Calorie restriction in nonhuman primates: mechanisms of reduced morbidity and mortality

Long term chronic calorie restriction (CR) of adult nonhuman primates significantly reduces morbidity and increases median age of death. The present review is focused upon an ongoing study of sustained adult- onset calorie restriction, which has been underway for 15 years. Monkeys, initially calorie restricted at about 10 years of age, are now approximately 25 years old. The median life span of these restricted monkeys is increasing, now exceeding that of ad libitum (AL)-fed monkeys. In our laboratory, maximum life span for AL-fed monkeys appears to be about 40 years. Thus, whether CR can also increase maximal life span, as it does in rodents, cannot be determined for at least another 15 years. The earliest detectable positive benefit on morbidity in these monkeys was previously reported as the prevention of obesity. Current evidence, as reviewed here, suggests that much obesity- associated morbidity is also mitigated by sustained calorie restraint in nonhuman primates. Furthermore, probably because of the prevention of obesity, diabetes has also been prevented. Recent findings include the identification of extraordinary changes in the glycogen synthesis pathway, and on the phosphorylation of glycogen synthase in response to insulin. This calorie restriction-induced prevention of morbidity does not require excessive leanness, but is clearly present when body fat is within the normal range of 10 to 22%, and this is likely to be true in humans as well.      

沙赛普肽注射液的细菌内毒素检测

目的：用鲎试剂检测沙赛普肽注射液中的细菌内毒素。方法：采用鲎试法（LT）与家兔法（RT）对沙赛普肽注射液进行细菌内毒素检测。结果：两种方法检查结果一致,用直接稀释法排除细菌内毒素的干扰。结论：以鲎试法用于控制沙赛普注射液的热原方法可行。     

Risk of prostate carcinoma death in patients with lymph node metastasis

BACKGROUND: The presence of lymph node metastasis is a poor prognostic sign for patients with prostate carcinoma. Results of published reports on survival among patients with lymph node metastasis are difficult to assess because of treatment selections. The extent to which lymph node status will have an impact on a patient's survival is uncertain. METHODS: The authors analyzed 3463 consecutive Mayo Clinic patients who underwent radical prostatectomy and bilateral pelvic lymphadenectomy for prostate carcinoma between 1987 and 1993. Of these patients, 322 had lymph node metastasis at the time of surgery, and 297 lymph node positive patients also received adjuvant hormonal therapy within 90 days of surgery. The progression free rate and the cancer specific survival rate were used as outcome endpoints in univariate and multivariate Cox proportional hazards models. The median follow-up was 6.3 years. Progression was defined by elevation of serum prostate specific antigen (PSA) > or = 0.4 ng/mL after surgery, development of local recurrence, or distant metastasis documented by biopsy or radiographic examination. RESULTS: The 5-year and 10-year progression free survival rates (+/- standard error [SE]) for patients with lymph node metastasis were 74% +/- 2% and 64% +/- 3%, respectively, compared with 77% +/- 1% and 59% +/- 2%, respectively, for patients without lymph node metastasis. The 5-year and 10-year cancer specific survival rates were 94% +/- 1% and 83% +/- 4%, respectively, compared with 99% +/- 0.1% and 97% +/- 0.5%, respectively, for patients without lymph node metastasis. Among patients with a single lymph node metastasis, the 5-year and 10-year cancer specific survival rates were 99% +/- 1% and 94% +/- 3%, respectively. After adjustment for extraprostatic extension, seminal vesicle invasion, Gleason grade, surgical margins, DNA ploidy, preoperative serum PSA concentration, and adjuvant therapy, the hazard ratio for death from prostate carcinoma among patients with a single lymph node metastasis compared with patients who were without lymph node metastasis was 1.5 (95% confidence interval, 0.5-5.0; P = 0.478), whereas the hazard ratio for death from prostate carcinoma was 6.1 (95% confidence interval, 1.9-19.6; P = 0.002) for those with two positive lymph nodes and 4.3 (95% confidence interval, 1.4-13.0; P = 0.009) for those with three or more positive lymph nodes. There was no significant difference in the progression free survival rate among patients with or without lymph node metastasis in multivariate analysis after controlling for all relevant variables, including treatments (hazard ratio,1.0; 95% CI, 0.7-1.3; P = 0.90). CONCLUSIONS: Patients with prostate carcinoma who have multiple regional lymph node metastases had increased risk of death from disease, whereas patients with single lymph node involvement appeared to have a more favorable prognosis after radical prostatectomy and immediate adjuvant hormonal therapy. Excellent local disease control was achieved by using combined surgery and adjuvant hormonal therapy in patients with positive lymph nodes.     

Reclassification of patients with pT3 and pT4 renal cell carcinoma improves prognostic accuracy

BACKGROUND: The significance of adrenal invasion and tumor thrombus in renal cell carcinoma (RCC) has been debated recently. The authors evaluated the associations of direct adrenal invasion, perinephric fat invasion, and tumor thrombus level with outcome to determine whether reclassification would improve the prognostic accuracy of the current primary tumor classification. METHODS: The authors studied 697 patients treated with nephrectomy for pT3 and pT4 RCC between 1970 and 2000. Associations with outcome were evaluated using Cox proportional hazards regression and prognostic accuracy was measured using the c index. RESULTS: Among patients with pT3 RCC, direct adrenal invasion was significantly associated with death from RCC (risk ratio, 2.11; P = 0.004). No significant difference in survival was found between patients with pT4 RCC and pT3 tumors with direct adrenal invasion (P = 0.490). Among patients with pT3b RCC, those with level I-III tumor thrombus were significantly more likely to die of RCC compared with patients harboring level 0 tumor thrombus (risk ratio, 1.62; P < 0.001). In addition, patients with fat invasion were more likely to die of RCC compared with pT3 patients without fat invasion (risk ratio, 1.87; P < 0.001). Therefore, patients with pT3 RCC were reclassified into 4 prognostic groups, and this reclassification significantly improved prediction of death from RCC compared with the current classification (c indices of 0.61 vs. 0.55, respectively). CONCLUSIONS: Direct adrenal invasion from RCC should be reclassified as pT4. In addition, the proposed reclassification for patients with pT3 RCC improved prognostic accuracy.     

Standard Versus Age-Specific Prostate Specific Antigen Reference Ranges Among Men With Clinically Localized Prostate Cancer: A Pathological Analysis

Purpose

Age-specific prostate specific antigen (PSA) reference ranges have been suggested to account for the age-dependent nature of the serum PSA concentration. It has been hypothesized that reference ranges of 0 to 2.5 ng./ml. serum PSA (40 to 49 years), 0 to 3.5 ng./ml. (50 to 59 years), 0 to 4.5 ng./ml. (60 to 69 years) and 0 to 6.5 ng./ml. (70 to 79 years) would detect fewer (potentially insignificant) prostate cancers in older men and more (potentially curable) cancers in younger men.

Materials and Methods

To investigate the pathological stage of tumors that would be affected by the use of age-specific PSA reference ranges, we reviewed the medical records for 4,597 men with clinically localized (stage T1c, T2 or T3a) prostate cancer, with an average age of 62 plus/minus 7 years (range 38 to 76), who underwent radical prostatectomy between 1984 and 1994 at our institutions. Favorable pathological results were defined as organ-confined disease or capsular perforation with a Gleason score of less than 7, and unfavorable pathological results were defined as capsular perforation with a Gleason score of 7 or more, seminal vesicle invasion or lymph node involvement.

Results

Overall, 18 percent of the men had PSA levels less than the standard PSA reference range (4.0 ng./ml.) compared to 22 percent when using the age-specific ranges. There were 74 more cancers detected in men younger than 60 years with the use of age-specific ranges, of which 81 percent had favorable pathological results. Among the men 60 years or older, 191 of 252 cancers (76 percent) not detected by using age-specific ranges were of favorable pathological status. Of those cancers not detected in older men with the age-specific ranges less than 3 percent were also stage T1c and 95 percent of these undetected T1c cancers were of favorable pathological status. Age-specific PSA reference ranges increased the potential for detection of prostate cancer by 18 percent in the younger men and decreased the detection by 22 percent in the older men.

Conclusions

Among these men with clinically localized prostate cancer, age-specific PSA reference ranges increased the detection of more potentially curable tumors in young men and decreased the detection of less advanced tumors in the older men compared to the standard reference range of 4.0 ng./ml. Among older men with nonpalpable (stage T1c) tumors age-specific PSA reference ranges would have detected fewer tumors. However, 95 percent of these “missed” tumors would have had favorable pathological findings.     

Transfusion-related acute lung injury caused by an NB2 granulocyte- specific antibody in a patient with thrombotic thrombocytopenic purpura

HLA and granulocyte-specific antibodies have been implicated in the production of transfusion-related acute lung injury (TRALI). Reported here is a case that suggests that the patient's preexisting condition may play an important role in determining whether TRALI develops upon transfusion of blood products containing anti-white cell (WBC) antibodies. A 29-year-old woman with thrombotic thrombocytopenic purpura (TTP) underwent an uneventful 1.5-volume plasma exchange, which was followed by the transfusion of 2 red cell (RBC) units. At the end of the second RBC transfusion, the patient developed clinical signs and symptoms of noncardiogenic pulmonary edema. Serologic studies demonstrated that the serum from the second RBC donor had no HLA antibodies but did have a granulocyte-specific antibody (anti-NB2) that caused the agglutination of the recipient's granulocytes, which were NB2 positive. Serum from the donor of the first RBC unit and serum from the donors of units used in the exchange had no HLA or granulocyte-specific antibodies that reacted with the recipient's WBCs. Because the donor implicated in this reaction had a history of 21 blood donations, none of which had been associated with a transfusion reaction, we suggest that the patient's preexisting condition played a significant role in this episode of TRALI, owing to the granulocyte-specific antibody.     

Open surgical partial nephrectomy

The goals of conservative resection of renal cell carcinoma are complete local surgical removal of the malignancy and preservation of adequate renal function. This is a delicate balance, which makes renal preserving surgery at times both challenging and controversial. Surgical management of renal cell carcinoma remains the most effective curative management. The increased use of cross-sectional imaging has led to an increased detection of incidental renal cell carcinomas at an earlier stage. The indications of nephron-sparing surgery (NSS) have evolved in the past decade. Clinically, there are scenarios where nephron-sparing surgery is absolutely indicated. However, in the setting of a normal contralateral kidney, radical nephrectomy is still considered by many to be the treatment of choice for localized renal cell carcinoma. There is now growing evidence that in the correct patient, the use of NSS in the above-mentioned situation is justified. Very recent data indicate that NSS provides effective and equivalent oncologic treatment for most renal cell carcinomas especially those 4 cm or smaller. Refined surgical techniques and new studies regarding the earlier diagnosis and biology of renal cell carcinoma, true incidence of occult multifocality, and comparable morbidity with radical nephrectomy make NSS an attractive tool in the armamentarium of the urologic surgeon.     

Outcomes for men with clinically nonmetastatic prostate carcinoma managed with radical prostactectomy, external beam radiotherapy, or expectant management: a retrospective analysis.

BACKGROUND: With a lack of data from randomized trials, the optimal management of men with nonmetastatic prostate carcinoma is controversial. The authors sought to define the outcomes of three common strategies for managing patients with nonmetastatic prostate carcinoma: expectant management, radiotherapy, and radical prostatectomy. METHODS: The authors conducted a retrospective cohort study with standardized collection of key prognostic data, including centralized assignment of Gleason grades from original biopsy specimens. Participants included all Connecticut hospitals (the expectant management cohort) and three academic medical centers in other states (the radiotherapy and surgery cohorts). Two thousand three hundred eleven consecutive men ages 55-74 years who were diagnosed during 1971-1984 with nonmetastatic prostate carcinoma and were treated at the participating sites were included. RESULTS: Kaplan-Meier estimates with 95% confidence intervals (95% CI) of overall survival at 10 years for each cohort were as follows: expectant management cohort, 42% of patients (95% CI, 38-46%); radiotherapy cohort, 52% of patients (95% CI, 46-58%); and radical prostatectomy cohort, 69% of patients (95% CI, 67-71%); for disease specific mortality, the estimates were as follows: expectant management cohort, 75% of patients (95% CI, 71-79%); radiotherapy cohort, 67% of patients (95% CI, 61-73%); and radical prostatectomy cohort, 86% of patients (95% CI, 84-88%). There were large differences in distributions of important prognostic factors among men in the different treatment groups. CONCLUSIONS: These data provide precise estimates of the outcomes of patients who have been treated with different modalities for nonmetastatic prostate carcinoma in the recent past. Direct comparisons of outcomes between treatment groups are inadvisable because of the different characteristics of patients who select these alternative management strategies.     

Treatment options for patients with stage D1 (T0-3,N1-2,M0) adenocarcinoma of prostate

Three hundred six patients with adenocarcinoma of the prostate underwent pelvic lymphadenectomy and had Stage D1 (T0-3,N1-2,M0) disease; 171 patients underwent radical retropubic prostatectomy with or without immediate adjuvant therapy (hormonal or radiation or both) or conservative (hormonal or radiation or both) treatment alone (n = 135). Follow-up was one-half to eighteen and one-half years (mean, 5 yrs). Immediate adjuvant orchiectomy significantly (P = 0.01) improved survival (87.4% at 10 years) and nonprogression rates for patients who underwent radical prostatectomy, but not for those who had lymphadenectomy. Overall patient survival was significantly better (P = 0.005) after prostatectomy than lymphadenectomy. Residual disease (n = 43) in patients who underwent prostatectomy and received adjuvant treatment (orchiectomy or radiation or both) did not affect disease outcome. Bilateral pelvic lymphadenectomy and radical prostatectomy with immediate adjuvant orchiectomy provided survival comparable to the expected survival; conservative treatment alone was associated with rapid disease progression and poor survival and significantly (P = 0.02) higher local morbidity.     

Commentary on the safety of red cells preserved in extended-storage media for neonatal transfusions

Red cells preserved in extended-storage media are the standard product dispensed by many regional blood centers. When the red cells are intended for neonatal transfusion, concern exists about the safety of the relatively high quantities of additives present in these media. Definitive studies to address these concerns are not available. Therefore, to estimate the effects of additives and to delineate circumstances in which they might be harmful, the quantities transfused in defined clinical settings were calculated, and the following recommendations are offered for transfusing infants less than 4 months of age. First, red cells preserved in extended-storage media should present no substantive risks when used for small-volume (approximately 10 mL/kg) transfusions of premature infants and can be used without additional processing. Second, the risks of the most premature neonatal patients or those with severe renal and/or hepatic insufficiency cannot be defined clearly, and, because data are not available to ensure safety for these infants, removal of the additive medium and resuspension of the red cells in saline or albumin solution immediately before transfusion are recommended. Third, following a similar rationale, it seems prudent to avoid using entire units of red cells preserved in extended-storage media in massive transfusion settings (e.g., exchange transfusion, cardiac surgery, and extracorporeal membrane oxygenation). In these settings, the preservative medium should be removed and the red cells resuspended in the fluid that is most appropriate for the procedure that is planned. It must be emphasized that these recommendations are based on calculations and hypothetical settings, not actual data. Accordingly, they are tentative and should be altered as definitive information becomes available.