Prolonged survival of patients with angioimmunoblastic T-cell lymphoma after high-dose chemotherapy and autologous stem cell transplantation: the GELTAMO experience

Abstract OBJECTIVES: Angioimmunoblastic T-cell lymphoma (AIL) is a rare lymphoma with a poor prognosis and no standard treatment. Here, we report our experiences with 19 patients treated with high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) within the GELTAMO co-operative group between 1992 and 2004. METHODS: The median age at transplantation was 46 yr. Fifteen patients underwent the procedure as front-line therapy and four patients as salvage therapy. Most patients received peripheral stem cells (90%) coupled with BEAM or BEAC as conditioning regimen (79%). RESULTS: A 79% of patients achieved complete response, 5% partial response and 16% failed the procedure. After a median follow-up of 25 months, eight patients died (seven of progressive disease and secondary neoplasia), while actuarial overall survival and progression-free survival at 3 yr was 60% and 55%. Prognostic factors associated with a poor outcome included bone marrow involvement, transplantation in refractory disease state, attributing more than one factor of the age-adjusted-International Prognostic Index, Pretransplant peripheral T-cell lymphoma (PTCL) Score or Prognostic Index for PTCL. CONCLUSIONS: More than half of the patients with AIL that display unfavourable prognostic factors at diagnosis or relapse would be expected to be alive and disease-free after 3 yr when treated with HDC/ASCT. Patients who are transplanted in a refractory disease state do not benefit from this procedure

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Complement anaphylatoxins C3a and C5a induce a failing regenerative program in cardiac resident cells. Evidence of a role for cardiac resident stem cells other than cardiomyocyte renewal

Cardiac healing, which follows myocardial infarction, is a complex process guided by intricate interactions among different components. Some resident cell populations with a potential role in cardiac healing have already been described in cardiac tissues. These non-cardiomyocyte cell subsets, globally described as cardiac pluripotent/progenitor cells (CPCs), are able to differentiate into all three major cardiac cell lineages (endothelial, smooth muscle and cardiomyocyte cells) in experimental settings. Nevertheless, physiological cardiac healing results in a fibrous scar, which remains to be fully modelled experimentally. Since a role for complement anaphylatoxins (C3a and C5a) has been described in several regeneration/repair processes, we examined the effects that C3a and C5a exert on a defined population of CPCs. We found that C3a and C5a are able to enhance CPC migration and proliferation. In vitro studies showed that this effect is linked to activation of telomerase mRNA and partial preservation of telomere length, in an NFκB-dependent manner. In addition, anaphylatoxin signalling modulates the CPC phenotype, increasing myofibroblast differentiation and reducing endothelial and cardiac gene expression. These findings may denote that C3a and C5a are able to maintain/increase the cardiac stem cell pool within the heart, whilst simultaneously facilitating and modulating resident cell differentiation. We found that this modulation was directed towards scar forming cells, which increased fibroblast/myofibroblast generation and suggests that both these anaphylatoxins could play a relevant role in the damage-coupled activation of resident cells, and regulation of the cardiac healing process after injury.This work was supported by grant to ADJ from the Ministry of Science and Innovation (SAF 2009–1000) and a MICCIN "Ramon y Cajal" contract and by a grant to ABM from GENOMA ESPAÑA (Spain) part of the MACIA research project.S

The results of consolidation with autologous stem-cell transplantation in patients with peripheral T-cell lymphoma (PTCL) in first complete remission: the Spanish Lymphoma and Autologous Transplantation Group experience

Abstract BACKGROUND: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive lymphomas associated with poor prognosis with standard chemotherapy. Consolidation with autologous stem-cell transplantation (ASCT) may improve survival. We present 74 patients transplanted in first complete response (CR) from the Spanish Lymphoma and Autologous Transplantation Group cooperative group. PATIENTS AND METHODS: Median age was 46 years. Eighty-eight percent presented advanced (III-IV) Ann Arbor stage; 53% had B symptoms; 52% had high lactate dehydrogenase; 65% had two or three risk factors of the adjusted-International Prognostic Index; 58% presented a high Tumor score and in 14% more than two adverse factors of the Prognostic Index for peripheral T-cell lymphoma (PIT) were observed. RESULTS: With a median follow-up of 67 months from diagnosis, the 5-year overall survival (OS) was 68% and progression-free survival (PFS) reached 63%. The multivariate analysis showed that the only factor associated with a shorter OS and PFS was the presence of more than two risk factors from the PIT risk system. CONCLUSIONS: In a retrospective study with a prolonged follow-up, consolidation with ASCT in CR patients who had presented unfavorable prognostic factors at diagnosis substantially increased the OS and PFS when compared with conventional chemotherapy. The PIT risk system identified 14% of patients without benefit from ASCT consolidation. Thus, other innovative therapies are still necessary in certain cases

The results of consolidation with autologous stem-cell transplantation in patients with peripheral T-cell lymphoma (PTCL) in first complete remission: the Spanish Lymphoma and Autologous Transplantation Group experience

Abstract BACKGROUND: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive lymphomas associated with poor prognosis with standard chemotherapy. Consolidation with autologous stem-cell transplantation (ASCT) may improve survival. We present 74 patients transplanted in first complete response (CR) from the Spanish Lymphoma and Autologous Transplantation Group cooperative group. PATIENTS AND METHODS: Median age was 46 years. Eighty-eight percent presented advanced (III-IV) Ann Arbor stage; 53% had B symptoms; 52% had high lactate dehydrogenase; 65% had two or three risk factors of the adjusted-International Prognostic Index; 58% presented a high Tumor score and in 14% more than two adverse factors of the Prognostic Index for peripheral T-cell lymphoma (PIT) were observed. RESULTS: With a median follow-up of 67 months from diagnosis, the 5-year overall survival (OS) was 68% and progression-free survival (PFS) reached 63%. The multivariate analysis showed that the only factor associated with a shorter OS and PFS was the presence of more than two risk factors from the PIT risk system. CONCLUSIONS: In a retrospective study with a prolonged follow-up, consolidation with ASCT in CR patients who had presented unfavorable prognostic factors at diagnosis substantially increased the OS and PFS when compared with conventional chemotherapy. The PIT risk system identified 14% of patients without benefit from ASCT consolidation. Thus, other innovative therapies are still necessary in certain cases

Frontline autologous stem cell transplantation in high-risk peripheral T-cell lymphoma: a prospective study from The Gel-Tamo Study Group

OBJECTIVE: Retrospective data shows that peripheral T-cell lymphoma (PTCL) patients sensitive to conventional chemotherapy for aggressive lymphomas may respond better if this treatment is consolidated with frontline autologous stem cell transplantation (ASCT). Here, we present data from a prospective phase II trial of high-dose chemotherapy and ASCT as a frontline consolidation therapy for aggressive nodal PTCL. METHODS: This study involved 26 gallium-scan-positive patients with high-risk nodal PTCL [excluding anaplastic lymphoma kinase (ALK) positive]. Patients received three courses of MegaCHOP before they were evaluated, and those that were gallium-scan-negative at this stage then received another course of MegaCHOP and ASCT. Patients who remained gallium-scan-positive received two courses of an IFE regimen (ifosfamide 10 g/m(2), etoposide 150 mg/m(2)/12 h on days 1-3) and if they at least achieved PR, they then received the transplant. RESULTS: Complete response (CR) was achieved by 12 patients (46%) after three courses of MegaCHOP and 12 patients received IFE as a salvage therapy. After the ASCT (n = 19), 89% of patients achieved CR. In contrast, six patients (23%) did not receive the transplant because of the progression of the disease (n = 5) or lethal toxicity (n = 1). One patient in first-line CR refused ASCT. After a median follow-up of 35 months, the overall survival (OS) and progression-free survival (PFS) at 3 yr was 73% and 53%, respectively. Moreover, the OS, PFS and disease-free survival (DFS) were 84%, 56% and 63%, respectively 2 yr after transplant in patients who received ASCT consolidation (n = 19). CONCLUSIONS: Early salvage therapy for patients with high-risk aggressive nodal PTCL that do not achieve CR after three courses of chemotherapy and ASCT frontline consolidation for chemosensitive patients may improve treatment outcome

Deep Underground Neutrino Experiment (DUNE), Far Detector Technical Design Report, Volume II: DUNE Physics

The preponderance of matter over antimatter in the early universe, the dynamics of the supernovae that produced the heavy elements necessary for life, and whether protons eventually decay -- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our universe, its current state, and its eventual fate. DUNE is an international world-class experiment dedicated to addressing these questions as it searches for leptonic charge-parity symmetry violation, stands ready to capture supernova neutrino bursts, and seeks to observe nucleon decay as a signature of a grand unified theory underlying the standard model. The DUNE far detector technical design report (TDR) describes the DUNE physics program and the technical designs of the single- and dual-phase DUNE liquid argon TPC far detector modules. Volume II of this TDR, DUNE Physics, describes the array of identified scientific opportunities and key goals. Crucially, we also report our best current understanding of the capability of DUNE to realize these goals, along with the detailed arguments and investigations on which this understanding is based. This TDR volume documents the scientific basis underlying the conception and design of the LBNF/DUNE experimental configurations. As a result, the description of DUNE's experimental capabilities constitutes the bulk of the document. Key linkages between requirements for successful execution of the physics program and primary specifications of the experimental configurations are drawn and summarized. This document also serves a wider purpose as a statement on the scientific potential of DUNE as a central component within a global program of frontier theoretical and experimental particle physics research. Thus, the presentation also aims to serve as a resource for the particle physics community at large