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CCGA [NCT02889978] is the largest study of cfDNA-based early cancer detection; the first CCGA learnings from multiple cfDNA assays are reported here. This prospective, multi-center, observational study has enrolled 10,012 of 15,000 demographically-balanced participants at 141 sites. Blood was collected from participants with newly diagnosed therapy-naive cancer (C, case) and participants without a diagnosis of cancer (noncancer [NC], control) as defined at enrollment. This preplanned substudy included 878 cases, 580 controls, and 169 assay controls (n=1627) across 20 tumor types and all clinical stages. All samples were analyzed by: 1) Paired cfDNA and white blood cell (WBC)-targeted sequencing (60,000X, 507 gene panel); a joint caller removed WBC-derived somatic variants and residual technical noise; 2) Paired cfDNA and WBC whole-genome sequencing (WGS; 35X); a novel machine learning algorithm generated cancer-related signal scores; joint analysis identified shared events; and 3) cfDNA whole-genome bisulfite sequencing (WGBS; 34X); normalized scores were generated using abnormally methylated fragments. In the targeted assay, non-tumor WBC-matched cfDNA somatic variants (SNVs/indels) accounted for 76% of all variants in NC and 65% in C. Consistent with somatic mosaicism (i.e., clonal hematopoiesis), WBC-matched variants increased with age; several were non-canonical loss-of-function mutations not previously reported. After WBC variant removal, canonical driver somatic variants were highly specific to C (e.g., in EGFR and PIK3CA, 0 NC had variants vs 11 and 30, respectively, of C). Similarly, of 8 NC with somatic copy number alterations (SCNAs) detected with WGS, 4 were derived from WBCs. WGBS data revealed informative hyper- and hypo-fragment level CpGs (1:2 ratio); a subset was used to calculate methylation scores. A consistent “cancer-like” signal was observed in 99% specificity for invasive cancer, and support the promise of cfDNA assay for early cancer detection. Additional data will be presented on detected plasma:tissue variant concordance and on multi-assay modeling. Citation Format: Alexander A. Aravanis, Geoffrey R. Oxnard, Tara Maddala, Earl Hubbell, Oliver Venn, Arash Jamshidi, Ling Shen, Hamed Amini, John A. Beausang, Craig Betts, Daniel Civello, Konstantin Davydov, Saniya Fazullina, Darya Filippova, Sante Gnerre, Samuel Gross, Chenlu Hou, Roger Jiang, Byoungsok Jung, Kathryn Kurtzman, Collin Melton, Shivani Nautiyal, Jonathan Newman, Joshua Newman, Cosmos Nicolaou, Richard Rava, Onur Sakarya, Ravi Vijaya Satya, Seyedmehdi Shojaee, Kristan Steffen, Anton Valouev, Hui Xu, Jeanne Yue, Nan Zhang, Jose Baselga, Rosanna Lapham, Daron G. Davis, David Smith, Donald Richards, Michael V. Seiden, Charles Swanton, Timothy J. Yeatman, Robert Tibshirani, Christina Curtis, Sylvia K. Plevritis, Richard Williams, Eric Klein, Anne-Renee Hartman, Minetta C. Liu. Development of plasma cell-free DNA (cfDNA) assays for early cancer detection: first insights from the Circulating Cell-Free Genome Atlas Study (CCGA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-343.

LBA8501 Background: Plasma cfDNA genomic analysis is used widely for the care of advanced lung cancer, but its suitability for early stage lung cancer detection is not well established. CCGA (NCT02889978) is a prospective, multi-center, observational study launched for the development of a noninvasive assay for cancer detection. Methods: Blood was prospectively collected (N = 1627) from 749 controls (no cancer diagnosis) and 878 participants (pts) with newly-diagnosed untreated cancer in this preplanned substudy, including 127 pts with lung cancer. Three prototype sequencing assays were performed: paired cfDNA and white blood cell (WBC) targeted sequencing (507 genes, 60,000X) for single nucleotide variants/indels; paired cfDNA and WBC whole genome sequencing (WGS) for copy number variation (30X); and cfDNA whole genome bisulfite sequencing (WGBS) for methylation (30X). For each assay, a classification model using 10-fold cross-validation was developed for all pts with cancer, then evaluated in the pts with lung cancer; sensitivity was estimated at 95% specificity. Results: We evaluated pts with lung cancer (127) and a subset of controls (580) with similar ages (mean±SD yrs: 67±9, 60±13), 85% and 43% were ever-smokers, and 46% and 22% were men, respectively. Of 3055 nonsynonymous mutations detected across 122 evaluable pts with lung cancer, > 50% were detected in WBC consistent with clonal hematopoiesis (CH). Accounting for CH, sensitivity in 63 stage I-IIIA pts evaluable across all 3 assays was 48% (35-61, targeted), 54% (41-67, WGS), and 56% (43-68, WGBS); in 54 stage IIIB-IV pts it was 85% (73-93, targeted), 91% (80-97, WGS), and 93% (82-98, WGBS) . Similar sensitivities were observed across histological subtypes (adenocarcinoma, squamous cell, small cell). Comparison to tumor WGS and multi-assay classification will be reported. Conclusions: Early stage lung cancers are detectable in cfDNA using a genome-wide sequencing approach. For lung cancer detection using targeted assays, CH must be accounted for to minimize false positives. Assay optimization is ongoing to allow further clinical development in the intended use population. Clinical trial information: NCT02889978.

6016Background: Lenvatinib (LEN) is a multikinase inhibitor of vascular endothelial growth factor receptor 1−3, fibroblast growth factor receptor 1−4, platelet-derived growth factor receptor α, RET...

e20567Background: Limited 2L therapy options and no established 3L standard of care make treating relapsed ED-SCLC challenging. This study explores current treatment and outcomes in patients receiv...

Purpose Gemcitabine (G) is standard therapy for pancreatic cancer. Enzastaurin (E) inhibits PKCβ and PI3K/AKT signaling pathways with a dose-dependent effect on growth of pancreatic carcinoma xenografts. Data suggest that the GE combination may improve clinical outcomes. Methods Primary objective was overall survival (OS); secondary objectives assessed progression-free survival (PFS), response rate (RR), quality of life (QOL), toxicity, and relationships between biomarker expression and clinical outcomes. Patients were randomly assigned (2:1) to GE or G treatment; GE arm: E 500 mg PO daily; loading-dose (1200 mg; Day 1 Cycle 1 only) and G 1000 mg/m2 IV Days 1, 8, and 15 in 28-day cycles; G arm: G as in GE. Biomarker expression was assessed by immunohistochemistry. Results Randomization totaled 130 patients (GE = 86, G = 44); 121 patients were treated (GE = 82, G = 39). GE/G median OS was 5.6/5.1 months; median PFS was 3.4/3.0 months. GE responses: 1 complete response (CR, 1.2%), 6 partial response (PR, 7.4%), and 33 stable disease (SD, 40.7%); disease control rate (DCR=CR+PR+SD, 49.4%). G responses: 2 PR (5.3%) and 16 SD (42.1%); DCR (47.4%). No QOL differences were noted between arms. GE/G Grade 3–4 toxicities included: neutropenia (18.3%/28.2%); thrombocytopenia (14.6%/25.6%); and fatigue (11.0%/7.7%). No statistically significant relationships between biomarker expression and outcomes were observed. However, patients with low expression of cytoplasmic pGSK-3β trended toward greater OS with GE treatment. Conclusions OS, PFS, QOL, and RR were comparable between arms. Adding E to G did not increase hematologic toxicities. GE does not warrant further investigation in unselected pancreatic cancer patients.

Purpose We previously reported that four cycles of docetaxel/cyclophosphamide (TC) produced superior disease-free survival (DFS) compared with four cycles of doxorubicin/cyclophosphamide (AC) in early breast cancer. Older women are under-represented in adjuvant chemotherapy trials. In our trial 16% of patients were ≥ 65 years. We now report 7-year results for DFS and overall survival (OS) as well as the impact of age, hormone receptor status, and HER2 status on outcome and toxicity. Patients and Methods Patients were randomly assigned to receive either four cycles of standard-dose AC (60/600 mg/m2; n = 510), or TC (75/600 mg/m2; n = 506), administered by intravenous infusion every 3 weeks. Results The median age in women younger than 65, was 50 years (range, 27 to 64) and for women ≥ 65 was 69 years (range, 65 to 77). Baseline characteristics in the two age subgroups were generally well matched, except that older women tended to have more lymph node involvement. At a median of 7 years follow-up, the difference in DFS between TC and AC was significant (81% TC v 75% AC; P = .033; hazard ratio [HR], 0.74; 95% CI 0.56 to 0.98) as was OS (87% TC v 82% AC; P = .032; HR, 0.69; 95% CI, 0.50 to 0.97). TC was superior in older patients as well as younger patients. There was no interaction of hormone-receptor status or HER-2 status and treatment. Older women experienced more febrile neutropenia with TC and more anemia with AC. Conclusion With longer follow-up, four cycles of TC was superior to standard AC (DFS and OS) and was a tolerable regimen in both older and younger patients.

This essay introduces or re-acquaints readers with the work of Wes Jackson and The Land Institute in Salinas, Kansas. At the center of this work is an effort to develop perennial poly-culture as an alternative to industrial agriculture. The latter dominant model of food and fiber production is shown to involve severe problems in terms of short-run ecological costs and long-run sustainability. It is also argued that the perennial poly-culture model has much to recommend it to radical economists as a corrective to capitalist inefficiency. Finally, notwithstanding Jackson's facile criticism of Marx, it is argued that Marx's own writing actually anticipates Jackson's agro-ecological critique of capitalism.

IntroductionWe undertook a phase II trial to assess the efficacy and safety of single-agent pemetrexed (P) in relapsed small-cell lung cancer (SCLC) patients.MethodsPatients had limited- or extensive-stage SCLC, performance status 0 to 2, and one prior chemotherapy regimen. Initial P dose was 500 mg/m2 every 21 days. Planned sample sizes were 36 sensitive (S) patients in a two-stage sequential fashion with early stopping rule, and 25 refractory (R) patients in a single-stage design without stopping rule. Patients received folic acid and Vitamin B12 prior to P, and B12 could be given up until P treatment. Primary outcome measure was response rate.ResultsEnrollment occurred from July 2004 to March 2006. The stopping rule was invoked when

XELIRI (capecitabine/irinotecan) is effective and well tolerated in metastatic colorectal cancer (mCRC). Cetuximab is active in mCRC alone or with chemotherapy. This study evaluated cetuximab plus XELIRI in first-line treatment of mCRC.Subjects had histologically confirmed unresectable colorectal adenocarcinoma (with T4 lesions) after preoperative chemoradiation and/or metastases. Treatment was capecitabine 1700 mg/m2 (850 mg/m2 orally twice a day on days 1-14 for 3 weeks), irinotecan 200 mg/m2 intravenously (I.V.) on day 1 every 3 weeks, and weekly cetuximab (initially 400 mg/m2 I.V. [120 minutes], subsequently 250 mg/m2 [30 minutes]).Baseline characteristics (N = 70): 43 men (61%); median age, 61.5 years; Eastern Cooperative Oncology Group performance status 0/1 = 66%/34%; 94% adenocarcinoma. Previous therapy: surgery (91%), chemotherapy (14%), or radiation therapy (7%). Responses (patients completingor = 2 cycles): complete response (5.7%), partial response (37.7%), stable disease (43.4%), and progressive disease (PD; 13.2%); 16 patients discontinued early (n = 4 allergic reaction, n = 2 withdrew consent, n = 2 death, and n = 8 other adverse events [AEs]). The overall per-protocol response rate was 43.4% (34% intent to treat [ITT]; disease control rate, 86.8%; 69% ITT). The median time to progression was 8.1 months (range,1-27.0 months), and the median time to response was 1.6 months (range, 1.1-8.4 months). The median survival was 20.5 months, and 45.7% of patients remain alive. Of the 38 deaths, 84% were because of PD. No death was treatment related. The most frequent grade 3/4 treatment-related AEs included diarrhea, neutropenia, and nausea/vomiting; 32% of patients required dose reductions. All patients are off the study primarily because of PD (34.3%) or AEs (40.0%).In summary, XELIRI plus cetuximab is a promising regimen that merits further study for first-line mCRC.

This paper examines the problems of public and institutional reforms within the context of a so‐called predatory state. The predatory state is one that acts in the interest of an elite rather than pursue a coherent strategy for economic development. The argument is that, even after the process of political transition is begun, important reforms are blocked by a lingering institutional overhang that continues to serve the predatory elite. We examine the experience of Paraguay that disposed of its dictator in 1989 and began a democratic transition. The failure to implement needed reforms is shown to have blocked a revival of economic growth and development.

Background Platinum-based chemotherapy is the standard treatment for advanced gastric cancer (GC). This trial explored the efficacy and tolerability of combined docetaxel (Taxotere) + oxaliplatin (DOCOX) in GC patients. Patients and methods Patients with untreated stage IV GC or adenocarcinoma of the gastroesophageal junction (AGEJ) received docetaxel 60 mg/m2 followed by oxaliplatin 130 mg/m2 on day 1 of each 21-day cycle until progression or unacceptable toxicity. The primary end points were response rate (RR), toxicity, progression-free survival (PFS), and overall survival (OS). Results Baseline characteristics (N = 71): median age 59 years, 72% male, 51% esophagogastric junction cancer, and Eastern Cooperative Oncology Group performance status of zero, one, two were 42%, 51%, 7%, respectively. The median number of cycles was 6 (range, 1–19). Grades 3–4 toxic effects: neutropenia (70%); vomiting (17%); nausea (16%); dehydration, fatigue, or diarrhea (13%, each); and thrombocytopenia or febrile neutropenia (7%, each). Sixty-six patients completed ≥2 cycles. The RR was 36% with 25 partial response (PR) and no complete responses (CRs); stable disease (SD) was 49%. Clinical benefit rate (CBR = CR + PR + SD ≥6 months) was 40%; median PFS was 4.3 months, and OS was 8.5 months. Conclusions DOCOX produced manageable toxicity in patients with advanced GC and AGEJ. The confirmed RR of 36%, CBR of 40%, and median survival of 8.5 months are encouraging and comparable to standard front-line regimens.

Purpose Hormonal breast cancer treatment increases menopausal symptoms in women. This study investigated differences between the symptoms associated with either adjuvant tamoxifen or exemestane. Patients and Methods Ten common symptoms were assessed by self-report questionnaire administered to 1,614 consecutive patients at baseline and every 3 months during the first year of a double-blind, randomized trial of postmenopausal women with early hormone receptor–positive breast cancer. Symptoms were categorized as none, mild, moderate, or severe. A hot flash score was calculated at each time point. Symptoms were analyzed by repeated-measures analysis of variance. Each time period was tested repeatedly against the baseline; an overall P value was assigned for each reported symptom. Results Compliance was excellent, with 7,286 questionnaires analyzed. Baseline symptom prevalence ranged from 2% (vaginal bleeding) to 60% to 70% (bone/muscle aches and low energy). There were no significant differences in vaginal bleeding, mood alteration, or low energy. Patients receiving tamoxifen had significantly more vaginal discharge (P < .0001). Exemestane patients reported more bone/muscle aches (P < .0001), vaginal dryness (P = .0004), and difficulty sleeping (P = .03). In both groups, the hot flash score peaked at 3 months and decreased thereafter. At 12 months, patients receiving tamoxifen had a significantly higher mean hot flash score (P = .03), with daily hot flashes increasing from baseline by 33% compared with a 7% increase from baseline with exemestane. Conclusion At 12 months, exemestane was associated with fewer hot flashes and less vaginal discharge than tamoxifen, but with more vaginal dryness, bone/muscle aches, and difficulty sleeping. Symptoms were common in both groups.

Gastric cancer is a major worldwide problem and is a leading cause of death. The incidence of distal gastric cancer is declining; however, there has been a rapid rise in the incidence of adenocarcinoma of the gastroesophageal junction, which is a more aggressive entity. Combination chemotherapy has significant activity in the treatment of both of these diseases, improving overall survival and quality of life. Despite these improvements, median survival remains at approximately 9 months in patients who are diagnosed at stage IV. This review examines recent advances in the treatment of gastroesophageal junction adenocarcinoma and gastric cancer, newer agents and the potential agents that are in development, which can be logically applied to the treatment of this devastating disease.

Meeting abstracts The majority of lung cancer in the U.S. is treated in the community. A prospective cohort study of stage IV NSCLC and extensive disease (ED) SCLC is being conducted in 70 U.S. community practices to assess outcomes during the pre- and post-immunotherapy eras of lung cancer

Purpose: To assess the safety and tolerability of the small-molecule allosteric MEK inhibitor refametinib combined with sorafenib, in patients with advanced solid malignancies. Experimental Design: This phase I dose-escalation study included an expansion phase at the maximum tolerated dose (MTD). Patients received refametinib/sorafenib twice daily for 28 days, from a dose of refametinib 5 mg plus sorafenib 200 mg to a dose of refametinib 50 mg plus sorafenib 400 mg. Plasma levels of refametinib, refametinib metabolite M17, and sorafenib were measured for pharmacokinetic assessments. Tumors were biopsied at the MTD for analysis of MEK pathway mutations and ERK phosphorylation. Results: Thirty-two patients were enrolled in the dose-escalation cohort. The MTD was refametinib 50 mg twice daily plus sorafenib 400 mg twice daily. The most common treatment-related toxicities were diarrhea and fatigue. Refametinib was readily absorbed following oral administration (plasma half-life of ∼16 hours at the MTD), and pharmacokinetic parameters displayed near-dose proportionality, with less than 2-fold accumulation after multiple dosing. Another 30 patients were enrolled in the MTD cohort; 19 had hepatocellular carcinoma. The combination was associated with significantly reduced ERK phosphorylation in 5 out of 6 patients biopsied, with the greatest reductions in those with KRAS or BRAF mutations. Disease was stabilized in approximately half of patients, and 1 patient with colorectal cancer achieved a partial response at the MTD lasting approximately 1 year. Conclusions: In this phase I study, refametinib plus sorafenib was well tolerated, with good oral absorption, near-dose proportionality, and target inhibition in a range of tumor types. Clin Cancer Res; 22(10); 2368–76. ©2015 AACR.

BACKGROUND: The objectives of this open-labeled, multicenter, phase II trial were to evaluate response, survival, and tolerability in patients at high risk (Eastern Cooperative Oncology Group performance status [PS] of 2 or age ≤ 70 years) with advanced-stage non–small-cell lung cancer (NSCLC) receiving single-agent paclitaxel poliglumex as first-line monotherapy. PATIENTS AND METHODS: Paclitaxel poliglumex was administered as a 10-20–minute infusion on day 1 of each 3-week cycle. Thirty patients were enrolled: 28 received paclitaxel poliglumex 175 mg/m 2 , and 2 received 235 mg/m 2 . Patients exhibiting a partial response (PR; by Response Evaluation Criteria in Solid Tumors) or stable disease (SD) continued uninterrupted treatment with paclitaxel poliglumex for=8 cycles. RESULTS: Neither patient treated at the 235 mg/m 2 dose was evaluable for response. The overall response rate was 7% (PR in 2 patients), and 16 patients (57%) experienced SD. Of the 20 patients with stage IV disease, 2 exhibited a PR, and 13 exhibited SD. Median duration of response in patients with SD or better was 9 weeks. Overall median survival was 6 months. Median survival for patients with a PS of 0/1 or 2 was 7.8 months and 5.7 months, respectively; median survival for patients aged ≤ 70 years was 7.8 months. No grade 4 nonhematologic toxicities were reported. Three patients experienced grade 3 neuropathy. Weekly hematologic assessments showed grade 3 anemia in 2 patients, grade 3 neutropenia (not associated with neutropenic fever) in 3 patients, and grade 4 neutropenia in 2 patients. No patient required growth factor support. CONCLUSION: The results of this study indicate that paclitaxel poliglumex is generally well tolerated and has activity at a dose level of 175 mg/m 2 as first-line monotherapy in patients at high risk with advanced NSCLC.

Major League Baseball currently faces a crisis calling for radical reform of its operations. This article critically examines two recent reform proposals that call for a luxury tax on team salaries combined with revenue sharing that would bring greater financial and competitive parity among and between the league’s constituent teams. It is argued that these reforms do not go far enough in reestablishing the basis for fan loyalty that is the essence of the national pastime. A far superior reform model would have the teams become the property of the municipalities in which they operate, combined with a reserve clause that ties players to particular teams for their playing careers. A predetermined salary structure would make player compensation a function of longevity rather than the market. Salary cost control, in turn, would enable teams to price tickets at levels that would enable more families of modest means to attend games.

Since the arrival of the World Trade Organization (WTO) in 1995 a number of side agreements have also been negotiated that seek further rationalization of the emerging global economy. Prominent among these is the agreement on trade‐related intellectual property rights (TRIPS). Enforcement of the TRIPS agreement would involve the multilateral trade sanctions mechanism of the WTO. By contrast, proponents advocating a parallel international agreement guaranteeing adequate protections for workers – trade‐related international labor standards (TRILS) – have not met with success. This paper examines how traditional justificatory arguments for the property rights might apply to the question of workers’ rights in the international economy. It is found that such arguments apply quite well to the right of access to a “decent living”. It is then investigated how a TRILS agreement administered and enforced by the WTO's disputes settlements mechanism might advance these rights.

Mass spectrometry plays a major role in the structural elucidation and characterisation of drug candidates and related substances. Accurate mass data allow the mathematical prediction of molecular formula of both precursor and fragment ions. In this paper, a comparison of the accurate mass data obtained for the fragmentation of fluconazole, an antifungal drug, by three different methods is made: electron ionisation (EI) using a magnetic sector instrument; electrospray ionisation (ES) using a Fourier transform ion cyclotron mass spectrometer (FTICRMS); and ES using a quadrupole-time-of-flight mass spectrometer (Q-ToF). It is clear from the data obtained that mass accuracy is not simply a function of instrument resolution. The subtle differences observed between collisionally activated dissociation (CAD) and sustained off-resonance collisionally activated dissociation (SORI-CAD) spectra are explained as a consequence of the excitation process. The advantages and disadvantages of the three techniques are discussed within the context of structural elucidation.

Since the arrival of the World Trade Organization (WTO) in 1995 a number of side agreements have also been negotiated that seek further rationalization of the emerging global economy. Prominent among these is the agreement on Trade-Related Intellectual Property Rights, or TRIPS. Enforcement of the TRIPS agreement would involve the multilateral trade sanctions mechanism of the WTO. This paper examines justificatory arguments for the defense of intellectual property rights in the international economy. These arguments are based on the "classic" philosophic writings of Locke, Hegel, and Bentham. It is found that these well-known philosophic defenses for exclusive property rights do not hold up well when applied to intellectual property.

8568 Background: Chemotherapy (chemo) has significant clinical utility, however consequent damage to hematopoietic stem and progenitor cells (HSPCs) and the immune system may limit activity. If chemo-mediated anti-tumor activity was maximized, while minimizing myelosuppression and immunosuppression, patient outcomes would be improved. Trilaciclib (T) is an intravenous CDK4/6 inhibitor in development to reduce myelosuppression and preserve immune system function during chemo. HSPCs are dependent on CDK4/6 for proliferation. Preclinical data demonstrated that transient T-induced G1 cell cycle arrest renders HSPCs resistant to chemo cytotoxicity, allowing faster hematopoietic recovery, preservation of long-term function, and enhancement of anti-tumor immunity and activity. Methods: Objectives of this ongoing multicenter Phase 1b/2a study are to assess dose limiting toxicities (DLTs), safety, tolerability, hematological profile, PK, and anti-tumor activity of T administered prior to EP. Phase 1b was open-label, dose-finding, and the ongoing Phase 2a is randomized (1:1), double-blind. Eligible pts had confirmed diagnosis of ES-SCLC, adequate organ function, ECOG PS 0-2, no prior chemo, and no symptomatic brain metastases. Results: 19 pts were enrolled in the Phase 1b: 10 pts received T 200 mg/m2 + EP and 9 pts received T 240 mg/m2 + EP. T + EP was well tolerated. 2 pts at T 200 mg/m2 and 1 pt at T 240 mg/m2 experienced asymptomatic DLTs in cycle 1. 2 pts (1 at each dose) had an ANC < 1500 on cycle 2 day 1, delaying the start of cycle 2, and 1 pt at the T 200 mg/m2dose had grade 4 thrombocytopenia. There were no cases of febrile neutropenia or bleeding. PK analysis showed no drug interactions between T and EP. 17/19 pts were evaluable: 1 pt had CR, 14 had PR (confirmed ORR = 88%); 1 pt had SD (clinical benefit rate = 94%). Conclusions: In the Phase 1b part of the study, T + EP was well tolerated. Early activity results are promising with a confirmed objective response rate of 88%. This novel approach allowing the administration of chemotherapy while preserving HSPC and immune system function could potentially improve treatment outcomes for SCLC pts. Clinical trial information: NCT02499770.

1047 Background: In the randomized, phase III MONALEESA-2 study (NCT01958021), first-line therapy with ribociclib (RIB; cyclin-dependent kinase 4/6 inhibitor; 600 mg/day; 3-weeks-on/1-week-off) + letrozole (LET; 2.5 mg/day) in postmenopausal women with HR+, HER2– ABC significantly prolonged progression-free survival vs placebo (PBO) + LET (hazard ratio: 0.556; p = 0.00000329; Hortobagyi GN et al. N Engl J Med 2016;375:1738–48). Here we present further safety analyses from MONALEESA-2. Methods: Adverse events (AEs) were characterized per CTCAE v4.03. Analyses of key AEs included time to first event, duration (time to AE resolution), and the rate of associated dose interruptions or reductions. Results: Safety analysis included 664 patients (pts; RIB + LET: 334; PBO + LET: 330). Neutropenia was the most common all-grade (G) and G3/4 AE in the RIB + LET arm (Table); febrile neutropenia rates were low (RIB + LET arm: 1.5%) with no associated deaths. Median time to first event for G ≥2 neutropenia in the RIB + LET arm (based on neutrophil counts) was 16 days. Other common G3/4 AEs (increased by ≥5% in the RIB + LET vs PBO + LET arm) were leukopenia (21% vs 1%), elevated alanine aminotransferase (ALT; 9% vs 1%), lymphopenia (7% vs 1%), and elevated aspartate aminotransferase (AST; 6% vs 1%). Neutropenia was the most common AE leading to dose interruptions/reductions; G3/4 neutropenia led to dose interruptions in 48% vs < 1% and reductions in 30% vs 0% of pts in the RIB + LET vs PBO + LET arm. 7.5% vs 2.1% of pts (RIB + LET vs PBO + LET) discontinued due to AEs; common AEs leading to discontinuation ( > 1% pts) were elevated ALT (5% vs < 1%), elevated AST (3% vs 1%), and vomiting (2% vs 0%). Conclusions: First-line RIB + LET had a manageable safety profile in postmenopausal women with HR+, HER2– ABC. Neutropenia was the most common AE in the RIB arm, and was transient and reversible with dose modifications. Additional AE analyses will be presented. Clinical trial information: NCT01958021. [Table: see text]

5548 Background: Napabucasin is a first-in-class cancer stemness inhibitor, identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al PNAS 112 (6):1839, 2015). Napabucasin has shown potent synergistic preclinical anti-tumor activity with paclitaxel (PTX). In a phase Ib dose escalation study in patients (pts) with advanced solid tumors, napabucasin plus weekly PTX was well tolerated. A phase II expansion cohort was opened for patients with platinum resistant ovarian cancer. Methods: Pts with advanced ovarian cancer who had disease progression either during or in the 6 months following platinum-based systemic therapy were enrolled. napabucasin was administered orally at a starting dose of 240, 480, or 500 mg twice daily with PTX 80 mg/m2 IV weekly on 3 of every 4 weeks. AEs were evaluated using CTCAE v4.03 and objective assessments were performed per RECIST 1.1 every 8 weeks. Results: A total of 98 pts were enrolled. The average number of prior lines of systemic treatment was 3.5, including prior taxane-based therapy in 100% of patients. Treatment was well tolerated. Related grade 3 adverse events occurring ≥ 5% of pts included diarrhea (12.2%) and vomiting (5.1%). Among pts who received RECIST evaluation (n = 76), the disease control rate (DCR, proportion with SD at 8 weeks + PR + CR) was 65%, and the objective response rate (ORR, PR+CR) was 20%, with complete response in 3 pts (4%). In all patients (ITT, n = 98), the median progression-free survival (mPFS) was 3.0 months and median overall survival (mOS) was 9.3 months. Conclusions: Clinical safety and encouraging signs of anti-cancer activity, including three complete responses, were observed in pts with pre-treated platinum resistant ovarian cancer who received treatment with napabucasin plus weekly PTX. Further clinical evaluation in controlled trials is warranted. Clinical trial information: NCT01325441.

4077 Background: Napabucasin, a first-in-class cancer stemness inhibitor in clinical development, suppresses cancer stemness by targeting STAT3-driven gene transcription. Amcasertib targets multiple serine threonine stemness kinases and inhibits Nanog and other cancer stemness pathways. Preclinically, potent and broad-spectrum anti-cancer activity was observed in vitro and in vivo, alone and in combination with sorafenib. Methods: A phase Ib/II open-label, multi-center study in adult patients with advanced HCC who have not received prior systemic chemotherapy was performed to determine the safety, tolerability, and recommended Phase II dose (RP2D) ,according to the criteria for DLT and for dose-escalation of Napabucasin (Arm 1), administered at 160 mg BID (dose level I) and at 240 mg BID (dose level II) in combination with sorafenib and of Amcasertib (Arm 2), administered at 100 mg QD (dose level I) and at 200 mg QD (dose level II) in combination with sorafenib. Results: 20 pts were enrolled, 10 in Arm 1 and 10 in Arm 2. 12 patients were evaluable for DLT determination; 2 pts d/c prior to starting protocol treatment; 11 pts received evaluation by RECIST, 6 pts in Arm 1 and 5 pts in Arm 2. The safety profile was consistent with that of each agent as monotherapy and most common AEs were attributed to (Sor) and included rash, PPE, grade 1/2 diarrhea, nausea, abdominal cramps, and vomiting. No signs of drug-drug interactions were observed in pharmacokinetics. Among all patients who received RECIST evaluation, Disease Control Rate (DCR=CR+PR+SD) for Arm 1 was 100% (6/6pts) and 100% (5/5pts) for Arm 2. DCR in ITT Arm 1 population was 67% and 50% in Arm 2. Median OS is not yet reached. Conclusions: In this phase Ib study, RP2D were determined for napabucasin and amcasertib to be safely combined with sorafenib at full dose, showing encouraging anti-tumor activity in patients with HCC who have not received prior systemic chemotherapy. A randomized phase II is schedule to start. Clinical trial information: NCD02279719. [Table: see text]

6032 Background: Amcasertib (BBI-503) is an oral first-in-class cancer stemness kinase inhibitor. By targeting multiple serine-threonine stemness kinases, amcasertib inhibits Nanog and other cancer stemness pathways. A phase I clinical trial of amcasertib showed safety and signs of anti-cancer activity in patients (pts) with advanced solid tumors during dose-escalation and RP2D expansion, including pts with advanced head & neck cancer. Methods: Pts with advanced, pre-treated head & neck cancers were enrolled. Amcasertib was administered orally, once or twice daily, in continuous 28-day cycles at a starting dose of 10 mg to 300 mg total daily. Adverse events were categorized according to CTCAE v4.03 and tumor imaging was evaluated per RECIST 1.1 guidelines every 8 weeks. Results: A total of 21 pts were enrolled, 15 with HNSCC and 6 with salivary or parotid gland cancers. Prior treatments included radiation in 90% (19/21), surgery in 71% (15/21) and prior systemic therapy in 90% (19/21, average 3 prior lines, range 1 to 6). Amcasertib was well tolerated with 43% of pts treated at 300 mg daily (n = 9), 33% at 150 mg BID (n = 7), 19% at 200 mg daily (n = 4), and 5% at 10 mg daily (n = 1). Grade 3 AE included diarrhea (n = 4) and nausea (n = 1). Among all patients who received an evaluation per RECIST (n = 16), the objective responses rate (ORR, proportion with partial response [PR] or complete response [CR] per RECIST) was 13% and the disease control rate (DCR, proportion with stable disease [SD] at 8 weeks, PR or CR) was 50%. At 12 months, in the intent-to-treat population (n = 21) 38% of pts were alive. Median overall survival (mOS) of 7.2 months. Conclusions: Clinical safety and encouraging signs of anti-cancer activity were observed in pts with advanced head and neck cancers who have received treatment with amcasertib. Objective response, prolonged disease control, and extended survival have been observed in this pre-treated population with a poor prognosis. Further clinical evaluation of amcasertib in patients with head and neck cancers is warranted. Clinical trial information: NCT01781455.

e15152 Background: Standard adjuvant therapy for colorectal cancer (CRC) is fluoropyrimidine or FOLFOX. The stage IIIC relapse rate is high with a median 5 year survival of only 28%. The multi-kinase inhibitor regorafenib has shown significantly improved overall survival (OS) versus placebo in 3rd-line+ metastatic CRC patients (pts) in 2 phase III trials. We explore whether adding regorafenib to standard adjuvant therapy is able to reduce the high relapse rates in stage IIIC CRC pts. Methods: This study compares efficacy and safety of adjuvant FOLFOX +/- 6 cycles of regorafenib in IIIC CRC pts. Study endpoints include: finding the starting dose of regorafenib that allows ≥75% pts to complete therapy after adjuvant FOLFOX. The first 50 pts are being randomly assigned to either 120 or 160 mg of regorafenib daily for 3 weeks followed by 1 week of rest for a total of 6 cycles. We report the initial safety results on the first 24 pts treated. 6 pts discontinued treatment; 2 received 120 mg and 4 received 160 mg Results: Of the pts completing 6 cycles of regorafenib 120 mg vs 160 mg, the most common grade 3 toxicities were hypertension (0 vs. 30%), rash (10 vs.30%), and lipase elevation (0 vs 10%). No grade 4 or 5 toxicities were observed. Conclusions: The interim analysis reveals no increased toxicities from the addition of regorafenib at either 120 mg or the approved dose (160 mg), to adjuvant FOLFOX. Toxicities observed were mostly grade 1 or 2 and medically manageable. No safety signals have been identified. This study continues to enroll pts. Clinical trial information: NCT02425683.

370 Background: The Phase 1 portion of a Phase 1/2 trial of Necuparanib (“Necu”) combined with nab-paclitaxel (nabP) + gemcitabine (gem) in patients with metastatic pancreatic cancer (ClinicalTrials.gov Identifier NCT01621243) showed acceptable safety and tolerability and encouraging signals of activity and established a dose for the randomized, placebo (PBO)-controlled Phase 2 portion. Methods: In Phase 2, patients received daily s.c. injections of either 5 mg/kg Necu daily or PBO, combined with i.v. 125 mg/m2 nabP and 1000 mg/m2 gem (Days 1, 8, 15 of each 28-day cycle). The primary endpoint was overall survival (OS); other endpoints included progression-free survival (PFS), response rates, safety, and CA19.9 levels. An interim futility analysis was conducted in July 2016 once 57 deaths (50% of the target number of 114 events required for trial completion) had occurred. Results: The analysis was conducted on data from 120 randomized patients (62 Necu, 58 PBO). The Z-score for futility was -0.42 (prespecified boundary of -0.148 was crossed as actual score was lower). Median OS was Necu = 10.71 and PBO = 9.99 months; hazard ratio (HR) = 1.12 (favoring PBO); OS curves were intertwined. PFS was Necu = 5.52 and PBO = 6.93 months; HR = 0.97. RECIST response rates were comparable between arms: complete response, Necu = 0%, PBO = 3%; partial response, Necu = 26%, PBO = 26%; stable disease, Necu = 31%, PBO = 34%; disease control rate, Necu = 56%, PBO = 64%. The most common Grade 3+ adverse events (AEs) were neutropenia (Necu = 33%, PBO = 33%), thrombocytopenia (Necu = 27%, PBO = 5%), and anemia (Necu = 22%, PBO = 11%). There were lower rate of serious AEs with Necu (48%) vs. PBO (60%). Modest increases in APTT, AST, and ALT were noted following Necu relative to PBO. 23% of Necu and 5% of PBO patients were IgG positive with an anti-heparin/PF4 antibody titer of ≥ 0.4 at any time. There were no treatment differences for decreases in CA19.9. Conclusions: No new safety signals were observed and the toxicity profile was considered manageable; however, Necu in combination with nabP and gem did not show a sufficient level of efficacy in metastatic pancreatic cancer to warrant continued enrollment. Clinical trial information: NCT01621243.

294 Background: CX-4945 is a first-in-class casein kinase-2 (CK2) threonine kinase small molecule inhibitor. CK2 is pleiotropic and regulates key cellular processes such as proliferation and DNA damage repair, and has been shown to enhance efficacy of gemcitabine (G) and cisplatin (C) in cell line and xenograft CCA model systems. A Phase IB study of G+C with CX-4945 was conducted in advanced cholangiocarcinoma (CCA) patients. Methods: A multi-center “3+3” dose escalation study was conducted in advanced CCA patients. Eligible patients had ECOG PS 0-1 and adequate hematologic, hepatic, and renal function. Primary endpoints were maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Secondary endpoints included pharmacokinetic (PK) analyses, overall toxicity evaluation and preliminary assessment of efficacy. Routine clinical dosing for G (1000 mg/m2) and C (25 mg/m2), both on days 1 and 8 every 21 days, was used. Dose escalation cohort were CX-4945 given twice daily on days 0,1,2 and 7,8,9 at 200 mg (DL1), 400mg (DL2), 600 mg (DL3), 800 mg (DL4) and 1000 (DL5) mg. NCI CTCAE v4.03 was used for toxicity assessment and RECIST v1.1 for efficacy evaluation. Results: Nineteen patients were enrolled (DL1:n = 3; DL2:n = 4 DL3:n = 3; DL4:n = 4; DL5:n = 5). No dose limiting toxicities were encountered. MTD and RP2D were ascertained to be DL5. No grade 3 or 4 toxicities at prevalence > 10% were encountered and the overall toxicity profile of the combination was reflective of standard G+C toxicity profile. At data cut-off, preliminary efficacy evaluation demonstrated disease control rate (CR+PR+SD) of 64% (PR:32%, SD:32% and CR:0%), along with median progression-free survival (PFS) of 5 months (range 0-14 months). PK analyses showed no evidence of drug-drug interactions between G, C and CX-4945. Conclusions: RP2D for G+C with CX-4945 is DL5 (CX-4945 dosed on days 0,1,2 and 7,8,9 at 1000 mg PO bid with standard G and C dosing). Preliminary clinical efficacy and tolerability of the regimen support planned controlled, randomized Phase 2 evaluation. Clinical trial information: NCT02128282.

Background This phase Ib study used a parallel, multi-arm design to examine tasisulam-sodium (hereafter tasisulam), a drug with complex pharmacology, combined with standard chemotherapies in patients with advanced solid tumors, with the ultimate goal of accelerating drug development. Methods Patients received escalating doses of tasisulam (3 + 3 schema; target Cmax 300–400 μg/mL) every 28 days plus 1,000 mg/m2 gemcitabine HCl (days 1 and 15), 60 mg/m2 docetaxel, 200 mg/m2/day temozolomide, 75 mg/m2 cisplatin, or 150 mg/day erlotinib. Following dose-escalation, patients were enrolled into specific tumor subtype arms, chosen based on the established activity of the standard agent. Because tasisulam is highly albumin-bound, patients in the tumor-specific confirmation arms were dosed targeting specific albumin-corrected exposure ranges (AUCalb) identified during dose-escalation (3,500 h*μg/mL [75th percentile] for docetaxel, temozolomide, and cisplatin; 4,000 h*μg/mL for gemcitabine and erlotinib). Results A total of 234 patients were enrolled. The safety profile of tasisulam with standard chemotherapies was sufficient to allow enrollment into the dose-confirmation phase in all arms. The primary dose-limiting toxicities were hematologic (thrombocytopenia and neutropenia). The most common grade ≥3 drug-related treatment-emergent adverse event was neutropenia, with the highest incidence in the docetaxel arm. Conclusions The multi-arm design allowed the efficient determination of the maximum tolerated dose of tasisulam across multiple combinations, and a preliminary characterization of pharmacokinetics, safety, and potential efficacy. Although enrollment into all planned groups was not completed due to termination of compound development, these data support the feasibility of this approach for accelerated cancer drug development, even for drugs with complex pharmacology.

Transforming growth factor β (TGF-β) plays an important role in cancer. Monoclonal antibodies (mAb) designed to specifically block the TGF-β ligands, are expected to inhibit tumor progression in patients with metastatic cancer. TβM1 is a humanized mAb optimized for neutralizing activity against TGF-β1. The objective of this clinical trial was to assess the safety and tolerability of TβM1 in patients with metastatic cancer. In this phase I, uncontrolled, non-randomized, dose-escalation study, 18 eligible adult patients who had measurable disease per RECIST and a performance status of ≤ 2 on the ECOG scale were administered TβM1 intravenously over 10 min at doses of 20, 60, 120 and 240 mg on day 1 of each 28-day cycle. Safety was assessed by adverse events (as defined by CTCAE version 3.0) and possible relationship to study drug, dose-limiting toxicities and laboratory changes. Systemic drug exposure and pharmacodynamic (PD) parameters were assessed. TβM1 was safe when administered once monthly. The pharmacokinetic (PK) profile was consistent with a mAb with a mean elimination half-life approximately 9 days. Although anticipated changes in PD markers such as serum VEGF, bFGF and mRNA expression of SMAD7 were observed in whole-blood, suggesting activity of TβM1 on the targeted pathway, these changes were not consistent to represent a PD effect. Additionally, despite the presence of an activated TGF-β1 expression signature in patients' whole blood, the short dosing duration did not translate into significant antitumor effect in the small number of patients investigated in this study.

This paper reviews recent Latin American presidential elections as a means of examining the quality of democracy in the region. Its principal hypothesis is that, notwithstanding the claims of mainstream analysis, the (re)introduction of formal democratic procedure has not represented a meaningful advance in authentic, broad-based political and economic enfranchisement of the region's working class and peasant majorities. In many cases the so-called democratic transition has merely disguised the adaption of previously authoritarian mechanisms of social control.

This paper empirically examines the proposition that levels of social welfare are related to a country's ability to provide itself with quasi-public goods. It also argues that less developed countries in recent years have been forced to reduce public spending on such goods as a result of the need to service external debt obligations. The result for these countries then is a reduction in broad-based social welfare.

This work describes the origins of Mercosur, South America's regional integration project. It examines issues to be tackled regarding the trade bloc's expansion, its transition from a customs union to a common market, and its relations with other trade groups such as the EU and the USA.

Active gibberellins (GAs) are endogenous factors that regulate plant growth and development in a dose-dependent fashion. Mutant plants that are GA deficient, or exhibit reduced GA responses, display a characteristic dwarf phenotype. Extragenic suppressor analysis has resulted in the isolation of Arabidopsis mutations, which partially suppress the dwarf phenotype conferred by GA deficiency and reduced GA-response mutations. Here we describe detailed studies of the effects of two of these suppressors,spy-7 and gar2–1, on several different GA-responsive growth processes (seed germination, vegetative growth, stem elongation, chlorophyll accumulation, and flowering) and on the in planta amounts of active and inactive GA species. The results of these experiments show that spy-7 and gar2–1affect the GA dose-response relationship for a wide range of GA responses and suggest that all GA-regulated processes are controlled through a negatively acting GA-signaling pathway.

In a recent book entitled Pop Internationalism Paul Krugman takes to task several prominent commentators who in recent years have published works decrying the loss of competitive position of the United States in an increasingly global economy. In particular, Krugman critically considers and rejects several arguments that he considers both wrong and dangerous. Among these are (1) the United States has lost, or is in the process of losing, its position of global technological leadership; (2) material standards of living in the US are threatened by the country's excessively liberal trade policies as compared with its trade partners; (3) stagnant or declining wages in the US are the result of trade with low wage Third World countries; (4) the US is in need of a new model and a corresponding policy approach that recognizes the changing structure of new global economic forces. The debate over the validity of the above assertions has been largely conducted between adherents of mainstream interpretations of inter...

The decade of the 1980s saw profound changes in the political economy of Latin America. The stabilisation and debt crises forced many countries in the region to re-examine their economic policies individually as well as collectively. The consequence was both a movement in the direction of neoliberal reform that included an emphasis on export promotion as well as a revival of interest in regional integration. The specific purpose of the present paper is to examine the consequences of these changes for the structure of intra-regional trade among and between Latin American countries. More specifically, we are interested in assessing the region's performance in terms of intra-regional, intra-industry trade over the period 1980–90.

The purpose of this research is to examine some competing assumptions regarding the hiring behaviour of major league baseball clubs. One hypothesis is that owners and general managers of teams enter the free agent market with a view to attracting the best talent available in order to win games. We might refer to this as the ‘win games’ strategy. A potentially alternative view is that they compete in this market for marquee players who will attract paying customers to the ball park. We can refer to this as the ‘fannies-in-the-seats’, or revenue, strategy. While these hypotheses are not necessarily inconsistent, we can imagine that for some teams, at some times, they are alternative approaches to hiring behaviour. A team committed to the ‘win games’ strategy may attempt to spread its resources in order to hire as many good players as possible without necessarily hiring elite players. A team committed to the revenue strategy may be content to surround a superstar with second rate talent. In order to test the...

Gibberellins (GAs) are tetracyclic diterpenoid growth factors that are essential regulators of stem elongation and other plant developmental processes (Hooley 1994; Swain and Olszewski 1996). GA-related mutants have been identified in several plant species, including Arabidopsis (Ross 1994). GA-deficient Arabidopsis mutants display characteristic phenotypes, including dark green leaves and a dwarf growth habit attributable to reduced stem elongation (Koornneef and van der Veen 1980; Talon et al. 1990a; Sun and Kamiya 1994; Peng and Harberd 1997). gai is a semidominant mutation of Arabidopsis, which also confers a dark green, dwarf phenotype (Koornneef et al. 1985; Peng and Harberd 1993, 1997; Wilson and Somerville 1995). The gai mutation affects GA reception or subsequent signal transduction, and does not result in GA deficiency (Koornneef et al. 1985; Talon et al. 1990b; Wilson et al. 1992; Peng and Harberd 1993; Wilson and Somerville 1995). Dominant mutations conferring visible phenotypes resembling those attributable to GA deficiency are also known in other plants, including maize (D8 allelic series; Harberd and Freeling 1989; Winkler and Freeling 1994) and wheat (Rht homeoallelic series; Gale et al. 1975). Previous genetic and physiological analyses of gai, D8, and Rht indicate that all are gain-of-function mutations (Gale et al. 1975; Harberd and Freeling 1989; Peng and Harberd 1993; Winkler and Freeling 1994; Wilson and Somerville 1995) conferring reduced GA responses and increased endogenous GA levels (Lenton et al. 1987; Fujioka et al. 1988; Talon et al. 1990b). The increased endogenous GA levels found in gai, D8, and Rht mutants are likely to arise through perturbation of the feedback control mechanisms by which GAs regulate in planta GA levels negatively (Croker et al. 1990; Chiang et al. 1995; Phillips et al. 1995; Xu et al. 1995). These dominant GA-response mutations are of considerable agricultural significance. The Rht mutations are especially important because they are the genetic basis of the high-yielding, semi-dwarf wheat varieties of the “green revolution” (Gale and Youssefian 1985). We cloned GAI to enhance our understanding of the mechanisms of GA signal transduction, and because of the potential use for gai in crop improvement. Previous experiments had identified a T-DNA insertion, genetically linked to GAI, which contained a Ds transposable element (Peng and Harberd 1993). This Ds was used to clone GAI through targeted insertional mutagenesis. Comparison of GAI and gai DNA sequences shows that the predicted mutant protein (gai) lacks a short (17-amino-acid) segment of the GAI protein sequence. We propose that this structural alteration is responsible for the dominant, gain-of-function properties of gai. In addition, presumed null alleles of GAI confer increased resistance to the growth-retarding effects of paclobutrazol (PAC), an inhibitor of GA biosynthesis. These observations suggest the following hypotheses to explain the role of GAI in GA signaling. First, GAI is proposed to be a negative regulator that represses GA responses but whose activity is opposed by GA. Second, gai is proposed to be a mutant repressor that is relatively resistant to the effects of GA and, therefore, maintains repression irrespective of the presence of GA. Several recent publications have described extragenic mutations that suppress the phenotype conferred by gai (Carol et al. 1995; Wilson and Somerville 1995; Jacobsen et al. 1996) or by GA deficiency mutations (Jacobsen and Olszewski 1993; Silverstone et al. 1997). Here we extend the analysis of the phenotypes conferred by two of these suppressors (spy-7 and gar2-1). First, we compare the effects of spy-7 and gar2-1 (alone and in combination) on the growth of and PAC resistance of plants containing gai. We have also investigated the effects of spy-7 and gar2-1 on the regulation of GA biosynthesis, by comparing the steady-state levels of gene transcripts encoding GA C-20 oxidase, the enzyme that catalyzes the penultimate step in the synthesis of biologically active GAs (Phillips et al. 1995; Xu et al. 1995). Finally, we have investigated the effects of spy-7 and gar2-1 on steady-state levels of gai transcripts. The results of the above experiments indicate that GAI, SPY, and GAR2 operate within, or modulate, a signal-transduction pathway that represses growth and whose activity is opposed by GA. Because of the existence of mutations having comparable effects to gai and spy in other plant species (Swain and Olszewski 1996), and because GA is an essential growth regulator in a wide variety of plant species (Hooley 1994), it seems likely that the Arabidopsis GAI, SPY, and GAR2 genes define a system for GA-mediated growth regulation that is common to all higher plants.

The cycle of various economic stabilisation efforts in Argentina during the 1980s has often been characterised as reflecting either policy confusion on the part of officials or their unwillingness to depart from an obsolete model of economic development. Hence, according to some, the alternation between orthodox and heterodox policy approaches has revealed an absence of either economic policy wisdom or political conviction. Less attention has been paid to the underlying real class‐based conflict for income that has manifested itself in terms of high rates of inflation and, at times, hyperinflation. Interpreting the issue from this perspective allows us to appreciate the essential continuity of the process of neo‐liberal reform of the Argentine political economy that commenced with the post‐Peronist military coup in 1976 and has more recently culminated with the rise of the nominally Peronist regime of Carlos Menem.

On May 26, 1991, the heads of state of Argentina, Brazil, Paraguay, and Uruguay met in the Paraguayan capital to sign the Treaty of Asuncion establishing the MERCOSUR-Latin America's latest formal attempt at regional economic cooperation and integration.' The Treaty of Asuncion provided for the gradual reduction of tariff and nontariff barriers among and between the member countries and their elimination by December 31, 1994, thereby creating a free-trade area. Moreover, the agreement envisioned the eventual creation of a full-blown common market embodying formal plans and agreements on the promotion of intraregional investment, joint ventures, intraregional mobility of labor, and regional macroeconomic stabilization. The purpose of this article is to examine the political-economic context in which the MERCOSUR has evolved to date so as to come to an understanding of its specific historical motivation, its objectives, and its likely consequences. The primary thesis of the article is that rather than representing an autonomous attempt on the part of the Southern Cone countries to create conditions for balanced and equitable development of their economies and cultures, the MERCOSUR serves the function of more thoroughly incorporating them within the world capitalist system while preserving their subordinate status in that system.2 Secondarily, the MERCOSUR potentially serves to provide the United States with a mechanism to recover its hegemonic position in the regional economy of the Southern Cone-a position that during the 1980s became increasingly uncertain.

Proponents of neo-liberal reform have pointed to a number of ‘success' stories in Latin America as models of the correct road to stable growth and development. Examining the component parts of the reform packages, the article offers a new interpretation of neo-liberalization in Latin America, arguing that from the perspective of the majority of the urban working class and rural peasantry neo-liberalism has had decidedly adverse consequences. In doing so, it calls into question the accuracy of academic and journalistic interpretations of Latin American neo-liberalism.