Ten-Year Outcome of Neoadjuvant Chemoradiotherapy Plus Surgery for Esophageal Cancer:The Randomized Controlled CROSS Trial

PURPOSE: Preoperative chemoradiotherapy according to the chemoradiotherapy for esophageal cancer followed by surgery study (CROSS) has become a standard of care for patients with locally advanced resectable esophageal or junctional cancer. We aimed to assess long-term outcome of this regimen. METHODS: From 2004 through 2008, we randomly assigned 366 patients to either five weekly cycles of carboplatin and paclitaxel with concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week) followed by surgery, or surgery alone. Follow-up data were collected through 2018. Cox regression analyses were performed to compare overall survival, cause-specific survival, and risks of locoregional and distant relapse. The effect of neoadjuvant chemoradiotherapy beyond 5 years of follow-up was tested with time-dependent Cox regression and landmark analyses. RESULTS: The median follow-up was 147 months (interquartile range, 134-157). Patients receiving neoadjuvant chemoradiotherapy had better overall survival (hazard ratio [HR], 0.70; 95% CI, 0.55 to 0.89). The effect of neoadjuvant chemoradiotherapy on overall survival was not time-dependent (P value for interaction, P = .73), and landmark analyses suggested a stable effect on overall survival up to 10 years of follow-up. The absolute 10-year overall survival benefit was 13% (38% v 25%). Neoadjuvant chemoradiotherapy reduced risk of death from esophageal cancer (HR, 0.60; 95% CI, 0.46 to 0.80). Death from other causes was similar between study arms (HR, 1.17; 95% CI, 0.68 to 1.99). Although a clear effect on isolated locoregional (HR, 0.40; 95% CI, 0.21 to 0.72) and synchronous locoregional plus distant relapse (HR, 0.43; 95% CI, 0.26 to 0.72) persisted, isolated distant relapse was comparable (HR, 0.76; 95% CI, 0.52 to 1.13). CONCLUSION: The overall survival benefit of patients with locally advanced resectable esophageal or junctional cancer who receive preoperative chemoradiotherapy according to CROSS persists for at least 10 years

The GATA-factor elt-2 is essential for formation of the Caenorhabditis elegans intestine

AbstractThe Caenorhabditis elegans elt-2 gene encodes a single-finger GATA factor, previously cloned by virtue of its binding to a tandem pair of GATA sites that control the gut-specific ges-1 esterase gene. In the present paper, we show that elt-2 expression is completely gut specific, beginning when the embryonic gut has only two cells (one cell cycle prior to ges-1 expression) and continuing in every cell of the gut throughout the life of the worm. When elt-2 is expressed ectopically using a transgenic heat-shock construct, the endogenous ges-1 gene is now expressed in most if not all cells of the embryo; several other gut markers (including a transgenic elt-2-promoter: lacZ reporter construct designed to test for elt-2 autoregulation) are also expressed ectopically in the same experiment. These effects are specific in that two other C. elegans GATA factors (elt-1 and elt-3) do not cause ectopic gut gene expression. An imprecise transposon excision was identified that removes the entire elt-2 coding region. Homozygous elt-2 null mutants die at the L1 larval stage with an apparent malformation or degeneration of gut cells. Although the loss of elt-2 function has major consequences for later gut morphogenesis and function, mutant embryos still express ges-1. We suggest that elt-2 is part of a redundant network of genes that controls embryonic gut development; other factors may be able to compensate for elt-2 loss in the earlier stages of gut development but not in later stages. We discuss whether elements of this regulatory network may be conserved in all metazoa

Bryan in History: Liberal, Celebrity, Social Gospeler

Sometimes, a great speech can obscure the larger significance of the man who makes it. On the afternoon of July 9, 1896, William Jennings Bryan stepped up to the podium at the Democratic convention in Chicago and secured his spot in the headlines of history. \u27Having behind us the producing masses of this nation and the world, supported by the commercial interests, the laboring interests, and the toilers everywhere,\u27 he declared, before raising his hands to his temples and stretching his fingers out along his forehead for the penultimate phrase, \u27we will answer their demand for a gold standard by saying to them: You shall not press down upon the brow of labor this crown of thorns, you shall not crucify mankind upon a cross of gold.\u27 As he spoke the final words, Bryan stunned the crowd with an inspired gesture of melodrama. He stepped back from the podium, pulled his hands away from his brow, and extended them straight out from his body-and held the Christlike pose for perhaps five seconds. The speech thrilled the huge crowd packed into the sweltering Chicago Coliseum and helped convince the delegates to award him the presidential nomination. Yet, it was not enough to lift the 36-year-old former congressman from Nebraska into the White House against William McKinley, the well-financed candidate of the GOP. In 1900 and 1908, the Democrats again nominated Bryan for the presidency. He did not come close to victory on either occasion. Republicans dominated the big industrial states which made for a sturdy majority in the Electoral College. The Cross of Gold speech thus looms in popular memory as the high-point of Bryan\u27s political life. But that oratorical triumph was just the overture to a long and influential career in both national politics and American culture. Bryan helped change U.S. society in three significant ways. First, he was a progressive reformer, the pivotal figure in transforming the Democrats from the more conservative of the two major parties into the more liberal one-particularly on using federal power to (1) aid small farmers and wage-earners and (2) to strictly regulate large corporations. Second, Bryan was a celebrity politician and a new type of campaigner. He was the first major-party presidential nominee to travel around the country throughout the whole campaign. Further, he kept speaking for the next thirty years before huge audiences at every possible venue and in nations around the world. This oratorical career made Bryan a small fortune and won him the admiration, as well as the love, of millions of Americans. Finally, Bryan was a grassroots exponent of the Social Gospel. In and out of election campaigns, he preached that progressive politics and altruistic religion should complement one another. For Bryan, the only true Christianity was what he called applied Christianity, which meant using one\u27s faith in Jesus and in Scripture to denounce the big industrialists and financiers he believed were exploiting the meek. It did not matter to him whether an individual magnate was himself a pious Christian. Commenting on John D. Rockefeller, a devout Baptist who helped finance the building of churches, Bryan wrote, It is not necessary that all Christian people shall sanction the Rockefeller method of making money merely because Rockefeller prays. Bryan\u27s faith also led him to hate war, and he spoke frequently under the auspices of the peace movement. Bryan was a national leader of his party until his death in 1925- long after he had stopped running for president. In critical ways, Woodrow Wilson, Franklin D. Roosevelt, Harry S. Truman, John F. Kennedy, Lyndon B. Johnson, and Bill Clinton all stood on the shoulders of this three-time loser with the resonant voice and inspirational stagecraft

10-year Outcome of a Randomized Trial Comparing Neoadjuvant Chemoradiotherapy and Surgery with Surgery Alone for Esophageal Cancer (CROSS trial)

Background: Neoadjuvant chemoradiotherapy according to the Chemo-Radiotherapy for Oesophageal cancer followed by Surgery Study (CROSS)has become a standard of care for patients with locally advanced resectableesophageal or junctional cancer. However, the long-term benefits andharms remain unclear.We aimed to assess the long-term outcomes of thisregimen.Materials and Methods: From 2004 through 2008, 366 patients wererandomly assigned to either five weekly cycles of intravenous carboplatin(area under the curve of 2 mg/mL/min) and paclitaxel (50 mg/m2 bodysurfacearea) on days 1, 8,15, 22, and 29 with concurrent radiotherapy (41.4Gy in 23 fractions, 5 days per week) followed by surgery, or surgery alone.Follow-up data were collected through 2018. Overall survival was estimatedwith the Kaplan-Meier method and compared with Cox regressionanalyses. The effect beyond 5 years of follow-up was assessed by usinglandmark analyses. Also, cause-specific mortality was estimated with cumulativeincidence functions and compared with Cox regression.Results: The median follow-up was 147 months (IQR 134-157). Patientswho received neoadjuvant chemoradiotherapy had better overall survival(HR 0.70, 95%CI 0.55-0.89), with 10-year overall survival of 38% (95%CI 31-45) in the neoadjuvant chemoradiotherapy plus surgery arm and 25% (95%CI 19-32) in the surgery alone arm. Landmark analyses showed that theoverall survival benefit that was gained in the first 5 years, persistedbeyond 5 years. The risk of death from esophageal cancer was lower forpatients who received neoadjuvant chemoradiotherapy plus surgery (HR0.60, 95% CI 0.46-0.80), while death from other causes was comparablebetween both study arms (HR 1.17, 95%CI 0.68-1.99).Conclusions: The overall survival benefit of patients with locally advancedresectable esophageal or esophagogastric junctional cancer who receivedneoadjuvant chemoradiotherapy plus surgery according to the CROSSregimen persists for at least 10 years, compared with surgery alone