Microfocus Small Angle X-ray Scattering Reveals Structural Features in Archaeological Bone Samples; Detection of Changes in Bone Mineral Habit and Size

Microfocus X-ray scattering provides a powerful nondestructive technique capable of providing important information about the size, habit, and arrangement of mineral crystals in bone. The technique is capable of probing textural differences in a sample at a micron scale resolution. The study presented here involved the analysis of a number of archaeological bones by microfocus X-ray scattering at the ESRF Grenoble in order to determine local changes in mineral durability. The results showed that regions of bone with a modified microscopic morphology contained a greater dispersion of crystal shape when compared with more intact regions and control contemporary bone samples, but the crystal thickness values showed similar consistency. We speculate that the persistence of collagen in the archaeological bone may allow diagenetic remodeling of bone in terms of crystallite shape but defines the size of remodelled crystallites. The ability to detect such local changes in texture has wide potential for determining crystal characteristics in healthy and diseased bone samples.     

Phase II trial of KW2189 in patients with advanced malignant melanoma

KW-2189, a semisynthetic duocarmycine antibiotic has been shown to exert antiproliferative effects against human tumor cell lines in vitro and animal tumor models in vivo. Phase I studies identified myelosuppression as the most noteworthy adverse effect. Presented are two concurrent phase II studies assessing the antitumor and toxicity profile of KW-2189 in metastatic melanoma patients. One of the studies accrued patients with a history of prior melanoma therapy and the other accrued patients without a history of prior melanoma therapy. KW-2189 was administered at 0.4 mg/m2 to previously treated patients and 0.5 mg/m2 to the previously untreated. Treatment was administered intravenously on day 1 of a 6-week cycle. Thirty previously untreated and 15 previously treated patients were accrued. The toxicity profiles of the both groups of patients were similar. Of the 15 previously treated patients, 8 completed once cycle of treatment, 2 completed 2 cycles, and 5 completed 3 cycles. Dose modification for neutropenia/ thrombocytopenia was necessary in six patients. Among the previously untreated cohort (30 patients), 16 completed 1 cycle, 5 completed 2 cycles, 4 completed 3 cycles, 3 completed 4 cycles, and 2 completed 6 cycles. Doses were modified (neutropenia or thrombocytopenia) in 11 patients. None of the 15 previously treated patients responded to therapy. Four patients remained stable during two cycles. Five of the previously untreated patients achieved a partial remission/regression. Response duration ranged from 2.8 to 16.6 months. Overall objective response rate was 17%. Regarding survival, one previously treated patient is still alive 2.9 years after study entry, and three previously untreated patients are still alive 1.6, 2.3, and 2.9 years after study entry. The 1-year survival rate for previously treated patients is 27% and for the untreated patients is 23%. In summary, the lack of significant antitumor activity of KW-2189 and its associated toxicity suggest that further testing of this regimen in patients with stage IV melanoma is not warranted.     

A phase II trial of docetaxel and CPT-11 in patients with metastatic adenocarcinoma of the esophagus, gastroesophageal junction, and gastric cardia

Purpose. The incidence of adenocarcinoma of the lower third of the esophagus, esophagogastric junction, and gastric cardia has been rising in the face of limited treatment options for patients with metastatic disease. With the emergence of data to suggest that single agent docetaxel and irinotecan carry antineoplastic effects in this setting, we determined the response rate of these agents when given in combination. Patients and Methods. Forty-six patients with metastatic adenocarcinoma of the lower third of the esophagus, esophagogastric junction, and gastric cardia were evaluated. Patients received docetaxel 50 mg/m²/d and irinotecan 130 mg/m²/d intravenously at 21-d intervals with a tumor assessment after 2 cycles. Because of unacceptable toxicity among the first 13 patients, dosing was reduced to docetaxel 40 mg/m²/d and irinotecan 100 mg/m²/d intravenously at 21-d intervals. Results. The response rate for the entire cohort was 26% (95% confidence interval: 14%, 41%) with 12 confirmed partial responses. Five of these 12 responses were observed in patients treated at the higher chemotherapy dose. However, because 8 of 13 patients suffered grade 4 neutropenia and fevers, a dose reduction was incorporated into the protocol, and the remainder of the cohort was treated at the lower dose. All except 4 of the 15 observed grade 4 toxicities occurred at the higher dose, and these toxicities included nausea and vomiting, dyspnea, hypotension, dysrhythmias, and diarrhea in addition to neutropenia and fevers. There were no grade 5 toxicities. The median survival for the entire cohort was 7.3 mo. Conclusion. The combination of docetaxel and irinotecan provides modest antineoplastic activity among patients with adenocarcinoma of the esophagus, esophagogastric junction, and gastric cardia. Doses of docetaxel 40 mg/m²/d and irinotecan 100 mg/m²/d at 21-d intervals provide an acceptable safety profile, but higher doses appear to result in unacceptable toxicity.     

Natural course and predicting self-reported improvement in patients with chronic fatigue syndrome with a relatively short illness duration

OBJECTIVE: To describe the course of fatigue in chronic fatigue syndrome (CFS) patients with a relatively short duration of complaints and to test which psychosocial factors predict spontaneous improvement 1 year later. METHODS: Seventy-nine patients with a complaint duration of less than 2 years were tested at baseline and 78 of the same group at 1-year follow-up. During this time period, no systematic intervention took place. Self-reported improvement and fatigue severity were the main outcome measures. RESULTS: Forty-six percent (95% confidence intervals, 95CI = 35-58%) of the patients with a short illness duration reported to be improved. This was a significantly (chi(2) = 20.3, P < .001) higher percentage compared to the 20% (95CI = 15-26%) self-reported improvement in a previously published natural-course study among 246 CFS patients with a longer illness duration. Persistence of complaints after 1-year follow-up was associated with high baseline levels of experienced concentration problems, less strong psychosocial causal explanations for the complaints, and higher levels of the experienced lack of social support. Baseline fatigue severity predicted fatigue severity at follow-up. CONCLUSION: The results showed that CFS patients with a relatively short duration of complaints had a more favourable outcome compared to patients with a long illness duration. The data also indicated that complete recovery only occurred in patients with a complaint duration of less than 15 months. This finding has important implications, since it suggests that after such a time period spontaneous recovery hardly occurs.     

The aging baboon: comparative demography in a non-human primate

Why do closely related primate genera vary in longevity, and what does this teach us about human aging? Life tables of female baboons (Papio hamadryas) in two wild populations of East Africa and in a large captive population in San Antonio, Texas, provide striking similarities and contrasts to human mortality patterns. For captive baboons at the Southwest Foundation for Biomedical Research, we estimate the doubling time of adult mortality rate as 4.8 years. Wild females in free-living populations in Tanzania and in Kenya showed doubling times of 3.5 and 3.8 years, respectively. Although these values are considerably faster than the estimates of 7-8 years for humans, these primates share a demographic feature of human aging: within each taxon populations primarily vary in the level of Gompertz mortality intercept (frailty) and vary little in the demographic rate of aging. Environmental and genetic factors within taxa appear to affect the level of frailty underlying senescence. In contrast, primate taxa are differentiated by rates of demographic aging, even if they cannot be characterized by species-specific lifespan.     

Neoadjuvant and adjuvant therapy combined with resection of hepatic colorectal cancer metastases

Liver-only metastases occur in approximately one third of patients with metastatic colorectal cancer. Surgery is possible in portion of patients and remains the only potentially curative procedure. The use of neoadjuvant therapy may enhance the portion of patients that may be considered for surgery. For patients with initially resectable liver-only metastases, adjuvant therapy has been shown to be of benefit when combined with liverdirected therapy. Adjuvant therapy can reduce the rate of recurrence and extend survival.     

Comparative pharmacokinetic study of continuous venous infusion fluorouracil and oral fluorouracil with eniluracil in patients with advanced solid tumors.

PURPOSE: To compare the pharmacokinetics of continuous venous infusion (CVI) fluorouracil (5-FU) with that of oral eniluracil/5-FU and to describe toxicities and clinical activity of prolonged oral administration of eniluracil/5-FU. PATIENTS AND METHODS: A randomized, open-label, cross-over study compared CVI 5-FU to an oral 5-FU/eniluracil combination. Seventeen patients (arm A) were randomly assigned to receive eniluracil/5-FU combination tablets (10:1 mg/m(2) BID for 7 days) during the first study period, followed by 5-FU (300 mg/m(2) CVI for 7 days) during period 2, with a 14-day washout between periods. Sixteen patients (arm B) received treatment in the opposite sequence. In period 3, all patients received eniluracil/5-FU tablets BID for 28 days. Plasma levels of 5-FU during CVI and oral administration were analyzed in periods 1 and 2. Dihydropyrimidine dehydrogenase (DPD) activity was determined by measuring plasma uracil, urinary alpha-fluoro-beta-alanine, and peripheral-blood mononuclear cell (PBMC) DPD activity. RESULTS: There were no grade 3 or 4 toxicities in either arm. Partial responses were observed in three patients. Another three patients had stable disease for > or = 3 months. Eniluracil and 5-FU pharmacokinetics were similar to those observed in previous studies and were unaffected by administration sequence. The mean +/- SD steady-state plasma concentration (C(P)) and area under the curve (AUC)(144-168h) for CVI 5-FU (104 +/- 45 ng/mL and 2,350 +/- 826 ng x h/mL, respectively) were three-fold greater than those for oral 5-FU (38.1 +/- 7.7 ng/mL and 722 +/- 182 ng x h/mL, respectively [P <.00001]). Individual 5-FU concentrations during CVI were highly variable, whereas those after eniluracil/5-FU were very reproducible. DPD activity in PBMCs before each study period was normal. CONCLUSION: Both CVI 5-FU and oral eniluracil/5-FU were well tolerated, with moderate activity in these heavily pretreated patients. However, 5-FU steady-state C(P) and AUCs achieved with oral eniluracil/5-FU were significantly less than with CVI 5-FU.     

Perinatal stimulation and adaptation of the neonate

The present report describes psychobiological studies of behavior around the time of birth. An adaptive, ecological perspective is presented in which stimulation of the fetus and newborn is purported to instigate adaptive postpartum behavior. Studies describing the perinatal sensory environment are reviewed, with a consideration of emergent sensory function of the fetus. It is asserted that afferent input associated with parturition perturbs the fetus and neonate, producing a general arousal state that facilitates breathing, suckling, and early learning. The view developed herein is that perinatal sensory input induces and canalizes the newborn's behavior, thereby regulating adaptive postpartum function. Deviations in afferent input may alter ontogenetic trajectories and compromise developmental outcome by reducing availability of conditions necessary for adequate postpartum adaptation.