Molecular-integrated risk profile to determine adjuvant radiotherapy in endometrial cancer: Evaluation of the pilot phase of the PORTEC-4a trial.

OBJECTIVE: The Post-Operative Radiation Therapy in Endometrial Carcinoma (PORTEC)-4a trial is a randomized trial for women with high-intermediate risk endometrial cancer (EC), comparing individualized adjuvant treatment based on a molecular-integrated risk profile to standard adjuvant treatment; vaginal brachytherapy. To evaluate patient acceptability and pathology logistics of determining the risk profile, a pilot phase was included in the study. METHODS: PORTEC-4a is ongoing and the first 50 patients enrolled were included in the pilot phase. Primary endpoints of the pilot phase were patient acceptance, evaluated by analyzing the screening logs of the participating centers, and logistical feasibility of determination of the risk profile within 2 weeks, evaluated by analyzing the pathology database. RESULTS: In the first year, 145 eligible women were informed about the trial at 13 centers, of whom 50 (35%) provided informed consent. Patient accrual ranged from 0 to 57% per center. Most common reasons for not participating were: not willing to participate in any trial (43.2%) and not willing to risk receiving no adjuvant treatment (32.6%). Analysis of the pathology database showed an average time between randomization and determination of the molecular-integrated risk profile of 10.2 days (1-23 days). In 5 of the 32 patients (15.6%), pathology review took >2 weeks. CONCLUSIONS: The PORTEC-4a trial design was proven feasible with a satisfactory patient acceptance rate and an optimized workflow of the determination of the molecular-integrated risk profile. PORTEC-4a is the first randomized trial to investigate use of a molecular-integrated risk profile to determine adjuvant treatment in EC.

Routine pelvic lymphadenectomy in apparently early stage endometrial cancer.

AIMS: Controversial issues with respect to the treatment of patients with endometrial cancer include indications for lymphadenectomy and adjuvant radiotherapy. PATIENT AND METHODS: Between 1998 and 2004 all women with endometrial cancer stage I were included (n = 335). They all underwent total abdominal hysterectomy and bilateral salpingo-oöphorectomy. Two hundred and thirty-seven women also had a pelvic lymphadenectomy. When pelvic lymphadenectomy was performed, radiotherapy was administered only to patients with lymph-node metastases. Otherwise, adjuvant radiotherapy was based on the presence of risk factors. RESULTS: Eleven patients had lymph-node metastases. The overall absolute and relative survival-estimate at 5 years was 85.0 and 93.7%, respectively. Loco-regional recurrence was 8.5%. In the group with pelvic lymphadenectomy and negative lymph nodes these rates were 88.2, 93.9 and 5.6%, respectively. In 58 patients without any of the risk factors tumour grade III, deep myometrial invasion, or age > or =60 years, no lymph-node metastases were found. CONCLUSION: In patients with endometrial cancer FIGO stage I without risk-factors, a phenomenon which occurs in about 25% of patients with clinical stage I endometrial cancer, a lymphadenectomy can be omitted. In other patients, the debate regarding the optimal treatment will remain.

Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03.

PURPOSE: To assess the efficacy of neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy in patients with muscle-invading bladder cancer treated with selective bladder preservation. PATIENTS AND METHODS: One hundred twenty-three eligible patients with tumor, node, metastasis system clinical stage T2 to T4aNXMO bladder cancer were randomized to receive (arm 1, n=61 ) two cycles of MCV before 39.6-Gy pelvic irradiation with concurrent cisplatin 100 mg/m2 for two courses 3 weeks apart. Patients assigned to arm 2 (n=62) did not receive MCV before concurrent cisplatin and radiation therapy. Tumor response was scored as a clinical complete response (CR) when the cystoscopic tumor-site biopsy and urine cytology results were negative. The CR patients were treated with an additional 25.2 Gy to a total of 64.8 Gy and one additional dose of cisplatin. Those with less than a CR underwent cystectomy. The median follow-up of all patients who survived is 60 months. RESULTS: Seventy-four percent of the patients completed the protocol with, at most, minor deviations; 67% on arm 1 and 81% on arm 2. The actuarial 5-year overall survival rate was 49%; 48% in arm 1 and 49% in arm 2. Thirty-five percent of the patients had evidence of distant metastases at 5 years; 33% in arm 1 and 39% in arm 2. The 5-year survival rate with a functioning bladder was 38%, 36% in arm 1 and 40% in arm 2. None of these differences are statistically significant. CONCLUSION: Two cycles of MCV neoadjuvant chemotherapy were not shown to increase the rate of CR over that achieved with our standard induction therapy or to increase freedom from metastatic disease. There was no impact on 5-year overall survival.

Sociodemographic analysis of patients in radiation therapy oncology group clinical trials.

PURPOSE: To assess the degree to which the sociodemographic characteristics of patients enrolled in Radiation Therapy Oncology Group (RTOG) clinical trails are representative of the general population. METHODS AND MATERIALS: Sociodemographic data were collected on 4016 patients entered in 33 open RTOG studies between July 1991 and June 1994. The data analyzed included educational attainment, age, gender, and race. For comparison, we obtained similar data from the U.S. Department of Census. We also compared our RTOG data with Surveillance Epidemiology and End Results (SEER) data for patients who received radiation therapy, to determine how RTOG patients compared with cancer patients in general, and with patients with cancers at sites typically treated with radiotherapy. RESULTS: Overall, the sociodemographic characteristics of patients entered in RTOG trials were similar to those of the Census data. We found that, in every age group of African-American men and at nearly every level of educational attainment, the proportion of RTOG trial participants mirrored the proportion in the census data. Significant differences were noted only in the youngest category of African-American men, where the RTOG accrues more in the lower educational categories and fewer with college experience. For African-American women, we found a similar pattern in every age group and at each level of educational attainment. As with men, RTOG trials accrued a considerably larger proportion of younger, less educated African-American women than the census reported. Using SEER for comparison, the RTOG enrolled proportionately more African-American men to trials all cancer sites combined, and for prostate and head and neck cancer. In head and neck trials, the RTOG enrolled nearly twice as many African-American men than would be predicted by SEER data. In lung cancer trials, RTOG underrepresented African-American men significantly; however, there was no difference for brain cancer trials. There were no racial differences in RTOG accrual and SEER incidence data for women on trials in brain, lung, and head and neck cancer. However, the RTOG trials accrued nearly twice the proportion of African-American women in cervical cancer trials and in all sites combined, compared to the SEER data. CONCLUSIONS: Comparisons with the U.S. Census and SEER show that African-Americans are proportionally well represented in cancer clinical trials conducted by the Radiation Therapy Oncology Group. The comparative analysis indicates that all educational levels in each age group of African-Americans generally mirror the U.S. Census, with one exception. The exception is a significant overrepresentation of less-educated African-Americans in the youngest age category. This exception is counter to the expectation that better-educated patients are more likely to enroll in trials. When compared with SEER data, the RTOG trials either parallel or overrepresent African-American men and women, with the only exception being in lung cancer, where men are underrepresented. These results show that, in comparison to the Census and SEER data, the RTOG has fulfilled its commitment to enroll African-American patients in its clinical trials.

The potential impact of treatment variations on the results of radiotherapy of the internal mammary lymph node chain: a quality-assurance report on the dummy run of EORTC Phase III randomized trial 22922/10925 in Stage I--III breast cancer(1).

PURPOSE: To present the results of the dummy run of the European Organization for Research and Treatment of Cancer (EORTC) trial investigating the role of adjuvant internal mammary and medial supraclavicular (IM-MS) irradiation in Stage I--III breast cancer. METHODS AND MATERIALS: All participating institutions were asked to produce a treatment plan without (Arm 1) and with (Arm 2) simultaneous IM-MS irradiation of 1 patient after mastectomy and of 1 patient after lumpectomy. Thirty-two dummy runs have been evaluated for compliance to protocol guidelines, with respect to treatment technique and dose prescription. RESULTS: A number of more or less important deviations in treatment setup and prescription have been found. The dose in the IM-MS region deviated significantly from the prescribed dose in 10% of the cases for Arm 1, and in 21% for Arm 2. Assuming a true 5% 10-year survival benefit from optimal IM-MS irradiation, an increase of only 3.8% will be found due to this suboptimal dose distribution. CONCLUSION: In the dummy run, a number of potential systematic protocol deviations that might lead to false-negative results were detected. By providing recommendations to the participating institutions, we expect to improve the interinstitutional consistency and to promote a high quality irradiation in all institutions participating in the trial.

The morbidity of treatment for patients with Stage I endometrial cancer: results from a randomized trial.

PURPOSE: To compare the treatment complications for patients with Stage I endometrial cancer treated with surgery and pelvic radiotherapy (RT) or surgery alone in a multicenter randomized trial. METHODS AND MATERIALS: The Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC) trial included patients with endometrial cancer confined to the uterine corpus, either Grade 1 or 2 with more than 50% myometrial invasion, or Grade 2 or 3 with less than 50% myometrial invasion. Surgery consisted of an abdominal hysterectomy and oophorectomy, without lymphadenectomy. After surgery, patients were randomized to receive pelvic RT (46 Gy), or no further treatment. A total of 715 patients were randomized. Treatment complications were graded using the French-Italian glossary. RESULTS: The analysis was done at a median follow-up duration of 60 months. 691 patients were evaluable. Five-year actuarial rates of late complications (Grades 1-4) were 26% in the RT group and 4% in the control group (p < 0.0001). Most were Grade 1 complications, with 5-year rates of 17% in the RT group and 4% in the control group. All severe (Grade 3-4) complications were observed in the RT group (3%). Most complications were of the gastrointestinal tract. The symptoms resolved after some years in 50% of the patients. Grade 1-2 genitourinary complications occurred in 8% of the RT patients, and 4% of the controls. Bone complications occurred in 4 RT patients (1%). Seven patients (2%) discontinued their RT due to acute RT-related symptoms. Patients with acute morbidity had an increased risk of late RT complications (p = 0.001). The 4-field box technique was associated with a lower risk of late complications (p = 0.06). CONCLUSION: Pelvic RT increases the morbidity of treatment in Stage I endometrial cancer. In the PORTEC trial, severe complications occurred in 3% of treated patients, and over 20% experienced mild (mostly Grade 1) symptoms. Patients with acute RT-related morbidity had an increased risk of late complications. As pelvic RT in Stage I endometrial carcinoma was shown to significantly reduce the rate of locoregional recurrence, but without a survival benefit, its use in the adjuvant setting requires careful patient selection (treating those at increased risk of relapse), and the use of treatment schemes with the lowest risk of morbidity.

Individual differences in the experience of emotions.

The purpose of this paper is to highlight the important role of individual difference factors in the experience of emotion. We begin by describing several commonalties across two major approaches to the study of emotion, namely, the neuropsychological and cognitive perspectives. Both approaches provide some degree of support for the role of individual differences and cognitive factors in the experience of emotion. This paper builds on these commonalities by reviewing personality and psychopathology findings that indicate the contribution of both positive and negative personality characteristics (e.g., extraversion, optimism vs. neuroticism, trait anxiety) to the types of cognitive appraisals and emotional responses exhibited by different individuals. A self-schema model of emotion is presented as a means of integrating more fully this individual differences perspective with a theory of emotion. In this model, self-schema content provides the basis for individual differences in underlying core themes and self-evaluative beliefs. The model describes how self-schema content distinctions across individuals may have a differential impact on the initial processing of an event, evaluation of this event with respect to the self, and emotional and behavioral output. Several examples are then presented to illustrate the increased predictability afforded by this individual differences-based self-schema model of emotion. The application of this model to treatment and prevention issues in clinical and health psychology is also briefly considered. Finally, the model is integrated with other theoretical perspectives on emotion by describing a number of additional research and theoretical implications. Emphasis is placed on the need for further clarification of both cognitive and emotional components of an individual differences perspective on the study of emotions.

Development and enhancement of agricultural biotechnology in some countries in Latin America.

A number of research institutions and both local and international agencles in Latin America are using biotechnology as part of an effort to enhance agricultural productivity. However, it is very much an open question as to whether all of these various organizations can provide the best means of realizing this goal. Latin American countries vary dramatically in their knowledge base and current use of modern biotechnology. Thus, while some countries lack the ability to develop, or possibly even implement, many aspects of modern biotechnology, others are quite advanced in this regard. This review provides a somewhat selective overview of current research in the area of agricultural biotechnology in Mexico, Costa Rica and Ecuador, with emphasis on how the existing agencies and institutions have responded to the challenge of biotechnology. In addition, general strategies for the development of agricultural biotechnology in these countries are presented and discussed.

Cycloheximide blocks changes in rat liver carnitine palmitoyltransferase 1 activity in starvation.

Starvation (24h) increased the maximum activity of carnitine palmitoyltransferase 1 in rat liver and increased the concentration of malonyl-CoA required to cause 50% inhibition of the enzyme (I50). Re-feeding (24h) with a standard cube diet or a high-carbohydrate diet reversed both of these changes, whereas re-feeding with a high-fat diet did not. Administration of cycloheximide (200 micrograms/100 g body wt.) blocked the increases in carnitine palmitoyltransferase 1 activity and I50 on starvation. It is suggested that increase in carnitine palmitoyltransferase 1 activity in starvation may involve synthesis of new enzyme.

Intercorrelations among milk production traits and body and udder measurements in Holstein heifers.

Data from 1341 Holstein heifers of 71 sires were used to study heritabilities of and genetic and phenotypic correlations among milk production traits (308-d milk, front and rear half yields), body measurements (heart girth, withers height, body length, and rump length), udder measurements (front teat length and diameter, rear teat length and diameter, teat distance and udder height), and age at first calving. Genetic and phenotypic parameters were estimated by the multitrait restricted maximum likelihood method. Multitrait estimates of heritability ranged from .37 to .47 for first lactation yield traits, from .19 to .51 for body measurements, and from .08 to .41 for udder measurements. Age at first calving averaged 22.3 mo with a heritability estimate of .11. Milk production traits were all positively correlated with body measurements, suggesting that high producing heifers would be taller, larger, and longer than low producing heifers. Multitrait estimates of genetic and phenotypic correlations between udder height and yield traits were all negative, suggesting that high producing heifers tend to have lower udders. Of four body measurements studied, rump length showed the greatest genetic correlations with yield traits. Among six udder measurements, udder height exhibited the highest degree of associations with yield traits. Thus, rump length and udder height merit greater attention for prediction of lactational performance.

Multitrait estimation of genetic parameters of lactation curves in Holstein heifers.

Weekly milk yields of 1022 Holstein heifers from 61 sires were used to derive coefficients of the lactation curves using modified gamma and inverse polynomial functions. The natural logarithm of a modified gamma function was ln(yn) = ln (a) + b ln (n) + cn + u sin (x) + v cos (x), where a, b, c, u, and v are coefficients to be estimated; n is the day of lactation; and x is the day of year. Estimates of a, b, and c were combined to define persistency [-(b + 1) ln c], week of peak yield (b/c), and peak yield [a(b/c)be-b]. The inverse polynomial function was n/yn = A0 + A1n + A2n2, where A0, A1, and A2 are coefficients to be estimated. Variance and covariance components for the coefficients of the lactation curve were estimated by the multitrait restricted maximum likelihood method using canonical transformation. Heritability estimates were ln (a) .11, b .07, c .04 u .01, v .04, A0 .28, A1 .26, A2 .21, persistency .21, week of peak .18, peak yield .23, and 308-d milk yield .41. Genetic correlations indicated that selection for faster rate of increase to peak production would result in higher 308-d milk production, higher peak yield, and greater persistency.

Are seeded endothelial cells the origin of neointima on prosthetic vascular grafts?

Although endothelial cell seeding has been demonstrated to be effective in producing uniform endothelial coverage on prosthetic grafts, no one has demonstrated that the seeded cells are the genetic precursors of the endothelial cells that ultimately line the graft. This study was performed to determine whether seeded endothelial cells were the source of the neoendothelial surface on Dacron vascular grafts implanted in the pig. Eight pairs of littermate male and female pigs were selected at birth and allowed to grow until their weight reached 20 to 25 kg. Endothelial cells were enzymatically harvested from the jugular vein of the female siblings and seeded onto 8 mm diameter grafts, 25 cm in length. The grafts were then implanted as a thoracoabdominal bypass into the male siblings. Seven other randomly selected pigs of similar size (four males and three females) had thoracoabdominal bypass with similar grafts, which were preclotted with autologous blood only, but not seeded. After 4 weeks, grafts in both groups were covered with a neointima that was more than 90% thrombus-free. The graft surface cells were grown in culture and were documented to be endothelium. Chromosome analysis demonstrated that the surface cells on the seeded grafts were from the male host and did not originate from the donor female cells. We conclude that seeded endothelial cells are not the source for the neointima on Dacron grafts in the porcine model. In addition, we have again documented that spontaneous endothelial coverage of grafts does occur without endothelial seeding.

Production and reproduction of early and late bred dairy heifers.

A total of 253 heifers bred at first estrus after 350 d of age (350-d breeding age group) and 249 contemporary heifers bred at first estrus after 462 d of age (462-d breeding age group) were used to study the effects of age at first breeding on productive and reproductive performances of first lactation heifers. Heifers of both breeding age groups were subject to similar feeding and management practices. The average age at first calving was 698 d for the 350-d breeding group and 796 d for the 462-d breeding group. Although not statistically significant, heifers of the 462-d breeding group tended to have a higher conception rate at first service (47 vs. 38%) and fewer days between first service and conception (39 vs. 44 d) than those of the 350-d breeding age group. Breeding heifers as early as 350 d of age has no adverse effects on calving ease or retained placenta but does result in calves 1.2 kg lighter at birth. Heifers of the 350-d breeding group had lower milk, protein, and fat yields at both 168 and 308 d of first lactation than those of the 462-d breeding group. A 1-d reduction in age at first calving decreased 308-d milk yield by 2.01 kg for the 350-d breeding group as compared with 4.74 kg for the 462-d breeding group.

Evaluation of cow reproduction in the pureline foundation phase of the Canadian National Dairy Cattle Breeding Project.

Five reproduction traits--number of inseminations per cow, days to first estrus, days open, calving interval, and culling rate for infertility--were studied on dairy cows from a long-term breeding project of the Agriculture Canada Research Branch. Five experimental farms maintained either Holstein line, Ayrshire line, or both. Traits were analyzed within each line by a model in which station, year, sire group (paternal parentage), and bull (cow's mate) were considered. Variation these factors caused was small; most represented less than 1% of the total sum of squares. Holstein cows at Lethbridge, Lennoxville, and Ottawa had 1.9, 2.3, and 2.0 inseminations per cow, 55.1, 63.9, and 51.2 days to first estrus, and 109.9, 125.2, and 112.4 days open. The same traits of Ayrshire cows at Charlottetown, Normandin, and Ottawa were 2.3, 2.2, and 2.0; 53.3, 61.4, and 53.0 days; and 105.2, 129.2, and 114.5 days. All three traits were derived from records of all cows, including those that did not complete calving intervals. Calving interval at all five stations varied from 376.1 to 412.4 days. Intensity of culling for infertility differed between stations, e.g., 5% in one and 31% in another. About 24% of all disposed cows were culled in both lines for infertility.

The influence of additive and nonadditive gene action on lifetime yields and profitability of dairy cattle.

Additive and nonadditive genetic effects on lifetime yields of milk and milk components and lifetime profitability were estimated from 5070 cattle in a Holstein pureline, an Ayrshire-based pureline, and 10 crossbred groups of these purelines. Lifetime yields of milk, fat, protein, and lactose and lifetime milk value and annualized discounted net returns were analyzed. Lifetime yields, lifetime milk value, and annualized discounted net returns of the Holstein x Ayrshire-based line F1 and an F1 x (F1 x F1) cross were not significantly different from those for the Holstein pureline. Net reproductive rate for F1 females was 9% greater than that of contemporary Holsteins. The Holstein pureline was superior to the Ayrshire-based pureline for direct additive genetic merit for all traits. Heterosis for the lifetime traits ranged from 16.6% for lifetime milk yield to 20.6% for annualized discounted net returns. Cytoplasmic maternal effect on annualized discounted net return was significant and favored the Ayrshire-based line. Potential economic benefit may derive from development of a crossbred cow that is superior to Holsteins. Maximum exploitation of additive and nonadditive genetic effects on lifetime yields and profitability appears to favor a rotational crossbreeding system with two breeds.

Reproductive performance of crossline and pureline dairy heifers.

Data of 2779 purebred and crossbred heifers collected from five research stations of Agriculture Canada were used to study additive and nonadditive genetic effects on ages at first heat and at first breeding and conception rate at first service. Of these heifers, 2378 heifers had information on ages at first conception and at first freshening, days from first service to conception, and gestation length. The model included station, year of birth, sire, breed additive, maternal, and heterosis effects where sire effects were treated as random. Station differences were a significant source of variation for all reproductive traits. Year of birth had significant effects on four of seven reproductive traits. Breed additive effects for all genetic groups were not significant except for Finnish Ayrshire and American Holstein. No significant maternal effects were detected. Of 21 combinations of heterosis effects, six combinations showed significance. Partial regression coefficients ranged from negative to positive, suggesting that breed additive, maternal, and heterosis effects could increase or decrease for each percent increase of genetic contribution, depending upon the trait, breed group, and type of inheritance.