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PubMed2006

Variations in the detection of ZAP-70 in chronic lymphocytic leukemia: Comparison with IgV(H) mutation analysis.

Lack of immunoglobulin heavy chain genes (IgV(H)) mutation in patients with chronic lymphocytic leukemia (CLL) is associated with rapid disease progression and shorter survival. The zeta-chain (T-cell receptor) associated protein kinase 70 kDa (ZAP-70) has been reported to be a surrogate marker for IgV(H) mutation status, and its expression in leukemic cells correlates with unmutated IgV(H). However, ZAP-70 detection by flow cytometry varies significantly dependant on the antibodies used, the method of performing the assay, and the condition of the cells in the specimen. The clinical value of ZAP-70 testing when samples are shipped under poorly controlled conditions is not known. Furthermore, testing in a research environment may differ from testing in a routine clinical laboratory. We validated an assay for ZAP-70 by comparing results with clinical outcome and the mutation status of the IgV(H). Using stored samples, we show significant correlation between ZAP-70 expression and clinical outcome as well as IgV(H) mutation at a cut-off point of 15%. While positive samples (>15% positivity) remain positive when kept in the laboratory environment for 48 h after initial testing, results obtained from samples from CLL patients tested after shipping at room temperature for routine testing showed no correlation with IgV(H) mutation status when 15% cut-off was used. In these samples, cut-point of 10% correlated with the IgV(H) mutation (P = 0.0001). This data suggests that although ZAP-70 positivity correlates with IgV(H) mutation status and survival, variations in sample handling and preparation may influence results. We show that IgV(H) mutation results, unlike ZAP-70 remain correlated with CD38 expression and beta-2 microglobulin in shipped samples, and ZAP-70 testing should not be used as the sole criterion for stratifying patients for therapy.

ADP-ribosyl Cyclase 1↗
PubMed2003

Ki-67 expression in breast carcinoma: its association with grading systems, clinical parameters, and other prognostic factors--a surrogate marker?

BACKGROUND: The number of mitoses and, thus, the proliferative capacity of a tumor is one of the most crucial variables for tumor grading. The Ki-67 nuclear antigen may be considered as an alternative to mitotic counts in grading schemes and as a single parameter that can be used in fine-needle aspirates and small biopsies. METHODS: Immunohistochemistry using the anti-Ki-67 antibody MIB-1 was performed on 434 breast carcinoma specimens from the International Breast Cancer Study Group (formerly Ludwig) Trial V. Three groups based on Ki-67 percent were used to replace the mitotic counts component in the Nottingham grade (NHG) to produce the Nottingham/Ki-67 grade (NKG) and to assess Ki-67 as a single parameter. RESULTS: In both the lymph node positive subgroup and the lymph node negative subgroup, the NKG and Ki-67 group was correlated significantly with Bloom-Richardson grade (BRG), NHG, and Nottingham type. Tumor size in the lymph node negative cohort and estrogen receptor status, progesterone receptor status, and c-erbB-2 expression in the lymph node positive cohort also were correlated significantly with NKG. Ki-67 percentage was correlated significantly with c-erbB-2 expression in the lymph node positive cohort only. NKG was similar to BRG and NHG when it was evaluated for prognostic significance. Patients with higher categoric Ki-67 percentages had worse overall and disease free survival in all groups except for the untreated, lymph node negative group. CONCLUSIONS: Ki-67 detection represents a valuable tool and is a good objective substitute for mitotic counts when used in a grading system. When it is used alone, Ki-67 detection provides valuable information, although it is necessary to combine this with other parameters in the study of core biopsies and fine-needle aspirates.

Breast Neoplasms↗
PubMed1994

Biological and biophysical techniques to assess radiation exposure: a perspective.

Biological dosimeters measure biologically relevant effects of radiation exposure that are in some sense an estimate of effective dose, whereas biophysical indicators serve as surrogates of absorbed dose in a manner analogous to conventional thermoluminescent dosimeters (TLD). The biological and biophysical dosimeters have the potential to play an important role in assessing unanticipated or occupational radiation exposures. For example, where the exposure is large and uncertain (i.e. radiation accidents), accurate dose information can help in deciding the most appropriate therapy and medical treatment. Another useful area is that of lifetime accumulated dose determination, and the ability to distinguish between and integrate the exposures from natural and anthropogenic (medical X-rays, indoor radon, natural background radiation, occupational and non-occupational exposures). Also, the possibility to monitor individual response and differences in inherent or induced radiation sensitivity may have important implications for radiation protection. More commonly, this type of dosimetry could be used for routine monitoring to detect and quantify unsuspected exposure, for regulatory purposes or for epidemiological studies of the long-term effects of radiation exposure (e.g. in Japanese A-bomb survivors or in the population surrounding Chernobyl). This review is a comparative study of the existing techniques and their future prospects. It summarizes the sensitivity, reproducibility, limiting dose, dose-rate, energy, LET response, sources of variability and uncertainty, and other practical aspects of each bio-indicator. The strengths and weaknesses of each approach are evaluated on the basis of common criteria for particular applications, and are summarized for each assay both in the text and in tabular form, for convenience. It is clear that no single indicator qualifies to reliably measure occupational exposures at the current levels of sensitivity conventional dosimetry services provide. Most of the bio-techniques are applicable to the detection of relatively high radiation exposures at relatively short times after exposure. Some of the bio-indicators have been identified that are, or offer future prospects for becoming, appropriate bio-indicators for dosimetry needs. However, all methods are subject to biological and other variables that are presently uncontrolled, and represent a major source of uncertainty. These include variations in background signals not directly associated with radiation exposure, inter- and intra-individual variability of radiation response, and genetic and environmental effects. Although these factors contribute to the lack of confidence in biological dosimetry, promising bio-indicators may be applied to large populations to establish the inherent variability and confounding factors that limit quantitative data collection and analysis, and reduce reliability and reproducibility.

Biological Assay↗
PubMed1991

Men, women and primary lung cancer--a Saskatchewan personal interview study.

In a previous study conducted by mail questionnaire and with a large proportion of surrogate responders, we found differences in smoking habits, age at diagnosis, tumour cell type distribution and occupational exposures between men and women who developed primary lung cancer. This study was designed to confirm those findings by conducting personal case interviews and extend them by examining the impact of certain biological factors. We have investigated demographic, smoking, occupational and medical history sex differences in cases with primary lung cancer by interviewing 273 male and 103 female cases diagnosed between November 1983 and July 1986. The females were significantly younger at diagnosis, a pattern consistent for all cell types. Squamous cell (40%), small cell anaplastic (20%) and adenocarcinomas (16%) were the most prevalent cell types in men. In women, similar frequencies of adenocarcinomas (32%) and squamous cell carcinomas (29%) occurred. Despite a higher prevalence of physician diagnosed allergy and asthma among women, minimal sex differences in the prevalence of atopy as measured by prick skin test were found. Female cases were more likely to be lifetime non-smokers (15% vs 3%), to have started smoking on average 3 years older and to smoke 6 fewer cigarettes per day. The mean pack years of female cases was significantly lower than males' for squamous, adenocarcinoma and small cell anaplastic tumours. The majority of these women had not been occupationally exposed to any substance known to be carcinogenic or to damage the lung. However, in a small subset of cases pulmonary function variables were as depressed in women as in men with significantly higher mean pack years.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed2000

Immunotherapy for advanced renal cell cancer.

BACKGROUND: The course of advanced renal cell carcinoma is extremely variable, ranging from spontaneous remission to disease progression refractory to chemotherapy. Immunotherapy has held promise of improved outcomes based on uncontrolled studies and randomized controlled trials generally limited by small size and low power. OBJECTIVES: To evaluate immunotherapy for advanced renal cell carcinoma by comparing: (1) high dose interleukin-2 to other options and (2) interferon-alpha to other options. SEARCH STRATEGY: A search of MEDLINE, Cancerlit, EMBASE and Cochrane Library databases from 1966 through the end of 1999. Handsearches were made of the proceedings of the annual meetings of the American Urologic Association, ASCO, and biennial European ECCO meetings, and the references of identified studies. SELECTION CRITERIA: Randomized controlled trials that selected (or stratified) patients with advanced renal cell carcinoma, utilized an immunotherapeutic agent in at least one study arm, and reported response or survival by allocation. Forty-two studies involving 4216 patients were eligible and reported response and 26 of these reported survival outcome (3089 patients). DATA COLLECTION AND ANALYSIS: Two independent reviewers abstracted each article by following a prospectively designed protocol. Dichotomous outcomes for treatment response (partial plus complete) and for deaths at one year were used for the main comparisons. Survival hazard ratios were also used for studies of interferon-alpha versus controls. MAIN RESULTS: The average response rate was 10.2 % (range by arm, 0 - 39%) and complete response rate was 3.2% (123/3852; n = 38 studies). Median survival averaged 11.6 months (range by arm, 6 - 28 months) and two-year survival averaged 22% (16 studies, range by arm 8 - 41%). There were no placebo-controlled studies and no randomized controlled studies examined survival for high dose interleukin-2 versus controls. Results from 6 studies (n = 963) indicate that interferon-alpha is superior to controls (OR for death at one year = 0.67, 95% CI 0.50 - 0.89. The pooled hazard ratio for survival of 0.78 (0.67 - 0.90) indicates that the treatment effect persisted until 24 months from randomization. The weighted average median improvement in survival was 2.6 months. Additional comparisons failed to prove a survival benefit from the addition of other agents to either modified schedules of interleukin-2 or to interferon-alpha. Dose-response studies examining survival for either agent could not be identified. The difference in response rate between arms was correlated with the difference in survival (P<0.001) suggesting that response rate difference may be a surrogate intermediate endpoint for survival. REVIEWER'S CONCLUSIONS: Interferon-alpha provides a modest survival benefit compared to other commonly used treatments and should be considered for the control arm of future studies of systemic agents. Interleukin-2 has not been validated in controlled randomized studies.

Antineoplastic Agents↗
PubMed1997

Pain during hospitalization is associated with continued pain six months later in survivors of serious illness. The SUPPORT Investigators. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments.

PURPOSE: To determine the level of pain reported by survivors of serious illness 2 and 6 months after study enrollment and to identify variables associated with later pain. PATIENTS AND METHODS: Observational cohort study of patients with interviews during hospitalization (5,652) and 2 (3,782) and 6 (2,984) months later admitted between June 1989 and January 1994 with 1 or more of 9 high mortality diagnoses admitted to 5 tertiary care academic centers in the United States. Patients' level of pain during the hospitalization and 2 and 6 months later was determined from interviews with patients and surrogates (most often family members). Separate ordinal logistic regressions were constructed with level of pain at months 2 or 6 as the dependent variable and 22 demographic, psychological, chronic, and acute illness measures at the time of hospitalization as independent variables. RESULTS: Of patients reporting level 4 (moderately severe pain occurring most of the time or extremely severe pain occurring half of the time) or 5 (moderately severe pain occurring most or all of the time or extremely severe pain occurring at least half of the time) pain to 5 during hospital interviews, 39.5% and 39.7% reported level 4 or 5 pain 2 and 6 months later, respectively. Level of hospital pain was the variable most strongly associated with later pain. Compared with patients with level 1 hospital pain, those with level 2 (not at all severe pain or moderate, occasional) had a 2.91 (95% confidence interval [CI] 2.50, 3.37) and 1.75 (CI 1.48, 2.07) times greater adjusted odds of increased levels of pain 2 and 6 months later, respectively. Compared with patients with level 1 hospital pain, those with level 5 pain had a 9.20 (CI 7.27, 11.65) and 4.40 (CI 3.39, 5.71) times greater adjusted odds of increased levels of pain 2 and 6 months later, respectively. Age, number of dependencies in activities of daily living, depression, and type of comorbid illnesses were also independently associated with level of pain both 2 and 6 months later. CONCLUSION: Survivors of the serious and common illnesses that we studied have a high level of pain during hospitalization and up to 6 months after hospitalization. Level of hospital pain was most strongly associated with later pain. Better pain control both during hospitalization and after discharge should be given a high priority. Pain during hospitalization should trigger future inquiries about pain and its treatment.

Adult↗
PubMed2002

Anti-hypertensive drugs in pregnancy and fetal growth: evidence for "pharmacological programming" in the first trimester?

OBJECTIVES: To determine the timing and exact nature of the effect of the drug atenolol upon fetal growth. Also to discover if the reduction in fetal growth is due to superimposed pre-eclampsia or any other confounding variable. DESIGN: A retrospective cohort study of prospectively collected data in a hypertensive pregnancy database. SETTING: Two district general hospitals in the midlands of England. Both hospitals have specialised medical antenatal clinics for pregnant women with chronic hypertension. PARTICIPANTS: 491 pregnancies in 380 women with essential or secondary hypertension. OUTCOME MEASURES: The outcome measures used were the infant birth weight, birth weight standardized for gestational age, and the ponderal index at birth, a surrogate measure for in utero growth restriction. RESULTS: The babies of women taking atenolol at conception or during the first trimester had significantly lower birth weights (by 139-512 g, p<0.01) than women on calcium channel blockers or no medication. Likewise the ponderal index was also significantly reduced, p<0.01. In addition most of these babies were small for gestational age (SGA) with 70% on or below the 10th centile and 40% below the third centile. No such independent association was seen with anti-hypertensives taken in the second trimester. CONCLUSIONS: Atenolol taken at the time of conception and/or during the first trimester of pregnancy was associated with low birth weight. This finding was independent of the development of superimposed pre-eclampsia. Other anti-hypertensives were not found to be associated with low birth weight. Use of atenolol in the second trimester of pregnancy did not produce the same effect and was not materially different in its effects from the other anti-hypertensive drugs. In the second trimester, the development of superimposed pre-eclampsia is the over-riding effect in the reduction of infant birth weight. Atenolol used in the first trimester could be pharmacologically programming these infants to restricted growth patterns.

Antihypertensive Agents↗
PubMed2005

Obesity and capsular incision at the time of open retropubic radical prostatectomy.

PURPOSE: The goal of radical prostatectomy (RP) is complete removal of the intact prostate. Obese men can represent a technical challenge. However, to our knowledge objective data linking obesity with technically inferior surgery are lacking. Therefore, we examined the association between body mass index (BMI) and capsular incision at RP as a surrogate of a poor technical operation in men treated for prostate cancer by several high volume surgeons at a center of excellence. MATERIALS AND METHODS: The study population consisted of 7,027 men treated with anatomical retropubic RP between 1996 and 2004 by 7 high volume surgeons. We evaluated the association between BMI and capsular incision using logistic regression, adjusting for clinical and pathological variables, and for the surgeon. RESULTS: Overall capsular incision was noted in 4.6% of all RP specimens. After adjustment for preoperative prostate specific antigen, patient race, height, year of surgery, clinical stage, pathological Gleason sum, prostate weight, extraprostatic extension and seminal vesicle invasion increased BMI was associated with increased odds of capsular incision (p trend = 0.005). After further adjustment for surgeon mild obesity was associated with 30% increased odds of capsular incision (OR 1.30, 95% CI 0.92 to 1.83), while moderate and severe obesity was associated with 57% increased odds of capsular incision (OR 1.57, 95% CI 0.82 to 3.00) relative to normal weight men (p trend = 0.06). CONCLUSIONS: In a study of more than 7,000 men treated by 7 experienced surgeons BMI was positively related to capsular incision. This suggests that open retropubic RP is technically more difficult in obese men, which results in a greater likelihood of a less than technically ideal operation. Although this may be predicted to have a negative impact on disease-free survival outcomes in obese men, it is unlikely to alone explain the worse outcomes in obese men noted in previous RP series.

Aged↗
PubMed2002

Laparoscopic versus open colorectal surgery: a randomized trial on short-term outcome.

OBJECTIVE: The primary endpoint was to compare the impact of laparoscopic and open colorectal surgery on 30-day postoperative morbidity. Lymphocyte proliferation to mitogens and gut oxygen tension were surrogate endpoints. SUMMARY BACKGROUND DATA: Evidence-based proof of the effect of laparoscopic colorectal surgery on immunometabolic response and clinically relevant outcome variables is scanty. Further randomized trials are desirable before proposing laparoscopy as a superior technique. METHODS: Two hundred sixty-nine patients with colorectal disease were randomly assigned to laparoscopic (n = 136) or open (n = 133) colorectal resection. Four trained members of the surgical staff who were not involved in the study registered postoperative complications. Lymphocyte proliferation to Candida albicans and phytohemagglutinin was evaluated before and 3 and 15 days after surgery. Operative gut oxygen tension was monitored continuously by a polarographic microprobe. RESULTS: In the laparoscopic group the conversion rate was 5.1%. The overall morbidity rate was 20.6% in the laparoscopic group and 38.3% in the open group. Postoperative infections occurred in 15 of the 136 patients in the laparoscopic group and 31 of the 133 patients in the open group. The mean length of hospital stay was 10.4 +/- 2.9 days in the laparoscopic group and 12.5 +/- 4.1 days in the open group. On postoperative day 3, lymphocyte proliferation was impaired in both groups. Fifteen days after surgery, the proliferation index returned to baseline values only in the laparoscopic group. Intraoperative gut oxygen tension was higher in the laparoscopic than in the open group. CONCLUSIONS: Laparoscopic colorectal surgery resulted in a significant reduction of 30-day postoperative morbidity. Lymphocyte proliferation and gut oxygen tension were better preserved in the laparoscopic group than in the open group.

Adenocarcinoma↗
PubMed2001

RAG1 and RAG2 expression by B cell subsets from human tonsil and peripheral blood.

It has been suggested that B cells acquire the capacity for secondary V(D)J recombination during germinal center (GC) reactions. The nature of these B cells remains controversial. Subsets of tonsil and blood B cells and also individual B cells were examined for the expression of recombination-activating gene (RAG) mRNA. Semiquantitative analysis indicated that RAG1 mRNA was present in all tonsil B cell subsets, with the largest amount found in naive B cells. RAG2 mRNA was only found in tonsil naive B cells, centrocytes, and to a lesser extent in centroblasts. Neither RAG1 nor RAG2 mRNA was routinely found in normal peripheral blood B cells. In individual tonsil B cells, RAG1 and RAG2 mRNAs were found in 18% of naive B cells, 22% of GC founder cells, 0% of centroblasts, 13% of centrocytes, and 9% of memory B cells. Individual naive tonsil B cells containing both RAG1 and RAG2 mRNA were activated (CD69(+)). In normal peripheral blood approximately 5% of B cells expressed both RAG1 and RAG2. These cells were uniformly postswitch memory B cells as documented by the coexpression of IgG mRNA. These results indicate that coordinate RAG expression is not found in normal peripheral naive B cells but is up-regulated in naive B cells which are activated in the tonsil. With the exception of centroblasts, RAG1 and RAG2 expression can be found in all components of the GC, including postswitch memory B cells, some of which may circulate in the blood of normal subjects.

Adult↗
PubMed2006

Neonatal behavior and infant cognitive development in rhesus macaques produced by assisted reproductive technologies.

Assisted reproductive technologies (ART) used in fertility clinics include in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), followed by embryo transfer into the biological or a surrogate mother. Over 1,000,000 liveborn offspring--an estimated 1 in 150 United States newborns--have been produced worldwide by ART since 1978. IVF appears to produce healthy children in singleton pregnancies, though concerns remain regarding preterm deliveries, multiple pregnancies, as well as the longer-term consequences of all ART procedures. Clinical studies remain difficult to interpret and subject to confounding variables, as developmental problems may be due to a parent's reproductive conditions rather than, or in addition to, an ART procedure. Also, because of expense and time commitments, the United States ART clinical population is not fully representative of society diversities. This socio-economic skewing might compensate for negative effects, masking small, or modest developmental deficits. Embryo splitting (ES), an ART procedure used only with animals, can produce genetically identical offspring. ES involves dividing four- to eight-cell embryos into separate blastomeres and implanting them into empty zona pellucida, followed by embryo transfer. Although these ART techniques have produced nonhuman primate offspring, there has been no research on behavioral safety. Here, we report the first study of behavioral development by rhesus macaques infants produced through ES, ICSI, and IVF. We assessed neonatal reflexes, self-feeding ability, recognition memory, object concept attainment, simple discrimination learning and reversal, and learning set (LS) acquisition. Although the sample sizes are small, we found no overall ART group delayed development. Surprisingly, the ES and ICSI monkeys appeared to be accelerated in attaining age milestones involving sensory-motor behaviors and a difficult Well Hiding object concept task. We conclude that macaque monkeys may provide an excellent model for the study of early human development by offspring of parents with conditions requiring ART pregnancies, as well as a model for the behavioral study of genetic-environment interactions using identical twins produced by ES.

Analysis of Variance↗
PubMed2003

Quantitative insulin sensitivity check index and the reciprocal index of homeostasis model assessment in normal range weight and moderately obese type 2 diabetic patients.

OBJECTIVE: To investigate whether the quantitative insulin sensitivity check index (QUICKI) and the reciprocal index of homeostasis model assessment (1/HOMA-IR) derived from fasting plasma glucose and insulin level are excellent surrogate indices of insulin resistance in both normal range-weight and moderately obese type 2 diabetic and healthy subjects. RESEARCH DESIGN AND METHODS: The association between QUICKI or 1/HOMA-IR and insulin resistance index assessed by euglycemic-hyperinsulinemic clamp (clamp-IR) was investigated in 121 type 2 diabetic and 29 healthy subjects recruited from among 120 (age 55 +/- 11, 48 +/- 15, and 52 +/- 15 years [means +/- SD], respectively). Type 2 diabetic subjects were divided into groups of 76 normal range-weight and 45 moderately obese subjects (BMI 21.4 +/- 2.3 vs. 27.2 +/- 2.2 kg/m(2), P < 0.0001). RESULTS: QUICKI and 1/HOMA-IR were significantly lower in the moderately obese group than in the normal range-weight type 2 diabetic and healthy groups (n = 120) (QUICKI, 0.338 +/- 0.030, 0.371 +/- 0.037, and 0.389 +/- 0.041, respectively, P < 0.0001; 1/HOMA-IR, 0.50 +/- 0.33, 0.92 +/- 0.55, and 1.24 +/- 0.82, P < 0.0001). QUICKI was strongly correlated with clamp-IR in normal range-weight, moderately obese type 2 diabetic, and healthy subjects (r = 0.641, 0.570, and 0.502, respectively; all subjects, r = 0.608, P < 0.01) and 1/HOMA-IR exhibited correlations comparable to those of QUICKI with clamp-IR (r = 0.637, 0.530, and 0.461, respectively; all subjects, r = 0.589, P < 0.001). In multiple regression models including QUICKI or 1/HOMA-IR as an independent variable, the estimation formula accounted for 55% of the variability of clamp-IR for the group of all type 2 diabetic subjects (R(2) = 0.547 and 0.551, respectively, P <or= 0.0001). CONCLUSIONS: QUICKI and 1/HOMA-IR were highly correlated with clamp-IR, with comparable coefficients in both normal range-weight and moderately obese type 2 diabetic patients and nondiabetic subjects. The latter can probably be applied clinically in view of its convenience.

Adult↗
PubMed2006

The price of alcohol: a consideration of contextual factors.

BACKGROUND: The current study considers the determinants of prices charged for alcoholic beverages by on-premise and off-premise outlets in Alaska. Alcohol outlet densities, a surrogate measure for local retail competition, are expected to be negatively associated with prices while costs associated with distribution are expected to be positively related to prices. Community demographic and economic characteristics may affect observed local prices via the level of demand, retail costs borne by retailers, or the quality of brands offered for sale. METHODS: The core data for these analyses came from a telephone survey of Alaskan retail establishments licensed to serve alcohol. This survey utilized computer-assisted telephone interviewing (CATI) techniques to collect alcohol-pricing information from on-premise (i.e., establishments where alcohol is consumed at the point of purchase such as bars and restaurants) and off-premise (i.e., establishments such as grocery stores and convenience markets where consumption occurs in other locations) alcohol retailers throughout the state of Alaska. Price estimates were developed for each beverage-type based on alcohol content. Separate regression analyses were used to model each of the 8 price indices (on-premise and off-premise measures for beer, spirits, wine, and the average price across beverage types). All regressions also controlled for a set of zip-code level indicators of community economic and demographic characteristics based on census data. RESULTS: Outlet density per roadway mile was unrelated to price for both on- and off-premise establishments, either across or between beverage types. In contrast, overall distribution costs did appear to be related to alcohol price. The demographic and economic variables, as a group, were significantly related to observed prices. CONCLUSIONS: More attention needs to be directed to the manner in which sellers and buyers behave relative to alcoholic beverages. Alcohol demand remains responsive to prices; yet, consumers have considerable latitude in determining the price that they pay for alcohol.

Alaska↗
PubMed2006

Prognostic scoring in patients with melanoma after adjuvant isolated limb perfusion.

BACKGROUND: The clinical course in melanoma is variable. The aim of the present study was to assess adjuvant isolated limb perfusion (ILP) efficacy using a surrogate comparison of observed survival versus Cochran-predicted survival. MATERIALS AND METHODS: All patients in a single university hospital with primary, non-ulcerated limb melanoma who had undergone adjuvant ILP over 10 years (1986-1995) were studied. Clinical and pathological details including follow-up and survival were prospectively recorded in a national database. All patients were risk scored, as described by Cochran et al., to yield individual survival probability at the end of 3, 5 and 10 years and this was compared with observed survival at corresponding intervals. RESULTS: There were 85 patients who had adjuvant ILP for primary non-ulcerated limb melanoma. Of these, 14 deaths were observed (O) within the 10-year follow-up period. The Cochran score predicted (E) 20 deaths within 10 years (O/E ratio 0.7). The O/E ratios for deaths in the 0 to 3, 3 to 5, and 5 to 10 year intervals were 8/7.4, 5/6.0, and 1/6.5, respectively; prediction of late deaths tended to be overestimated. When patients were grouped by predicted 10-year mortality (<20%, 20-40%, >40%) the overestimation was found to occur mainly in the highest risk group: O/E ratios were 6/5.9, 6/8.4, and 2/5.6, respectively (P = 0.10, Hosmer-Lemeshow test). CONCLUSION: The observed and expected survival in patients receiving adjuvant ILP at the end of 3 and 5 years are comparable. The Cochran scoring system overestimated deaths during the 5 to 10 year interval. It is not clear whether this observation is a consequence of ILP efficacy or inaccuracy of the Cochran score.

Antineoplastic Agents↗
PubMed2005

Individual variability in esterase activity and CYP1A levels in Chinook salmon (Oncorhynchus tshawytscha) exposed to esfenvalerate and chlorpyrifos.

Acetylcholinesterase (AChE) activity has traditionally been monitored as a biomarker of organophosphate (OP) and/or carbamate exposure. However, AChE activity may not be the most sensitive endpoint for these agrochemicals, because OPs can cause adverse physiological effects at concentrations that do not affect AChE activity. Carboxylesterases are a related family of enzymes that have higher affinity than AChE for some OPs and carbamates and may be more sensitive indicators of environmental exposure to these pesticides. In this study, carboxylesterase and AChE activity, cytochrome P4501A (CYP1A) protein levels, and mortality were measured in individual juvenile Chinook salmon (Oncorhynchus tshawytscha) following exposure to an OP (chlorpyrifos) and a pyrethroid (esfenvalerate). As expected, high doses of chlorpyrifos and esfenvalerate were acutely toxic, with nominal concentrations (100 and 1 microg/l, respectively) causing 100% mortality within 96 h. Exposure to chlorpyrifos at a high dose (7.3 microg/l), but not a low dose (1.2 microg/l), significantly inhibited AChE activity in both brain and muscle tissue (85% and 92% inhibition, respectively), while esfenvalerate exposure had no effect. In contrast, liver carboxylesterase activity was significantly inhibited at both the low and high chlorpyrifos dose exposure (56% and 79% inhibition, respectively), while esfenvalerate exposure still had little effect. The inhibition of carboxylesterase activity at levels of chlorpyrifos that did not affect AChE activity suggests that some salmon carboxylesterase isozymes may be more sensitive than AChE to inhibition by OPs. CYP1A protein levels were approximately 30% suppressed by chlorpyrifos exposure at the high dose, but esfenvalerate had no effect. Three teleost species, Chinook salmon, medaka (Oryzias latipes) and Sacramento splittail (Pogonichthys macrolepidotus), were examined for their ability to hydrolyze a series of pyrethroid surrogate substrates and in all cases hydrolysis activity was undetectable. Together these data suggest that (1) carboxylesterase activity inhibition may be a more sensitive biomarker for OP exposure than AChE activity, (2) neither AChE nor carboxylesterase activity are biomarkers for pyrethroid exposure, (3) CYP1A protein is not a sensitive marker for these agrochemicals and (4) slow hydrolysis rates may be partly responsible for acute pyrethroid toxicity in fish.

Acetylcholinesterase↗
PubMed2001

Validation of a specific activity questionnaire to estimate exercise tolerance in patients referred for exercise testing.

BACKGROUND: Physical activity and symptom questionnaires have been used as surrogates for exercise testing to estimate a patient's functional capacity and to individualize an exercise testing protocol in accordance with exercise testing guidelines. To validate these approaches, they must be compared with measured oxygen uptake (peak VO (2)). METHODS: Before exercise testing was performed, a brief, self-administered questionnaire (Veterans Specific Activity Questionnaire [VSAQ]) was given to 337 patients referred for exercise testing for clinical reasons. The VSAQ was used to estimate exercise tolerance on the basis of symptoms during daily activities to individualize ramp rates on the treadmill so that the test duration would be approximately 10 minutes. Clinical and demographic variables were added to the VSAQ responses in a stepwise regression model to determine their ability to predict both directly measured peak VO (2) and peak metabolic equivalents (METs) predicted from the treadmill workload. RESULTS: The mean exercise time was 9.6 +/- 3 minutes. Responses to the VSAQ and age were the strongest predictors of both measured and predicted exercise capacity. Small but significant contributions to the explanation of variance in both measured and estimated METs were made by resting heart rate, forced expiratory volume in 1 second expressed as a percentage of normal, exercise capacity predicted for age, and body mass index. The multiple R values from the regression equations for measured and estimated METs were 0.58 and 0.72, respectively. CONCLUSIONS: Estimating a patient's symptoms associated with daily activities along with age are the strongest predictors of a patient's exercise tolerance. The VSAQ, combined with pretest clinical data, predicts the estimated MET value from treadmill speed and grade better than directly measured METs do. When used for estimating a patient's symptom limits to individualize ramp rates on a treadmill, this approach yields an appropriate test duration in accordance with recent exercise testing guidelines.

Activities of Daily Living↗
PubMed1994

Prevention and regression of coronary atherosclerosis. Is it safe and efficacious therapy?

OBJECTIVE: Atherosclerotic coronary heart disease (CHD) continues to be the dominant disease in Western society. A large body of evidence directly linking serum cholesterol levels and CHD risk has stimulated population treatment strategies designed to reduce cholesterol and CHD risk. Data indicating a relation between low cholesterol and non-CHD risk have, however, suggested that cholesterol reduction may not always be desirable. The primary goal of this evaluative review of the available evidence was to answer the following question: Is prevention/regression therapy for CHD safe and effective? DATA SOURCES: Three lines of evidence were reviewed: epidemiologic studies; primary and secondary prevention trials with clinical end points; and secondary prevention trials with quantitative coronary angiography as a surrogate end point for clinical CHD. STUDY SELECTION: Original studies and meta-analyses were reviewed. The principal selection criteria for the epidemiologic studies were large size and prolonged follow-up; for the trials, randomization and viable clinical (CHD events, CHD mortality, total mortality) or angiographic end points. DATA EXTRACTION: The data were initially extracted by a single reviewer using common qualitative guidelines. The data were then evaluated by all authors acting as a data interpretation team. DATA SYNTHESIS: Overall, the epidemiologic data revealed excess risk of fatal and nonfatal CHD events was directly related to total cholesterol and low-density lipoprotein (LDL) cholesterol levels, for both men and women and for both younger (< 65 years) and older (> or = 65 years) patients, over a wide range of serum cholesterol levels. The predictive value was higher in younger men than older men and women, although part of this quantitative interaction may be due to fewer studies, with fewer end points, in the older and female populations. The CHD events and CHD mortality, but not total mortality, were consistently reduced in trials of cholesterol-lowering therapy. The regression trials, predominantly in CHD patients with high cholesterol values (mean 7.1 mmol/L), demonstrated improvement in angiographic atherosclerosis in every study. The evidence for elevated risk of non-CHD death at very low levels of cholesterol is uncertain and controversial. The most likely possibilities for this apparent relationship are unknown confounding variables and the play of chance. CONCLUSIONS: Serum cholesterol levels are directly associated with CHD risk, and there is no threshold level below which there is no risk. Reduction of high serum cholesterol levels reduces CHD risk. Whether lipid-lowering and adjunctive antiatherosclerotic therapies are effective and safe in the majority of CHD patients who have desirable or borderline cholesterol levels remains undetermined.

Aged↗
PubMed2003

Comparative performance of serum cystatin-c versus serum creatinine in diabetic subjects.

OBJECTIVE: Serum cystatin-C, a protein with constant production rate, undergoes glomerular filtration. Cystatin-C is a candidate surrogate marker, allegedly superior to serum creatinine, for estimating glomerular filtration rate, due to its high correlation with absolute measurement of the latter. The aim of this study was to assess from intra- and inter-subject variability the performance of cystatin-C in a cohort of diabetic patients spanning a wide range of kidney function and to compare it to that of serum creatinine. RESEARCH DESIGN AND METHODS: 98 consecutive diabetic in-patients (45 type 1 and 53 type 2) were included. Mean age was 53 +/- 15 years (1SD). Creatinine clearance was 98 ml/min (median; range: 16-244). We used the discriminant ratio (DR) methodology to compare the performance of serum cystatin-C vs. that of creatinine to segregate subjects according to their glomerular filtration rate. RESULTS: Serum creatinine values on day 1 and 2 were 1.10 +/- 0.76 and 1.07 +/- 0.89 mg/dl and concentrations of cystatin-C were 1.10 +/- 0.60 and 1.06 +/- 0.63 mg/L. A close linear relationship was observed between means of duplicates for creatinine and cystatin-C (Pearson product-moment correlation 0.92). DR was obtained from the ratio of the underlying between-subject to the within-subject standard deviations. DR values were 5.23 for creatinine and 8.82 for cystatin-C (P<0.0001), implying superior discriminating ability for cystatin-C. Once adjusted for attenuation, measured Pearson product-moment correlation rose from 0.92 to 0.97. The DR methodology allowed for deriving an unbiased linear regression equation between methods, with slope and intercept at 0.79 and 0.23, respectively. CONCLUSIONS: Serum cystatin-C better discriminates among a population of type 1 and 2 diabetic patients with regard to their estimated glomerular filtration rate when compared with conventional serum creatinine measurement.

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