The first comprehensive biography of Elihu Palmer tells
the life story of a freethinker who was at the heart of the early
United States' protracted contest over religious freedom and free
speech.
...When the United States was new, a lapsed minister named Elihu
Palmer shared with his fellow Americans the radical idea that
virtue required no religious foundation. A better source for
morality, he said, could be found in the natural world: the
interconnected web of life that inspired compassion for all living
things. Religions that deny these universal connections should be
discarded, he insisted. For this, his Christian critics denounced
him as a heretic whose ideas endangered the country.
Although his publications and speaking tours made him one of the
most infamous American freethinkers in his day, Elihu Palmer has
been largely forgotten. No cache of his personal papers exists and
his book has been long out of print. Yet his story merits telling,
Kirsten Fischer argues, and not only for the dramatic account of a
man who lost his eyesight before the age of thirty and still became
a book author, newspaper editor, and itinerant public speaker. Even
more intriguing is his encounter with a cosmology that envisioned
the universe as interconnected, alive with sensation, and
everywhere infused with a divine life force.
Palmer's "heresy" tested the nation's recently proclaimed
commitment to freedom of religion and of speech. In this he was not
alone. Fischer reveals that Palmer engaged in person and in print
with an array of freethinkers-some famous, others now obscure. The
flourishing of diverse religious opinion struck some of his
contemporaries as foundational to a healthy democracy while others
believed that only a strong Christian faith could support
democratic self-governance. This first comprehensive biography of
Palmer draws on extensive archival research to tell the life story
of a freethinker who was at the heart of the new nation's
protracted contest over religious freedom and free speech-a debate
that continues to resonate today.
The first comprehensive biography of Elihu Palmer tells the life story of a freethinker who was at the heart of the early United States' protracted contest over religious freedom and free speech. ...When the United States was new, a lapsed minister named Elihu Palmer shared with his fellow Americans the radical idea that virtue required no religious foundation. A better source for morality, he said, could be found in the natural world: the interconnected web of life that inspired compassion for all living things. Religions that deny these universal connections should be discarded, he insisted. For this, his Christian critics denounced him as a heretic whose ideas endangered the country.Although his publications and speaking tours made him one of the most infamous American freethinkers in his day, Elihu Palmer has been largely forgotten. No cache of his personal papers exists and his book has been long out of print. Yet his story merits telling, Kirsten Fischer argues, and not only for the dramatic account of a man who lost his eyesight before the age of thirty and still became a book author, newspaper editor, and itinerant public speaker. Even more intriguing is his encounter with a cosmology that envisioned the universe as interconnected, alive with sensation, and everywhere infused with a divine life force.Palmer's "heresy" tested the nation's recently proclaimed commitment to freedom of religion and of speech. In this he was not alone. Fischer reveals that Palmer engaged in person and in print with an array of freethinkers—some famous, others now obscure. The flourishing of diverse religious opinion struck some of his contemporaries as foundational to a healthy democracy while others believed that only a strong Christian faith could support democratic self-governance. This first comprehensive biography of Palmer draws on extensive archival research to tell the life story of a freethinker who was at the heart of the new nation's protracted contest over religious freedom and free speech—a debate that continues to resonate today.
Summary Background Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab is the standard therapy for physically fit patients with advanced chronic lymphocytic leukaemia. This ...international phase 3 study compared the efficacy and tolerance of the standard therapy with a potentially less toxic combination consisting of bendamustine and rituximab. Methods Treatment-naive fit patients with chronic lymphocytic leukaemia (aged 33–81 years) without del(17p) were enrolled after undergoing a central screening process. Patients were randomly assigned (1:1) with a computer-generated randomisation list using randomly permuted blocks with a block size of eight and were stratified according to participating country and Binet stage. Patients were allocated to receive six cycles of intravenous fludarabine (25 mg/m2 per day) and cyclophosphamide (250 mg/m2 per day) for the first 3 days or to intravenous bendamustine (90 mg/m2 per day) for the first 2 days of each cycle. Rituximab 375 mg/m2 was given intravenously in both groups on day 0 of cycle 1 and subsequently was given at 500 mg/m2 during the next five cycles on day 1. The primary endpoint was progression-free survival with the objective to assess non-inferiority of bendamustine and rituximab to the standard therapy. We aimed to show that the 2-year progression-free survival with bendamustine and rituximab was not 67·5% or less with a corresponding non-inferiority margin of 1·388 for the hazard ratio (HR) based on the 90·4% CI. The final analysis was done by intention to treat. The study is registered with ClinicalTrials.gov , number NCT%2000769522. Findings 688 patients were recruited between Oct 2, 2008, and July 11, 2011, of which 564 patients who met inclusion criteria were randomly assigned. 561 patients were included in the intention-to-treat population: 282 patients in the fludarabine, cyclophosphamide, and rituximab group and 279 in the bendamustine and rituximab group. After a median observation time of 37·1 months (IQR 31·0–45·5) median progression-free survival was 41·7 months (95% CI 34·9–45·3) with bendamustine and rituximab and 55·2 months (95% CI not evaluable) with fludarabine, cyclophosphamide, and rituximab (HR 1·643, 90·4% CI 1·308–2·064). As the upper limit of the 90·4% CI was greater than 1·388 the null hypothesis for the corresponding non-inferiority hypothesis was not rejected. Severe neutropenia and infections were more frequently observed with fludarabine, cyclophosphamide, and rituximab (235 84% of 279 vs 164 59% of 278, and 109 39% vs 69 25%, respectively) during the study. The increased frequency of infectious complications with fludarabine, cyclophosphamide, and rituximab was more pronounced in patients older than 65 years. Interpretation The combination of fludarabine, cyclophosphamide, and rituximab remains the standard front-line therapy in fit patients with chronic lymphocytic leukaemia, but bendamustine and rituximab is associated with less toxic effects. Funding Roche Pharma AG, Mundipharma, German Federal Ministry of Education and Research.
For more than a decade, the New York–based freethinker Elihu Palmer (1764–1806) lectured and wrote on “vitalism,” the idea that a divine life force inheres in the tiny particles of matter that ...comprise everything in the universe. The idea was transformative, Palmer believed. When people recognize that all creatures are made of the same eternal and divinely propelled particles, they will radically change their behavior toward all living things. Palmer was a minister by training who never left the United States. Where did he learn about a vital power infusing all matter? Three men inspired him: Dr. Isaac Ledyard of Long Island, who first introduced Palmer to a vitalist cosmology; John “Walking” Stewart, an eccentric Englishman who persuaded Palmer that atoms register and remember pain; and comte de Volney, a French philosophe attached to the idea of a life force in matter. Fully persuaded, Palmer made it his life's work to undermine all “religious superstition” and spread the good news of vital matter in eternal motion. He believed vitalism would naturally evoke a “universal benevolence” that would in turn end all oppression, making vitalism, in his view, the most radically egalitarian philosophy in the early Republic.
To determine the clinical significance of flow cytometric minimal residual disease (MRD) quantification in chronic lymphocytic leukemia (CLL) in addition to pretherapeutic risk factors and to compare ...the prognostic impact of MRD between the arms of the German CLL Study Group CLL8 trial.
MRD levels were prospectively quantified in 1,775 blood and bone marrow samples from 493 patients randomly assigned to receive fludarabine and cyclophosphamide (FC) or FC plus rituximab (FCR). Patients were categorized by MRD into low- (< 10(-4)), intermediate- (≥ 10(-4) to <10(-2)), and high-level (≥ 10(-2)) groups.
Low MRD levels during and after therapy were associated with longer progression-free survival (PFS) and overall survival (OS; P < .0001). Median PFS is estimated at 68.7, 40.5, and 15.4 months for low, intermediate, and high MRD levels, respectively, when assessed 2 months after therapy. Compared with patients with low MRD, greater risks of disease progression were associated with intermediate and high MRD levels (hazard ratios, 2.49 and 14.7, respectively; both P < .0001). Median OS was 48.4 months in patients with high MRD and was not reached for lower MRD levels. MRD remained predictive for OS and PFS in multivariate analyses that included the most important pretherapeutic risk markers in CLL. PFS and OS did not differ between treatment arms within each MRD category. However, FCR induced low MRD levels more frequently than FC.
MRD levels independently predict OS and PFS in CLL. Therefore, MRD quantification might serve as a surrogate marker to assess treatment efficacy in randomized trials before clinical end points can be evaluated.
Almost one-third of all patients with chronic lymphocytic leukemia (CLL) express stereotyped B cell receptor immunoglobulins (BcR IG) and can be assigned to distinct subsets, each with a particular ...BcR IG. The largest stereotyped subsets are #1, #2, #4 and #8, associated with specific clinicobiological characteristics and outcomes in retrospective studies. We assessed the associations and prognostic value of these BcR IG in prospective multicenter clinical trials reflective of two different clinical situations: i) early-stage patients (watch-and-wait arm of the CLL1 trial) (n=592); ii) patients in need of treatment, enrolled in 3 phase III trials (CLL8, CLL10, CLL11), treated with different chemo-immunotherapies (n=1861). Subset #1 was associated with del(11q), higher CLL international prognostic index (CLL-IPI) scores and similar clinical course to CLL with unmutated immunoglobulin heavy variable (IGHV) genes (U-CLL) in both early and advanced stage groups. IGHV-mutated (M-CLL) subset #2 cases had shorter time-to-first-treatment (TTFT) versus other M-CLL cases in the early-stage cohort (HR: 4.2, CI: 2-8.6, p<0.001), and shorter time-to-next-treatment (TTNT) in the advanced-stage cohort (HR: 2, CI: 1.2-3.3, p=0.005). M-CLL subset #4 was associated with lower CLL-IPI scores and younger age at diagnosis; in both cohorts, these patients showed a trend towards better outcomes versus other M-CLL. U-CLL subset #8 was associated with trisomy 12. Overall, this study shows that major stereotyped subsets have distinctive characteristics. For the first time in prospective multicenter clinical trials, subset # 2 appeared as an independent prognostic factor for earlier TTFT and TTNT and should be proposed for risk stratification of patients.
Data on long-term outcomes and biological drivers associated with depth of remission after BCL2 inhibition by venetoclax in the treatment of chronic lymphocytic leukemia (CLL) are limited. In this ...open-label parallel-group phase-3 study, 432 patients with previously untreated CLL were randomized (1:1) to receive either 1-year venetoclax-obinutuzumab (Ven-Obi, 216 patients) or chlorambucil-Obi (Clb-Obi, 216 patients) therapy (NCT02242942). The primary endpoint was investigator-assessed progression-free survival (PFS); secondary endpoints included minimal residual disease (MRD) and overall survival. RNA sequencing of CD19-enriched blood was conducted for exploratory post-hoc analyses. After a median follow-up of 65.4 months, PFS is significantly superior for Ven-Obi compared to Clb-Obi (Hazard ratio HR 0.35 95% CI 0.26-0.46, p < 0.0001). At 5 years after randomization, the estimated PFS rate is 62.6% after Ven-Obi and 27.0% after Clb-Obi. In both arms, MRD status at the end of therapy is associated with longer PFS. MRD + ( ≥ 10
) status is associated with increased expression of multi-drug resistance gene ABCB1 (MDR1), whereas MRD6 (< 10
) is associated with BCL2L11 (BIM) expression. Inflammatory response pathways are enriched in MRD+ patient solely in the Ven-Obi arm. These data indicate sustained long-term efficacy of fixed-duration Ven-Obi in patients with previously untreated CLL. The distinct transcriptomic profile of MRD+ status suggests possible biological vulnerabilities.
The objective of this trial was to evaluate safety and efficacy of bendamustine combined with rituximab (BR) in patients with relapsed and/or refractory chronic lymphocytic leukemia (CLL).
...Seventy-eight patients, including 22 patients with fludarabine-refractory disease (28.2%) and 14 patients (17.9%) with deletion of 17p, received BR chemoimmunotherapy. Bendamustine was administered at a dose of 70 mg/m(2) on days 1 and 2 combined with rituximab 375 mg/m(2) on day 0 of the first course and 500 mg/m(2) on day 1 during subsequent courses for up to six courses.
On the basis of intent-to-treat analysis, the overall response rate was 59.0% (95% CI, 47.3% to 70.0%). Complete response, partial response, and nodular partial response were achieved in 9.0%, 47.4%, and 2.6% of patients, respectively. Overall response rate was 45.5% in fludarabine-refractory patients and 60.5% in fludarabine-sensitive patients. Among genetic subgroups, 92.3% of patients with del(11q), 100% with trisomy 12, 7.1% with del(17p), and 58.7% with unmutated IGHV status responded to treatment. After a median follow-up time of 24 months, the median event-free survival was 14.7 months. Severe infections occurred in 12.8% of patients. Grade 3 or 4 neutropenia, thrombocytopenia, and anemia were documented in 23.1%, 28.2%, and 16.6% of patients, respectively.
Chemoimmunotherapy with BR is effective and safe in patients with relapsed CLL and has notable activity in fludarabine-refractory disease. Major but tolerable toxicities were myelosuppression and infections. These promising results encouraged us to initiate a further phase II trial evaluating the BR regimen in patients with previously untreated CLL.
We investigated the safety and efficacy of bendamustine and rituximab (BR) in previously untreated patients with chronic lymphocytic leukemia (CLL).
In all, 117 patients, age 34 to 78 years, 46.2% of ...patients at Binet stage C, and 25.6% of patients age 70 years or older received BR chemoimmunotherapy for first-line treatment of CLL. Bendamustine was administered at a dose of 90 mg/m(2) on days 1 and 2 combined with 375 mg/m(2) rituximab on day 0 of the first course and 500 mg/m(2) on day 1 during subsequent courses for up to six courses.
Overall response rate was 88.0% (95% CI, 80.7% to 100.0%) with a complete response rate of 23.1% and a partial response rate of 64.9%. Ninety percent of patients with del(11q), 94.7% with trisomy 12, 37.5% with del(17p), and 89.4% with unmutated IGHV status responded to treatment. After a median observation time of 27.0 months, median event-free survival was 33.9 months, and 90.5% of patients were alive. Grade 3 or 4 severe infections occurred in 7.7% of patients. Grade 3 or 4 adverse events for neutropenia, thrombocytopenia, and anemia were documented in 19.7%, 22.2%, and 19.7% of patients, respectively.
Chemoimmunotherapy with BR is effective and safe in patients with previously untreated CLL.
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