss at night as effectively as men.

Distant metastases in papillary thyroid carcinoma: 100 cases observed at one institution during 5 decades.

The present study was designed to define the factors that predict survival in patients with distant metastases (DM) from papillary thyroid carcinoma. We performed a retrospective review of the records of 100 consecutive patients (45 females and 55 males; age range, 8-91 yr) who developed DM after primary treatment at our institution from, 1940-1989. Median follow-up for the 20 survivors was 21 yr (range, 3-38). Cause-specific survival rates at 5, 10, and 15 yr were 40%, 27%, and 24%, respectively, and were not significantly different between the eras 1940-1954, 1955-1969, and 1970-1989 (P = 0.74). By univariate analysis, age at diagnosis of DM was the most important predictor of survival (P < 0.0001), with improved survival occurring in younger patients. Tumor-related factors associated with improved survival included complete resection of the primary tumor (P < 0.005), histological grade 1 (P = 0.006), diploid nuclear DNA (P = 0.03), and lung as first site of DM (P = 0.018). By univariate analysis, use of radioiodine therapy was associated with improved survival (vs. other forms of therapy, P < 0.001). However, by multivariate analysis only age, site of DM, and degree of extrathyroidal invasion of the primary tumor were identified as significant predictors of survival. None of the four treatment variables (external radiation, surgery, chemotherapy, or radioiodine) was a significant predictor of survival in the Cox model. Our retrospective data indicate that 1) outcome has changed little over 5 decades for patients with DM from papillary thyroid carcinoma; and 2) current forms of therapy do not appear to impact on survival.

Pituitary adenomas in childhood and adolescence.

A clinicopathological study of 56 pediatric patients with non-ACTH-secreting pituitary adenomas removed by a transsphenoidal neurosurgical approach was undertaken to better define the clinical presentation, to assess demographic factors, to determine the immunohistochemical staining characteristics of the tumors, and to evaluate the outcome of transsphenoidal surgical treatment and other adjuvant therapies. A separate analysis of prolactinoma patients was performed. All tumors were confirmed histologically and immunophenotyped for pituitary hormones. Forty-one patients had tumors that stained for PRL alone, eight patients had tumors that stained for PRL and GH, six patients had plurihormonal adenomas, and one patient had a tumor that stained for glycoprotein hormones. No tumors contained GH alone. Macroadenomas exceeded microadenomas (1.4:1). There were no male patients with microadenomas of any type. Females outnumbered males (3.3:1). Patients presented most frequently with headache, menstrual dysfunction (in females), galactorrhea, and hypopituitarism. All but one of the patients with hypopituitarism at presentation had macroadenomas. Tumor staining characteristics did not always correlate well with clinical status, especially with regard to GH-containing tumors. Pediatric pituitary tumors did not appear to be more invasive or more aggressive than adult pituitary tumors, contrary to some previous reports. The patients with microadenomas had a 70% operative cure rate and a 65% long term cure rate; the recurrence rate for microadenoma patients was 25%. Macroadenoma patients had a 33% operative cure rate, a 55% long term cure rate, and a recurrence rate of 33%. Thus, microadenoma and macroadenoma patients had similar long term cure rates, but macroadenoma patients required more aggressive adjuvant therapy (second surgery, radiation, or bromocriptine) and had higher rates of hypopituitarism (52% of macroadenoma patients vs. 0% of microadenoma patients required long term hormone replacement).

Distant metastases in differentiated thyroid carcinoma: a multivariate analysis of prognostic variables.

From a cohort of 988 patients with differentiated thyroid carcinoma receiving primary surgical treatment between 1946 and 1970, we studied the 85 (9%) patients who had distant metastases diagnosed during life. Clinically detected metastases were found in 7% of the 859 patients with papillary cancers, 19% of the 100 patients with follicular cancers, and 34% of the 29 patients with Hürthle cell cancers. The total experience amounted to 607 patient-years of observation after the diagnosis of metastases, with a median follow-up in the 12 survivors of 23 yr (range, 13-32 yr). At the time of first diagnosis of metastases, the lungs only were involved in 53%, and bones only in 20%; 16% had multiple organ involvement. The overall mortality rates 5 and 10 yr after the diagnosis of metastases were 65% and 75%, respectively. Seventy-eight percent of all deaths were directly attributable to thyroid cancer; 82% of cancer deaths occurred within 5 yr. By univariate analysis, patient age, tumor extent, pattern of lung involvement, radioiodine uptake of the metastases, and radioiodine treatment were significant prognostic factors. By multivariate analysis, only age (as a continuous variable) at the time of first diagnosis of distant metastases (P less than 0.0001) and involvement of multiple organ sites (P = 0.0003) were independently associated with cancer mortality. The survival at 5 yr in 12 patients aged less than 40 yr with only a single organ involved was 92%. Older patients (aged greater than or equal to 40 yr) with a single metastasis (n = 59) had a lower survival (38% at 5 yr). The highest risk of cancer death (92% at 5 yr) was found in the 14 patients (any age) who at the time of first diagnosis of metastases had multiple organ involvement. The Cox regression model suggested that radioiodine therapy did not have a significant influence on survival, after adjusting for age and extent of metastatic involvement.

Systemic mast cell disease. Analysis of 58 cases and literature review.

Based on study of 58 histologically proved cases of SMCD, we believe that the prognosis of most SMCD patients can be anticipated at the time of initial diagnosis by using 5 independent significant predictors developed in a multivariate model. Our study confirms the significance of several previously reported poor prognostic factors: absence of skin involvement and the presence of hepatosplenomegaly, cytologic atypia, and a hypercellular bone marrow. However, in contrast to previous reports we did not find a uniform correlation between the presence or absence of skin involvement and prognosis. The observation that anemia was strongly related to so many prognostic variables may be due to the number of patients in our study with associated hematologic disorders. Alternatively, this evidence of ineffective erythropoiesis may support the concept that SMCD is a myeloid stem cell disorder and frequently affects other hematopoietic cell lines. The observation that death occurs within the first 3 years in most fatal cases of SMCD suggests that these patients should be followed carefully for this interval after initial diagnosis, especially if poor prognostic features are present. Currently there is no curative therapy for SMCD.

Three-year controlled, randomized trial of the effect of dose-specified loading and strengthening exercises on bone mineral density of spine and femur in nonathletic, physically active women.

The objectives of this study were to evaluate (1) the effect of spinal muscle strengthening by loading exercises on the bone mineral density (BMD) of the spine, and (2) the effect of upper extremity loading exercises on the BMD of the midradius and femur in healthy, premenopausal women. The study design was a randomized, controlled trial of 3 years' duration. Ninety-six healthy, premenopausal, white women aged 30-40 years participated; 67 completed the study. All subjects were in good health (normal menses) and were active, but not athletic (that is, not involved in a regular sport activity). Subjects were randomized to an exercise or control group. The exercise group performed a supervised, non-strenuous, weight-lifting exercise program. Exercise performance was supervised once a week at the medical facility. In addition, the subjects performed the exercises twice a week on their own. Dietary calcium intake was to be maintained at 1,500 mg/day in both groups. Bone density was measured at the lumbar spine and hip with dual-energy X-ray absorptiometry at 0, 1, and 3 years. BMD of the midradius was measured with single photon absorptiometry. Measurements of muscle strength were obtained at baseline and every 3 months for 3 years. Maximal oxygen uptake was measured, and the level of physical activity was recorded. Compliance with the exercise program was excellent during the first year of the study, but decreased thereafter. At the end of 3 years, subject withdrawal was about 34% from the exercise group and about 22% from the control group (total subject withdrawal was about 30%). Muscle strength in the exercise group increased significantly at all involved skeletal sites (p values all < 0.001). There was a modest positive correlation between the BMD of Ward's triangle with spinal flexor strength (r = 0.32, p = 0.008) and with grip strength (r = 0.38, p = 0.001). Comparing study groups, we found no significant effect of the loading and nonstrenuous strengthening exercises in the exercise group or free physical activity group (our control group) on BMD at the spine, hip, or midradius measurement sites. In active, but not athletic premenopausal women, additional moderate weight-lifting exercises showed no significant effect on BMD.

Cancer volume of lymph node metastasis predicts progression in prostate cancer.

Clinical outcome is variable in prostate cancer patients with regional lymph node metastasis. We studied 269 patients who had regional lymph node metastasis at the time of radical retropubic prostatectomy and bilateral pelvic lymphadenectomy at the Mayo Clinic between January 1987 and December 1992. Two hundred fifty-three (94%) patients received androgen deprivation therapy within 90 days of radical prostatectomy. Patients ranged in age from 47 to 79 years (median, 67 years). Median follow-up was 6.1 years (range, 0.3-10.5 years). Nodal cancer volume (size) was measured by the grid-counting method. Cox proportional hazards models were used to determine the impact of numerous clinical and pathologic findings on systemic progression-free survival. Systemic progression was defined as the presence of distant metastasis documented by biopsies or radiographic examinations (abdominal computerized tomography, plain radiographs, or bone scan). Five-year progression-free survival was 90%. In predicting systemic progression using Cox multivariate analysis, only nodal cancer volume added significantly to the model containing the primary cancer variables (Gleason score, cancer volume, and DNA ploidy). The relative hazard rate for a doubling in nodal cancer volume was 1.6 (95% confidence interval, 1.3 to 2.0; p < 0.0001). Spearman rank analysis showed a correlation between nodal cancer volume and Gleason score of the primary cancer, the number of positive nodes, the aggregate length of metastases, and the largest nodal cancer diameter (correlation efficient = 0.37, 0.63, 0.96, and 0.95, respectively). Our data indicate that nodal cancer volume was the most significant nodal determinant of progression to distant metastasis in lymph node-positive prostate cancer patients. We recommend that the diameter of the largest metastasis be evaluated in patients with metastases, because this is a more powerful predictor of patient outcome than current methods, which recommend mere counting of the number of positive nodes.