Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06)

BACKGROUND Chemotherapy plus bevacizumab is a standard option for first-line treatment in metastatic colorectal cancer (mCRC) patients. We assessed whether no continuation is non-inferior to continuation of bevacizumab after completing first-line chemotherapy. PATIENTS AND METHODS In an open-label, phase III multicentre trial, patients with mCRC without disease progression after 4-6 months of standard first-line chemotherapy plus bevacizumab were randomly assigned to continuing bevacizumab at a standard dose or no treatment. CT scans were done every 6 weeks until disease progression. The primary end point was time to progression (TTP). A non-inferiority limit for hazard ratio (HR) of 0.727 was chosen to detect a difference in TTP of 6 weeks or less, with a one-sided significance level of 10% and a statistical power of 85%. RESULTS The intention-to-treat population comprised 262 patients: median follow-up was 36.7 months. The median TTP was 4.1 [95% confidence interval (CI) 3.1-5.4] months for bevacizumab continuation versus 2.9 (95% CI 2.8-3.8) months for no continuation; HR 0.74 (95% CI 0.58-0.96). Non-inferiority could not be demonstrated. The median overall survival was 25.4 months for bevacizumab continuation versus 23.8 months (HR 0.83; 95% CI 0.63-1.1; P = 0.2) for no continuation. Severe adverse events were uncommon in the bevacizumab continuation arm. Costs for bevacizumab continuation were estimated to be ∼30,000 USD per patient. CONCLUSIONS Non-inferiority could not be demonstrated for treatment holidays versus continuing bevacizumab monotheray, after 4-6 months of standard first-line chemotherapy plus bevacizumab. Based on no impact on overall survival and increased treatment costs, bevacizumab as a single agent is of no meaningful therapeutic value. More efficient treatment approaches are needed to maintain control of stabilized disease following induction therapy. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, number NCT00544700.

Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial

BACKGROUND One of the standard options in the treatment of stage IIIA/N2 non-small-cell lung cancer is neoadjuvant chemotherapy and surgery. We did a randomised trial to investigate whether the addition of neoadjuvant radiotherapy improves outcomes. METHODS We enrolled patients in 23 centres in Switzerland, Germany and Serbia. Eligible patients had pathologically proven, stage IIIA/N2 non-small-cell lung cancer and were randomly assigned to treatment groups in a 1:1 ratio. Those in the chemoradiotherapy group received three cycles of neoadjuvant chemotherapy (100 mg/m(2) cisplatin and 85 mg/m(2) docetaxel) followed by radiotherapy with 44 Gy in 22 fractions over 3 weeks, and those in the control group received neoadjuvant chemotherapy alone. All patients were scheduled to undergo surgery. Randomisation was stratified by centre, mediastinal bulk (less than 5 cm vs 5 cm or more), and weight loss (5% or more vs less than 5% in the previous 6 months). The primary endpoint was event-free survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00030771. FINDINGS From 2001 to 2012, 232 patients were enrolled, of whom 117 were allocated to the chemoradiotherapy group and 115 to the chemotherapy group. Median event-free survival was similar in the two groups at 12·8 months (95% CI 9·7-22·9) in the chemoradiotherapy group and 11·6 months (8·4-15·2) in the chemotherapy group (p=0·67). Median overall survival was 37·1 months (95% CI 22·6-50·0) with radiotherapy, compared with 26·2 months (19·9-52·1) in the control group. Chemotherapy-related toxic effects were reported in most patients, but 91% of patients completed three cycles of chemotherapy. Radiotherapy-induced grade 3 dysphagia was seen in seven (7%) patients. Three patients died in the control group within 30 days after surgery. INTERPRETATION Radiotherapy did not add any benefit to induction chemotherapy followed by surgery. We suggest that one definitive local treatment modality combined with neoadjuvant chemotherapy is adequate to treat resectable stage IIIA/N2 non-small-cell lung cancer. FUNDING Swiss State Secretariat for Education, Research and Innovation (SERI), Swiss Cancer League, and Sanofi.

Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial

BACKGROUND VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib. METHODS In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy, had Child-Pugh A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, had previously received sorafenib (stopped because of progression or intolerance), and had adequate haematological and biochemical parameters. Patients were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) or placebo every 2 weeks, plus best supportive care, until disease progression, unacceptable toxicity, or death. Randomisation was stratified by geographic region and cause of liver disease with a stratified permuted block method. Patients, medical staff, investigators, and the funder were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01140347. FINDINGS Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo. Median overall survival for the ramucirumab group was 9·2 months (95% CI 8·0-10·6) versus 7·6 months (6·0-9·3) for the placebo group (HR 0·87 [95% CI 0·72-1·05]; p=0·14). Grade 3 or greater adverse events occurring in 5% or more of patients in either treatment group were ascites (13 [5%] of 277 patients treated with ramucirumab vs 11 [4%] of 276 patients treated with placebo), hypertension (34 [12%] vs ten [4%]), asthenia (14 [5%] vs five [2%]), malignant neoplasm progression (18 [6%] vs 11 [4%]), increased aspartate aminotransferase concentration (15 [5%] vs 23 [8%]), thrombocytopenia (13 [5%] vs one [<1%]), hyperbilirubinaemia (three [1%] vs 13 [5%]), and increased blood bilirubin (five [2%] vs 14 [5%]). The most frequently reported (≥1%) treatment-emergent serious adverse event of any grade or grade 3 or more was malignant neoplasm progression. INTERPRETATION Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma. No new safety signals were noted in eligible patients and the safety profile is manageable. FUNDING Eli Lilly and Co.

14-3-3 zeta overexpression in early stage breast disease and tumor progression

Recent progress in diagnostic tools allows many breast cancers to be detected at an early pre-invasive stage. Thus, a better understanding of the molecular basis of early breast cancer progression is essential. 14-3-3 is a family of highly conserved and ubiquitously expressed proteins that are expressed in all eukaryotic organisms. In mammals there are seven isoforms, which bind to phosphor-serine/threonine residues regulating essential cellular processes such as signal transduction, cell cycle progression, and apoptosis. Our laboratory has discovered that a particular 14-3-3 family member, Zeta, is overexpressed in over 40% of breast tumor tissues. Furthermore, I examined the stage of breast disease in which 14-3-3ζ overexpression occurs and found that increased expression of 14-3-3ζ begins at the stage of atypical ductal hyperplasia, a very early stage of breast disease that confers increased risk for progress toward breast cancer. To determine whether 14-3-3ζ overexpression is a decisive early event in breast cancer, I overexpressed 14-3-3ζ in MCF10A cells, a non-transformed mammary epithelial cell (MEC) line and examined its impact on acini formation in a three dimensional (3D) culture model which simulates a basic unit of structure in the mammary gland. I discovered that 14-3-3ζ overexpression severely disrupted the acini architecture resulting in the disruption of polarity and luminal filling. Both are critical morphological events in the pre-neoplastic breast disease. This thesis focuses on the molecular mechanism of luminal filling. Proper lumen formation is a result of anoikis, a specific type apoptosis of cells not attached to the basement membrane. I found that 14-3-3ζ overexpression conferred a resistance to anoikis. Additionally, 14-3-3ζ overexpression in MCF10A cells and in MECs from 14-3-3ζ transgenic mice reduced expression of p53, which is known to mediate anoikis. Mechanistically, 14-3-3ζ induced hyperactivation of the PI3K/Akt pathway which led to phosphorylation and translocation of the MDM2 to the nucleus resulting in increased p53 degradation. Ectopic expression of p53 restored luminal apoptosis in 14-3-3ζ overexpressing MCF10A acini in 3D cultures. These data suggest that 14-3-3ζ overexpression is a critical event in early breast disease and down-regulation of p53 is one of the mechanisms by which 14-3-3ζ alters MEC acini structure and may increase the risk of progression to breast cancer. ^

Cost-effectiveness analysis of a 2-stage community-based hepatocellular carcinoma screening program in Taiwan

Hepatocellular carcinoma (HCC) has been ranked as the top cause of death due to neoplasm malignancy in Taiwan for years. The high incidence of HCC in Taiwan is primarily attributed to high prevalence of hepatitis viral infection. Screening the subjects with liver cirrhosis for HCC was widely recommended by many previous studies. The latest practice guideline for management of HCC released by the American Association for the Study of Liver Disease (AASLD) in 2005 recommended that the high risk groups, including cirrhotic patients, chronic HBV/HCV carriers, and subjects with family history of HCC and etc., should undergo surveillance.^ This study aims to investigate (1) whether the HCC screening program can prolong survival period of the high risk group, (2) what is the incremental cost-effectiveness ratio of the HCC screening program in Taiwan, as compared with a non-screening strategy from the payer perspective, (3) which high risk group has the lowest ICER for the HCC screening program from the insurer's perspective, in comparison with no screening strategy of each group, and (4) the estimated total cost of providing the HCC screening program to all high risk groups.^ The high risk subjects in the study were identified from the communities with high prevalence of hepatitis viral infection and classified into three groups (cirrhosis group, early cirrhosis group, and no cirrhosis group) at different levels of risk to HCC by status of liver disease at the time of enrollment. The repeated ultrasound screenings at an interval of 3, 6, and 12 months were applied to cirrhosis group, early cirrhosis group, and no cirrhosis group, respectively. The Markov-based decision model was constructed to simulate progression of HCC and to estimate the ICER for each group of subjects.^ The screening group had longer survival in the statistical results and the model outcomes. Owing to the low HCC incidence rate in the community-based screening program, screening services only have limited effect on survival of the screening group. The incremental cost-effectiveness ratio of the HCC screening program was $3834 per year of life saved, in comparison with the non-screening strategy. The estimated total cost of each group from the screening model over 13.5 years approximately consumes 0.13%, 1.06%, and 0.71% of total amount of adjusted National Health Expenditure from Jan 1992 to Jun 2005. ^ The subjects at high risk of developing HCC to undergo repeated ultrasound screenings had longer survival than those without screening, but screening was not the only factor to cause longer survival in the screening group. The incremental cost-effectiveness ratio of the 2-stage community-based HCC screening program in Taiwan was small. The HCC screening program was worthy of investment in Taiwan. In comparison with early cirrhosis group and no cirrhosis group, cirrhosis group has the lowest ICER when the screening period is less than 19 years. The estimated total cost of providing the HCC screening program to all high risk groups consumes approximately 1.90% of total amount of adjusted 13.5-year NHE in Taiwan.^

Outcomes associated with chemotherapy in elderly patients with early stage operable breast cancer

Background. Various clinical trials have proved the efficacy of adjuvant chemotherapy in women with breast cancer. Chemotherapy efficacy and guidelines for its use differ by stage of tumor and age of the patient with no clear recommendations for patients aged 70 and above. Objective. To examine the clinical and economic outcomes associated with chemotherapy use in and to examine the disparities in treatment and survival in elderly patients with early stage operable breast cancer by age and axillary node status. Methods. We studied a cohort of 23,110 node positive and 31,572 node negative women aged 65 and over diagnosed with incident American Joint Committee on Cancer (AJCC) stage I, II or IIIa breast cancer between January 1, 1991 and December 31, 2002 using SEER-Medicare data. Total patient costs were estimated using the phase of care approach and adjusted cost estimates were obtained from regression analysis using a 3% discount rate. Cox proportional hazard ratio of mortality was used to determine the effectiveness of chemotherapy. Propensity score approach was also used to minimize the bias associated with receipt of chemotherapy. To assess disparity in treatment, multivariate logistic regression analyses were performed to assess the relative odds of receiving surgery, chemotherapy and radiation after BCS for African Americans compared to Whites. Results. Regression adjusted cost estimates for all node positive patients receiving chemotherapy was approximately $2,300 and was significantly higher (p<0.05) than for patients not receiving chemotherapy. Mortality was significantly lower in node positive and node negative women aged 65-74 years receiving chemotherapy. There was a significant difference between African American and White women in receiving BCS and radiation after BCS; however this difference was explained by patient demographics, tumor characteristics and socioeconomic status (SES). African American node positive women were 21% less likely to receive chemotherapy than White women (OR, 0.79; CI, 0.68-0.92) in multivariate analysis. Conclusion. Chemotherapy is associated with increased survival in patients aged 65-74 and total costs attributable to chemotherapy differ by phase and age of the patient. Underutilization of systemic adjuvant chemotherapy in African American women requires attention and may serve as potential areas for appropriate intervention.^

Geographic variation in the utilization and survival associated with oxaliplatin chemotherapy in patients with stage III colon cancer

Background: Overall objectives of this dissertation are to examine the geographic variation and socio-demographic disparities (by age, race and gender) in the utilization and survival of newly FDA-approved chemotherapy agents (Oxaliplatin-containing regimens) as well as to determine the cost-effectiveness of Oxaliplatin in a large nationwide and population-based cohort of Medicare patients with resected stage-III colon cancer. Methods: A retrospective cohort of 7,654 Medicare patients was identified from the Surveillance, Epidemiology and End Results – Medicare linked database. Multiple logistic regression was performed to examine the relationship between receipt of Oxaliplatin-containing chemotherapy and geographic regions while adjusting for other patient characteristics. Cox proportional hazard model was used to estimate the effect of Oxaliplatin-containing chemotherapy on the survival variation across regions using 2004-2005 data. Propensity score adjustments were also made to control for potential bias related to non-random allocation of the treatment group. We used Kaplan-Meier sample average estimator to calculate the cost of disease after cancer-specific surgery to death, loss-to follow-up or censorship. Results: Only 51% of the stage-III patients received adjuvant chemotherapy within three to six months of colon-cancer specific surgery. Patients in the rural regions were approximately 30% less likely to receive Oxaliplatin chemotherapy than those residing in a big metro region (OR=0.69, p=0.033). The hazard ratio for patients residing in metro region was comparable to those residing in big metro region (HR: 1.05, 95% CI: 0.49-2.28). Patients who received Oxalipaltin chemotherapy were 33% less likely to die than those received 5-FU only chemotherapy (adjusted HR=0.67, 95% CI: 0.41-1.11). KMSA-adjusted mean payments were almost 2.5 times higher in the Oxaliplatin-containing group compared to 5-FU only group ($45,378 versus $17,856). When compared to no chemotherapy group, ICER of 5-FU based regimen was $12,767 per LYG, and ICER of Oxaliplatin-chemotherapy was $60,863 per LYG. Oxaliplatin was found economically dominated by 5-FU only chemotherapy in this study population. Conclusion: Chemotherapy use varies across geographic regions. We also observed considerable survival differences across geographic regions; the difference remained even after adjusting for socio-demographic characteristics. The cost-effectiveness of Oxaliplatin in Medicare patients may be over-estimated in the clinical trials. Our study found 5-FU only chemotherapy cost-effective in adjuvant settings in patients with stage-III colon cancer.^

Effect of insurance status on stage of breast cancer diagnosis

Objective: The purpose of this study is to compare the stages of breast cancer presented between the insured and uninsured patients diagnosed at The Rose, an active non-profit breast healthcare organization to determine if uninsured patients present with more advanced stage breast cancer as compared to their insured counterparts. ^ Study Design: Retrospective cross-sectional study. ^ Methods: The study included 1,265 patients who received breast healthcare services and were diagnosed with breast cancer at The Rose between FY 2007 and FY 2012. 738 of the patients in the study were presumably uninsured since their breast healthcare services were sponsored through various funding sources and they were navigated into treatment through The Rose patient navigation program. We compared breast cancer stages for women who had insurance with those who did not have insurance. The effects of age and race/ethnicity along with the insurance status on the stage of reast cancer diagnosis were also analyzed. We calculated the odds ratio using the contingency tables; and estimated odds ratios (ORs) and 95% confidence intervals (CIs) using ordinal logistic regression by applying multiple imputation method for missing tumor stage data. ^ Results: The ordered logistic regression analysis with ordered tumor stage as dependent variable and uninsured as independent variable gave us an odds ratio of 1.73 (OR=1.73; p-value<0.05; 95% CI: 1.36 - 2.12). ^ Conclusions: Insurance status is a strong predictor of stage of breast cancer diagnosed among women seen at The Rose. Uninsured women seen at The Rose are almost twice as likely to present at a advanced stage of breast cancer as opposed to their insured counterparts.^

Element concentrations of plagioclase and clinopyroxene in poikilitic olivine gabbros from ODP Hole 153-923A (Table 4)

Ocean Drilling Program Hole 923A, located on the western flank of the Mid-Atlantic Ridge south of the Kane Fracture Zone, recovered primitive gabbros that have mineral trace element compositions inconsistent with growth from a single parental melt. Plagioclase crystals commonly show embayed anorthitic cores overgrown by more albitic rims. Ion probe analyses of plagioclase cores and rims show consistent differences in trace element ratios, indicating variation in the trace element characteristics of their respective parental melts. This requires the existence of at least two distinct melt compositions within the crust during the generation of these gabbros. Melt compositions calculated to be parental to plagioclase cores are depleted in light rare earth elements, but enriched in yttrium, compared to basalts from this region of the Mid-Atlantic Ridge, which are normal mid-ocean ridge basalt (N-MORB). Clinopyroxene trace element compositions are similar to those predicted to be in equilibrium with N-MORB. However, primitive clinopyroxene crystals are much more magnesian than those produced in one-atmosphere experiments on N-MORB, suggesting that the major element composition of the melt was unlike N-MORB. These data require that the diverse array of melt compositions generated within the mantle beneath mid-ocean ridges are not always fully homogenised during melt extraction from the mantle and that the final stage of mixing can occur efficiently within crustal magma chambers. This has implications for the process of melt extraction from the mantle and the liquid line of descent of MORB

Age models and stabile isotope ratios from SO35 cores

Stable isotope measurements on the planktonic foraminifer Globigerinoides ruber (white) have been carried out on a number of selected deep-seas sediment cores from the South Lau and Norlh Fiji Basins. The d18O-curves show good correlation with the inter-ocean oraphic correlation composite d18O-record of the standard reference section (Prell et al. 1986), which, in combination with the chronostratigraphic classifications of Herterich & Sarnthein (1984, modified) and Imbrie et al. 1984), allows a detailed dating of the sedimentary sequences. The deepest layers in core no. 119 (southern Lau Basin) could be assigned to Isotope Stage 24. Measurements made on bulk carbonate in two cores show a much higher glacial-interglacial amplitude, allowing the general identification of the conventional oxygen isotope stages. The d13C-values of the benthic foraminifer Cibicidoides wuellerstorfi show progressively lighter values northwards reflecting an increasing contribution of the isotopically lighter CO2 from the remineralisation of organic matter during the general northward movement of the deep water masses. Cyclicities in the sedimentation rates were observed in core nos. 117 and 119 (both southern Lau Basin) where the interglacials exhibit higher levels than the glacials. Calculated new or export paleoproductivity show that the glacials had higher productivity in the euphotic zone. From the oxygen isotope stratigraphy, the five ash layers in core nos. 117 and 119 could be dated as about 530 ka B.P. in Stage 14, 695 ka B.P. in Stage 18, 775 ka B.P. in Stage 21, 790 ka B.P. and 825 ka B.P. in Stage 22. Carbonate dissolution occurred during stages 5, 8 and 10 to 12.

(Table 1) Concentrations and isotopic ratio of Argon in Cretaceous deep-sea basaltic glass of DSDP Hole 51-417D

The abundance and isotopic composition of rare gas in the mantle provides an important constraint on the origin and evolution of the Earth's atmosphere. One of sources of such information is basalts which erupted from ocean ridges. Ozima (1975, doi:10.1016/0016-7037(75)90054-X) stated that a high 40Ar/36Ar ratio in the mantle suggests sudden degassing at an early stage of the Earth's evolution. Several authors (Funkhouser et al., 1968, doi:10.1016/S0012-821X(68)80021-4; Darlymple and Moor, 1968, doi:10.1126/science.161.3846.1132) have reported excess 40Ar and high 40Ar/36Ar ratios in rapidly quenched rims of young deep-sea basalts. However, the Ar composition in old ridge basalts was not known. We report here a measurement of the isotopic composition of Ar in old deep-sea basalts. The Glomar Challenger drilled a Cretaceous ocean floor near the southern end of the Bermuda Rise in Deep Sea Drilling Project. The drilled site (Site 417) is on the magnetic anomaly MO which has been estimated to be 108 Myr old.

(Table 1) Characteristics of silicified sediments at DSDP Site 61-462 according to host-rock lithology, opal-CT-to-quartz ratio, and the origin of the quartz phase

This study deals with the mineralogical variability of siliceous and zeolitic sediments, porcellanites, and cherts at small intervals in the continuously cored sequence of Deep Sea Drilling Project Site 462. Skeletal opal is preserved down to a maximum burial depth of 390 meters (middle Eocene). Below this level, the tests are totally dissolved or replaced and filled by opal-CT, quartz, clinoptilolite, and calcite. Etching of opaline tests does not increase continously with deeper burial. Opal solution accompanied by a conspicuous formation of authigenic clinoptilolite has a local maximum in Core 16 (150 m). A causal relationship with the lower Miocene hiatus at this level is highly probable. Oligocene to Cenomanian sediments represent an intermediate stage of silica diagenesis: the opal-CT/quartz ratios of the silicified rocks are frequently greater than 1, and quartz filling pores or replacing foraminifer tests is more widespread than quartz which converted from an opal-CT precursor. As at other sites, there is a marked discontinuity of the transitions from biogenic opal via opal-CT to quartz with increasing depth of burial. Layers with unaltered opal-A alternate with porcellanite beds; the intensity of the opal-CT-to-quartz transformation changes very rapidly from horizon to horizon and obviously is not correlated with lithologic parameters. The silica for authigenic clinoptilolite was derived from biogenic opal and decaying volcanic components.

CaCO3, foraminifer fragmentation, benthic carbon isotopes, coarse lithic counts and radiogenic isotopes (Sr, Nd, Pb) of the Pliocene and earliest Pleistocene terrigenous component (3.3-2.4 Ma) of IODP Site 306-U1313

We present Plio-Pleistocene records of sediment color, %CaCO3, foraminifer fragmentation, benthic carbon isotopes (d13C) and radiogenic isotopes (Sr, Nd, Pb) of the terrigenous component from IODP Site U1313, a reoccupation of benchmark subtropical North Atlantic Ocean DSDP Site 607. We show that (inter)glacial cycles in sediment color and %CaCO3 pre-date major northern hemisphere glaciation and are unambiguously and consistently correlated to benthic oxygen isotopes back to 3.3 million years ago (Ma) and intermittently so probably back to the Miocene/Pliocene boundary. We show these lithological cycles to be driven by enhanced glacial fluxes of terrigenous material (eolian dust), not carbonate dissolution (the classic interpretation). Our radiogenic isotope data indicate a North American source for this dust (~3.3-2.4 Ma) in keeping with the interpreted source of terrestrial plant wax-derived biomarkers deposited at Site U1313. Yet our data indicate a mid latitude provenance regardless of (inter)glacial state, a finding that is inconsistent with the biomarker-inferred importance of glaciogenic mechanisms of dust production and transport. Moreover, we find that the relation between the biomarker and lithogenic components of dust accumulation is distinctly non-linear. Both records show a jump in glacial rates of accumulation from Marine Isotope Stage, MIS, G6 (2.72 Ma) onwards but the amplitude of this signal is about 3-8 times greater for biomarkers than for dust and particularly extreme during MIS 100 (2.52 Ma). We conclude that North America shifted abruptly to a distinctly more arid glacial regime from MIS G6, but major shifts in glacial North American vegetation biomes and regional wind fields (exacerbated by the growth of a large Laurentide Ice Sheet during MIS 100) likely explain amplification of this signal in the biomarker records. Our findings are consistent with wetter-than-modern reconstructions of North American continental climate under the warm high CO2 conditions of the Early Pliocene but contrast with most model predictions for the response of the hydrological cycle to anthropogenic warming over the coming 50 years (poleward expansion of the subtropical dry zones).

Sedimentology and geochemistry of Oxygen Isotope Stage 3 and Holocene sediments from Laguna Potrok Aike, Patagonia

Seismic reflection studies in the maar lake Laguna Potrok Aike (51°58? S, 70°23? W) revealed an erosional unconformity associated with a sub-aquatic lake-level terrace at a water depth of 30m. Radiocarbon-dated, multi-proxy sediment studies of a piston core from this location indicate that the sediment below this discontinuity has an age of 45kyr BP (Oxygen Isotope Stage 3), and was deposited during an interval of high lake level. In comparison to the Holocene section, geochemical indicators of this older part of the record either point towards a different sediment source or to a different transport mechanism for Oxygen Isotope Stage 3 sediments. Holocene sedimentation started again before 6790cal. yr BP, providing a sediment record of hydrological variability until the present. Geochemical and isotopic data indicate a fluctuating lake level until 5310cal. yr BP. During the late Holocene the lake level shows a receding tendency. Nevertheless, the lake level did not drop below the 30m terrace to create another unconformity. The geochemical characterization of volcanic ashes reveals evidence for previously unknown explosive activity of the Reclús and Mt. Burney volcanoes during Oxygen Isotope Stage 3.

Chemistry and accumulation rates of Jurassic to early Cretaceous sediments from the central equatorial Pacific

Sedimentation in the central Pacific during the Jurassic and Early Cretaceous was dominated by abundant biogenic silica. A synthesis of the stratigraphy, lithology, petrology, and geochemistry of the radiolarites in Sites 801 and 800 documents the sedimentation processes and trends in the equatorial central Pacific from the Middle Jurassic through the Early Cretaceous. Paleolatitude and paleodepth reconstructions enable comparisons with previous DSDP sites and identification of the general patterns of sedimentation over a wide region of the Pacific. Clayey radiolarites dominated sedimentation on Pacific oceanic crust within tropical paleolatitudes from at least the latest Bathonian through Tithonian. Radiolarian productivity rose to a peak within 5° of the paleoequator, where accumulation rates of biogenic silica exceeded 1000 g/cm**2/m.y. Wavy-bedded radiolarian cherts developed in the upper Tithonian at Site 801 coinciding with the proximity of this site to the paleoequator. Ribbon-bedding of some radiolarian cherts exposed on Pacific margins may have formed from silicification of radiolarite deposited near the equatorial high-productivity zone where radiolarian/clay ratios were high. Silicification processes in sediments extensively mixed by bioturbation or enriched in clay or carbonate generally resulted in discontinuous bands or nodules of porcellanite or chert, e.g., a "knobby" radiolarite. Ribbon-bedded cherts require primary alternations of radiolarian-rich and clay-rich layers as an initial structural template, coupled with abundant biogenic silica in both layers. During diagenesis, migration of silica from clay-rich layers leaves radiolarian "ghosts" or voids, and the precipitation in adjacent radiolarite layers results in silicification of the inter-radiolarian matrix and infilling of radiolarian tests. Alternations of claystone and clay-rich radiolarian grainstone were deposited during the Callovian at Site 801 and during the Berriasian-Valanginian at Site 800, but did not silicify to form bedded chert. Carbonate was not preserved on the Pacific oceanic floor or spreading ridges during the Jurassic, perhaps due to an elevated level of dissolved carbon dioxide. During the Berriasian through Hauterivian, the carbonate compensation depth (CCD) descended to approximately 3500 m, permitting the accumulation of siliceous limestones at near-ridge sites. Carbonate accumulation rates exceeded 1500 g/cm**2/m.y. at sites above the CCD, yet there is no evidence of an equatorial carbonate bulge during the Early Cretaceous. In the Barremian and Aptian, the CCD rose, coincident with the onset of mid-plate volcanic activity. Abundance of Fe and Mn and the associated formation of authigenic Fe-smectite clays was a function of proximity to the spreading ridges, with secondary enrichments occurring during episodes of spreading-center reorganizations. Callovian radiolarite at Site 801 is anomalously depleted in Mn, which resulted either from inhibited precipitation of Mn-oxides by lower pH of interstitial waters induced by high dissolved oceanic CO2 levels or from diagenetic mobilization of Mn. Influx of terrigenous (eolian) clay apparently changed with paleolatitude and geological age. Cyclic variations in productivity of radiolarians and of nannofossils and in the influx of terrigenous clay are attributed to Milankovitch climatic cycles of precession (20,000 yr) and eccentricity (100,000 yr). Diagenetic redistribution of biogenic silica and carbonate enhanced the expression of this cyclic sedimentation. Jurassic and Lower Cretaceous sediments were deposited under oxygenated bottom-water conditions at all depths, accompanied by bioturbation and pervasive oxidation of organic carbon and metals. Despite the more "equable" climate conditions of the Mesozoic, the super-ocean of the Pacific experienced adequate deep-water circulation to prevent stagnation. Efficient nutrient recycling may have been a factor in the abundance of radiolarians in this ocean basin.