Adjuvant IMRT/XELOX radiochemotherapy improves long-term overall- and disease-free survival in advanced gastric cancer.

PURPOSE: In a retrospective analysis, adjuvant intensity-modulated radiation therapy (IMRT) combined with modern chemotherapy improved advanced gastric cancer survival rates compared to a combination of three-dimensional conformal radiation therapy (3D-CRT) and conventional chemotherapy. We report on the long-term outcomes of two consecutive patient cohorts that were treated with either IMRT and intensive chemotherapy, or 3D-CRT and conventional chemotherapy. PATIENTS AND METHODS: Between 2001 and 2008, 65 consecutive gastric cancer patients received either 3D-CRT (n = 27) or IMRT (n = 38) following tumor resection. Chemotherapy comprised predominantly 5-fluorouracil/folinic acid (5-FU/FA) in the earlier cohort and capecitabine plus oxaliplatin (XELOX) in the latter. The primary endpoints were overall survival (OS) and disease-free survival (DFS). RESULTS: Median OS times were 18 and 43 months in the 3D-CRT and IMRT groups, respectively (p = 0.0602). Actuarial 5-year OS rates were 26 and 47 %, respectively. Within the IMRT group, XELOX gave better results than 5-FU/FA in terms of OS, but this difference was not statistically significant. The primary cause of death in both groups was distant metastasis. Median DFS times were 14 and 35 months in the 3D-CRT and IMRT groups, respectively (p = 0.0693). Actuarial 5-year DFS rates were 22 and 44 %, respectively. Among patients receiving 5-FU/FA, DFS tended to be better in the IMRT group, but this was not statistically significant. A similar analysis for the XELOX group was not possible as 3D-CRT was almost never used to treat these patients. No late toxicity exceeding grade 3 or secondary tumors were observed. CONCLUSION: After a median follow-up period of over 5 years, OS and DFS were improved in the IMRT/XELOX treated patients compared to the 3D-CRT/5-FU/FA group. Long-term observation revealed no clinical indications of therapy-induced secondary tumors or renal toxicity.

Bone and body mass changes during space flight.

Body mass, calcium and skeletal changes occur in humans who have worked in microgravity. Physiologic changes are seen as early as one week and are still occurring 312 days into space flight. The physiologic changes in bone and mineral metabolism may be among those which limits long duration space flight if an adequate countermeasure is not developed. The purpose of this paper is to summarize what is known about calcium dynamics and bone mineral changes as well as associated changes of body mass induced by space flight. The data reported is from a variety of studies conducted in both actual and simulated space flight.

Calcium absorption, endogenous excretion, and endocrine changes during and after long-term bed rest.

Negative calcium balance is a known consequence of bed rest, and is manifested in elevated urine and fecal calcium (Ca). Elevated fecal Ca can result from either decreased absorption, increased endogenous fecal excretion, or both. We measured the Ca absorption and endogenous fecal excretion in eight healthy male volunteers before and during 4 months of bed rest. Dual isotope (n = 6) or single isotope (n = 2) methods in conjunction with Ca balance were used to calculate true and net Ca absorption and endogenous fecal excretion. Stool Ca increased from 797 mg/day (mean intake 991 mg/day) to 911 mg/day during bed rest, whereas urine Ca excretion increased from 174 to 241 mg/day. True Ca absorption decreased from 31 +/- 7% of Ca intake pre-bed rest to 24 +/- 2% during bed rest, (p < 0.05) and returned toward pre-bed rest values within 5-6 weeks following reambulation. Endogenous fecal excretion did not change significantly, and therefore, most of the increased fecal Ca resulted from changes in absorption. However, in one individual, endogenous fecal Ca excretion was the major contributor to Ca loss. Ionized Ca and pyridinium crosslinks increased and 1,25(OH)2 vitamin D decreased during bed rest, similar to the decrease in Ca absorption; parathyroid hormone (PTH), calcitonin, serum albumin, phosphorus, and total serum Ca were unchanged. Although alkaline phosphatase, osteocalcin, and PTH were unchanged during bed rest, they were elevated during reambulation. These changes accompanied by increased Ca absorption and balance and decreased ionized and total serum Ca suggest a rebound in bone formation following immobilization.

Haplotype analysis for CF-linked DNA polymorphisms in Switzerland.

A total of 295 patients, parents and unaffected sibs from 106 CF-families in central and northeastern Switzerland were investigated with probes 7C22(D7S16), metH, metD, pKM19, pXV-2c and pJ3.11(D7S8) for eight DNA polymorphisms (RFLP's). Linkage disequilibrium to the CF locus and haplotype frequencies were compared to those in other populations. They are comparable to other Caucasian populations and, for pKM 19 and pXV-2c, very close to the findings in Italy. The prevalence of certain haplotypes among the CF and the normal allele-bearing chromosomes indicate that the majority of the CF cases are probably the result of one ancient mutation in a common ancestor, but that there may be allelic heterogeneity accounting for an important proportion of patients, that may differ between countries or regions. Informative family constellations for the different polymorphisms in Switzerland and strategies for carrier detection and prenatal diagnosis are discussed. Haplotype analyses for each country and its ethnic subgroups are recommended.

Effects of weight lifting on bone mineral density in premenopausal women.

A group of 68 premenopausal women participated in a controlled 12 month exercise program. Two groups were matched according to age, body size (body mass index), and typical activity level. Data collection included bone mineral density (BMD) of the lumbar spine with dual-photon absorptiometry and of the os calcis with single-photon absorptiometry, lean body mass, urinary calcium/creatinine, and urinary gamma-carboxyglutamic acid (Gla). Subjects were given a daily 500 mg supplement of elemental calcium. There was no significant difference between groups in terms of diet, in urinary calcium/creatinine or Gla, or in lean body mass. The weight lifting group had a nonsignificant increase in mean lumbar BMD of 0.81% and the control group exhibited a nonsignificant decrease of 0.5%. However, a paired t-test revealed a significant change in the means in either group or as matched pairs. The relatively small change seen as a result of this modified Nautilus exercise program may prevent moderate weight lifting from being a practical answer for osteoporosis, even in a highly motivated population.

Zinc, copper, and nitrogen balances during bed rest and fluoride supplementation in healthy adult males.

The effects of bed rest and fluoride supplementation on zinc, copper, and nitrogen balances and Zn and Cu serum levels were measured in 15 healthy males. Subjects aged 19-54 y remained on a metabolic research ward for 10 wk. During weeks 1-5, subjects were ambulatory. During wks 6-10 they remained in continuous bed rest. During weeks 3-10 nine subjects received 10 or 20 mg F/d as sodium fluoride. Daily urine and weekly fecal composites were made and biweekly fasting blood samples were taken. Dietary intakes were 1.40 +/- 0.17 mg Cu/d (22.0 +/- 2.7 mumol Cu/d), 10.82 +/- 0.49 mg Zn/d (165.6 +/- 7.6 mumol Zn/d), and 14.27 +/- 0.23 g N/d (1019 +/- 16 mmol N/d). Bed rest increased urinary Zn and N excretions and fecal Zn excretions and decreased Zn balance (p less than 0.05) whereas Cu balance was unchanged. During bed rest, F supplementation increased Zn and N balances compared with untreated control subjects (p less than 0.05). These results are compatible with bone and muscle atrophy during bed rest and increased bone formation with F supplementation.

Effect of prolonged bedrest on the propensity for renal stone formation.

The effect of prolonged bedrest immobilization on urinary risk factors for stone formation and on the propensity for the crystallization of calcium salts was examined in eight normal subjects. During 5 weeks of bedrest, the mean urinary calcium excretion rose during the first week and remained elevated (from 5.68 to approximately 7.50 mmol/day). Mean urinary phosphorus excretion increased by the second week of bedrest and remained elevated (from 2.70 to approximately 30.6 mmol/day). Urinary sodium and uric acid excretion rose slightly, as did urinary magnesium. Urinary pH, oxalate, and citrate changed slightly or not at all. Owing to these biochemical alterations, urinary saturation of calcium phosphate, calcium oxalate, and monosodium urate increased significantly during bedrest, but that of uric acid did not change. The inhibitor activity against the spontaneous nucleation of brushite (CaHPO4.2H2O) and calcium oxalate was not altered significantly by bedrest. Thus, the propensity for the crystallization of stone-forming calcium salts was enhanced by bedrest, suggesting that immobilization may confer increased risk for the formation of calcium-containing renal stones.

Fatal poisoning with selenium dioxide.

Two hours after suicidal ingestion of an unknown amount of selenium dioxide, a 17-year-old male was admitted to hospital with asystolia and apnea. Attempts at resuscitation failed and the patient was pronounced dead. Findings at autopsy included congestion of lungs and kidneys, diffuse swelling of the heart, and brain edema. The most impressive finding was an orange-brown discoloration of the skin and all viscera, probably due to hemolysis and/or pigmentation related to ingestion of selenium dioxide. Selenium blood and tissue levels were increased by a factor of 100-1000 as compared to normal. The highest concentrations were found in pancreas, spleen, liver, and adipose tissue. For elucidation of the chemical nature of selenium in tissues, a new analytical method which was based on carbon disulfide extraction was developed. Carbon disulfide is a good solvent for non-polar selenium compounds like elemental selenium and selenium disulfide, but not for polar compounds like selenite and selenoproteins. A major fraction of selenium in tissues was extractable by carbon disulfide, which seems to indicate the presence of elemental selenium and/or selenium disulfide. The color of these substances is red and orange, respectively. This might explain at least part of the discoloration of skin and tissues. In vitro experiments suggested that trace amounts of hydrogen selenide, which is an intermediate of selenite metabolism, probably induced hemolysis. For evaluation of the therapeutic value of hemoperfusion in selenium poisoning in vitro hemoperfusion experiments were performed, which revealed only a moderate effect on selenium blood levels.

Skeletal calcium homeostasis and countermeasures to prevent disuse osteoporosis.

Maintenance of a skeleton capable of resisting the stresses of everyday life is dependent on the mechanical forces applied to the skeleton during normal activity in a 1-G environment. When the effects of 1-G on the longitudinal skeleton are removed, as with space travel or inactivity, bone and bone mineral are lost because bone resorption is greater than bone formation. Ninety healthy young men were studied during 5-36 weeks of continuous bed rest. During inactivity, urinary calcium increases rapidly and by the sixth week of bed rest, output has risen by 100 mg/day, plateaus for several weeks, and then decreases but remains above ambulatory baseline thereafter. This occurred even though they received vitamin D supplements throughout the study. Calcium balance becomes negative after 2 weeks and by the end of the first month, 200 mg/day is lost. The loss continues at this rate for at least 36 weeks. Calcaneal mineral loses 5% of its mass each month. Attempts to prevent disuse osteoporosis with both mechanical and biochemical means, including exercise, skeletal compression, increased hydrostatic pressure to the lower body, supplemental calcium and/or phosphorus, calcitonin, or etidronate were not successful.

Fluoride balance studies in healthy men during bed rest with and without a fluoride supplement..

In a program of studies of disuse osteoporosis, fluoride balances were determined in healthy men during ambulation and then during bed rest for 6 to 17 wk. Control subjects ingested basal diets containing 0.4 mg fluoride per day, whereas experimental subjects received 10-mg fluoride supplements in divided doses with meals. Fluoride and calcium were measured in diets, urine, and feces. Serum analyses included calcium and ionic fluoride. Fluoride balances during both phases were uniformly negative in control subjects (mean -0.46 mg/day) but uniformly positive in supplement subjects (mean +2.58 mg/day). Calcium balances were markedly negative during bed rest in both groups. Serum fluoride concentrations increased proportionally to fluoride intake, averaging 0.016 ppm in the controls and 0.045 ppm in the supplement subjects. The supplement of 10 mg fluoride daily did not protect against bed rest-induced calcium loss, or cause any clinical or laboratory abnormality in any subject.

Effect of the diphosphonate EHDP on bone mineral metabolism during prolonged bed rest.

The effect of disodium ethane-1-hydroxy-1, 1-diphosphonate (EHDPTM) on bone mineral metabolism was tested in 4 healthy young men during 20 weeks of continuous bed rest. Two subjects received an oral dose of 5 mg/kg/day and the other 2 20 mg/kg/day. The low dose had two minor effects: the increase in bone accretion rate which usually occurs during bed rest was prevented, and there was an accentuation of the bed rest induced increase in hydroxyproline excretion. Skeletal mineral loss, assessed by calcium balance measurements and gamma ray absorptiometry of the calcaneus, occurred at the rate previously noted in untreated control subjects. Two types of drug effect were apparent at the higher dosage: one was immediate and sustained--a rise in serum phosphorus concentration and a fall in serum alkaline phosphatase activity. The other was delayed and progressive--a decline in urinary hydroxyproline excretion and in the rates of bone accretion and resorption. Skeletal mineral loss may have been affected; the usual negative mineral balance developed during the first half of the study, then disappeared during the last few weeks. However, gamma ray absorptiometry revealed no attenuation of the calcaneal mineral losses.

Altered hypothalamic-pituitary-adrenal responsiveness to dexamethasone-insulin tolerance test in active acromegaly.

Eight acromegalic patients showed a plasma cortisol (11-OHCS) rise after insulin hypoglycemia which was similar to that seen in control patients, with mean peak values (+/-SEM) of 23.2 +/- 3.5 mug/100 ml and 27.2 +/- 3.3 mug/100 ml, respectively. One mg of dexamethasone was given the evening prior to repeat insulin hypoglycemia (DEX-ITT). After dexamethasone, the control subjects showed a mean post hypoglycemic plasma 11-OHCS rise to 18.3 +/- 2.3 mug/100 ml. In contrast, acromegalic patients had a negligible rise is plasma 11-OHCS, despite a comparable degree of hypoglycemia. These data indicate that, in active acromegaly, abnormal hypothalamic-pituitary-adrenal suppressibility can be induced to insulin hypoglycemia after dexamethasone.