Older Breast Cancer Survivors: Geriatric Assessment Domains Are Associated With Poor Tolerance of Treatment Adverse Effects and Predict Mortality Over 7 Years of Follow-Up

Purpose To evaluate geriatric assessment (GA) domains in relation to clinically important outcomes in older breast cancer survivors. Methods Six hundred sixty women diagnosed with primary breast cancer in four US geographic regions (Los Angeles, CA; Minnesota; North Carolina; and Rhode Island) were selected with disease stage I to IIIA, age ≥ 65 years at date of diagnosis, and permission from attending physician to contact. Data were collected over 7 years of follow-up from consenting patients' medical records, telephone interviews, physician questionnaires, and the National Death Index. Outcomes included self-reported treatment tolerance and all-cause mortality. Four GA domains were described by six individual measures, as follows: sociodemographic by adequate finances; clinical by Charlson comorbidity index (CCI) and body mass index; function by number of physical function limitations; and psychosocial by the five-item Mental Health Index (MHI5) and Medical Outcomes Study Social Support Survey (MOS-SSS). Associations were evaluated using t tests, χ2 tests, and regression analyses. Results In multivariable regression including age and stage, three measures from two domains (clinical and psychosocial) were associated with poor treatment tolerance; these were CCI ≥ 1 (odds ratio [OR] = 2.49; 95% CI, 1.18 to 5.25), MHI5 score less than 80 (OR = 2.36; 95% CI, 1.15 to 4.86), and MOS-SSS score less than 80 (OR = 3.32; 95% CI, 1.44 to 7.66). Four measures representing all four GA domains predicted mortality; these were inadequate finances (hazard ratio [HR] = 1.89; 95% CI, 1.24 to 2.88; CCI ≥ 1 (HR = 1.38; 95% CI, 1.01 to 1.88), functional limitation (HR = 1.40; 95% CI, 1.01 to 1.93), and MHI5 score less than 80 (HR = 1.34; 95% CI, 1.01 to 1.85). In addition, the proportion of women with these outcomes incrementally increased as the number of GA deficits increased. Conclusion This study provides longitudinal evidence that GA domains are associated with poor treatment tolerance and predict mortality at 7 years of follow-up, independent of age and stage of disease.

Local targeting of malignant gliomas by the diffusible peptidic vector 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid-substance p

PURPOSE: Malignant glial brain tumors consistently overexpress neurokinin type 1 receptors. In classic seed-based brachytherapy, one to several rigid (125)I seeds are inserted, mainly for the treatment of small low-grade gliomas. The complex geometry of rapidly proliferating high-grade gliomas requires a diffusible system targeting tumor-associated surface structures to saturate the tumor, including its margins. EXPERIMENTAL DESIGN: We developed a new targeting vector by conjugating the chelator 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid to Arg(1) of substance P, generating a radiopharmaceutical with a molecular weight of 1,806 Da and an IC(50) of 0.88 +/- 0.34 nmol/L. Cell biological studies were done with glioblastoma cell lines. neurokinin type-1 receptor (NK1R) autoradiography was done with 58 tumor biopsies. For labeling, (90)Y was mostly used. To reduce the "cross-fire effect" in critically located tumors, (177)Lut and (213)Bi were used instead. In a pilot study, we assessed feasibility, biodistribution, and early and long-term toxicity following i.t. injection of radiolabeled 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid substance P in 14 glioblastoma and six glioma patients of WHO grades 2 to 3. RESULTS: Autoradiography disclosed overexpression of NK1R in 55 of 58 gliomas of WHO grades 2 to 4. Internalization of the peptidic vector was found to be specific. Clinically, the radiopharmeutical was distributed according to tumor geometry. Only transient toxicity was seen as symptomatic radiogenic edema in one patient (observation period, 7-66 months). Disease stabilization and/or improved neurologic status was observed in 13 of 20 patients. Secondary resection disclosed widespread radiation necrosis with improved demarcation. CONCLUSIONS: Targeted radiotherapy using diffusible peptidic vectors represents an innovative strategy for local control of malignant gliomas, which will be further assessed as a neoadjuvant approach.

Occurrence of hiatuses PH and NH 1 through NH 7 in DSDP holes

Miocene paleoceanographic evolution exhibits major changes resulting from the opening and closing of passages, the subsequent changes in oceanic circulation, and development of major Antarctic glaciation. The consequences and timing of these events can be observed in variations in the distribution of deep-sea hiatuses, sedimentation patterns, and biogeographic distribution of planktic organisms. The opening of the Drake Passage in the latest Oligocene to early Miocene (25-20 Ma) resulted in the establishment of the deep circumpolar current, which led to thermal isolation of Antarctica and increased global cooling. This development was associated with a major turnover in planktic organisms, resulting in the evolution of Neogene assemblages and the eventual extinction of Paleogene assemblages. The erosive patterns of two widespread hiatuses (PH, 23.0-22.5 Ma; and NH 1, 20-18 Ma) indicate that a deep circumequatorial circulation existed at this time, characterized by a broad band of carbonate-ooze deposition. Siliceous sedimentation was restricted to the North Atlantic and a narrow band around Antarctica. A major reorganization in deep-sea sedimentation and hiatus distribution patterns occurred near the early/middle Miocene boundary, apparently resulting from changes in oceanic circulation. Beginning at this time, deep-sea erosion occurred throughout the Caribbean (hiatus NH 2, 16-15 Ma), suggesting disruption of the deep circumequatorial circulation and northward deflection of deep currents, and/or intensification of the Gulf Stream. Sediment distribution patterns changed dramatically with the sudden appearance of siliceous-ooze deposition in the marginal and east equatorial North Pacific by 16.0 to 15.5 Ma, coincident with the decline of siliceous sedimentation in the North Atlantic. This silica switch may have been caused by the introduction of Norwegian Overflow Water into the North Atlantic acting as a barrier to outcropping of silica-rich Antarctic Bottom Water. The main aspects of the present oceanic circulation system and sediment distribution pattern were established by 13.5 to 12.5 Ma (hiatus NH 3), coincident with the establishment of a major East Antarctic ice cap. Antarctic glaciation resulted in a broadening belt of siliceous-ooze deposition around Antarctica, increased siliceous sedimentation in the marginal and east equatorial North Pacific and Indian Oceans, and further northward restriction of siliceous sediments in the North Atlantic. Periodic cool climatic events were accompanied by lower eustatic sea levels and widespread deep-sea erosion at 12 to 11 Ma (NH 4), 10 to 9 Ma (NH 5), 7.5 to 6.2 Ma (NH 6), and 5.2 to 4.7 Ma (NH 7).

Basalt density, basement age, and intrusive/extrusive relations from DSDP Legs 2 through 7, 9, and 14

Densities of layer 2 basalt recovered during the Deep Sea Drilling Project have been found to decrease steadily with age, a finding ascribed to progressive submarine weathering in the context of sea-floor spreading. The least-squares solution for 52 density measurements gives a rate of decrease in density of (Delta p)/(Delta t) = -0.0046 g per ccm m.y. = -16 percent per 100 m.y., which is in excellent agreement with earlier estimates based on observed chemical depletion rates of dredged oceanic basalt. Weathering of sea-floor basalt, should it penetrate to any considerable depth in layer 2, will decrease layer 2 seismic refraction velocities, act as a source of geothermal heat, and substantially influence the chemistry of sea water and the overlying column of sediment.

Chemical, isotopic and mineral compositions of basal metalliferous sediments from DSDP Legs 5 and 7

Sediments from near the basement of a number of Deep Sea Drilling Project (DSDP) sites, from the Bauer Deep, and from the East Pacific Rise have unusually high transition metal-to-aluminum ratios. Similarities in the chemical, isotopic, and mineralogical compositions of these deposits point to a common origin. All the sediments studied have rare-earth-element (REE) patterns strongly resembling the pattern of sea water, implying either that the REE's were coprecipitated with ferromanganese hydroxyoxides (hydroxyoxides denote a mixture of unspecified hydrated oxides and hydroxides), or that they are incorporated in small concentrations of phosphatic fish debris found in all samples. Oxygen isotopic data indicate that the metalliferous sediments are in isotopic equilibrium with sea water and are composed of varying mixtures of two end-member phases with different oxygen isotopic compositions: an iron-manganese hydroxyoxide and an iron-rich montmorillonite. A low-temperature origin for the sediments is supported by mineralogical analyses by x-ray diffraction which show that goethite, iron-rich montmorillonite, and various manganese hydroxyoxides are the dominant phases present. Sr87/Sr86 ratios for the DSDP sediments are indistinguishable from the Sr87/Sr86 ratio in modern sea water. Since these sediments were formed 30 to 90 m.y. ago, when sea water had a lower Sr87/Sr86 value, the strontium in the poorly crystalline hydroxyoxides must be exchanging with interstitial water in open contact with sea water. In contrast, uranium isotopic data indicate that the metalliferous sediments have formed a closed system for this element. The sulfur isotopic compositions suggest that sea-water sulfur dominates these sediments with little or no contribution of magmatic or bacteriologically reduced sulfur. In contrast, ratios of lead isotopes in the metalliferous deposits resemble values for oceanic tholeiite basalt, but are quite different from ratios found in authigenic marine manganese nodules. Thus, lead in the metalliferous sediments appears to be of magmatic origin. The combined mineralogical, isotopic, and chemical data for these sediments suggest that they formed from hydrothermal solutions generated by the interaction of sea water with newly formed basalt crust at mid-ocean ridges. The crystallization of solid phases took place at low temperatures and was strongly influenced by sea water, which was the source for some of the elements found in the sediments.