Adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) and high-dose interleukin-2 (IL-2) administered to lymphodepleted patients with melanoma can cause durable tumor ...regressions. The optimal TIL product for ACT is unknown.
Patients with metastatic melanoma were prospectively assigned to receive unselected young TILs versus CD8(+)-enriched TILs. All patients received lymphodepleting chemotherapy and high-dose IL-2 therapy and were assessed for response, toxicity, survival, and immunologic end points.
Thirty-four patients received unselected young TILs with a median of 8.0% CD4(+) lymphocytes, and 35 patients received CD8(+)-enriched TILs with a median of 0.3% CD4(+) lymphocytes. One month after TIL infusion, patients who received CD8(+)-enriched TILs had significantly fewer CD4(+) peripheral blood lymphocytes (P = .01). Twelve patients responded to therapy with unselected young TILs (according to Response Evaluation Criteria in Solid Tumors RECIST), and seven patients responded to CD8(+)-enriched TILs (35% v 20%; not significant). Retrospective studies showed a significant association between response to treatment and interferon gamma secretion by the infused TILs in response to autologous tumor (P = .04), and in the subgroup of patients who received TILs from subcutaneous tumors, eight of 15 patients receiving unselected young TILs responded but none of eight patients receiving CD8(+)-enriched TILs responded.
A randomized selection design trial was feasible for improving individualized TIL therapy. Since the evidence indicates that CD8(+)-enriched TILs are not more potent therapeutically and they are more laborious to prepare, future studies should focus on unselected young TILs.
In organisms with complex life cycles, physiological stressors during early life stages may have fitness-level impacts that are delayed into later stages or habitats. We tested the hypothesis that ...body size and date of metamorphosis, which are highly responsive to aquatic stressors, influence post-metamorphic survival and movement patterns in the terrestrial phase of an ephemeral pond-breeding frog by examining these traits in two populations of northern red-legged frogs (Rana aurora aurora). To increase variation of body size at metamorphosis, we manipulated food availability for 314 of 1045 uniquely marked tadpoles and estimated the probability that frogs survived and emigrated using concentric rings of drift fencing surrounding ponds and Bayesian capture-recapture modeling. The odds of surviving and emigrating from the ponds to the innermost drift fences, ~12 m, increased by factors of 2.20 (95% credibility intervals 1.39-4.23) and 2.54 (0.94-4.91) with each millimeter increase in snout-vent length and decreased by factors of 0.91 (0.85-0.96) and 0.89 (0.80-1.00) with each day's delay in metamorphosis for the two ponds. The odds of surviving and moving to the next ring of fencing, 12 m to ~40 m from the ponds, increased by a factor of 1.20 (0.45-4.06) with each millimeter increase in size. Our results demonstrated that body size and timing of metamorphosis relate strongly to the performance of newly metamorphosed frogs during their initial transition into terrestrial habitat. Carryover effects of aquatic stressors that reduce size and delay metamorphosis may have population-level impacts that are not expressed until terrestrial stages. Since changes in both aquatic and terrestrial systems are implicated in many amphibian declines, quantifying both immediate and delayed effects of stressors on demographic rates is critical to sound management.
Objectives/Hypothesis
To assess balloon dilation of the Eustachian tube with Eustachian tube balloon catheter in conjunction with medical management as treatment for Eustachian tube dilatory ...dysfunction.
Study Design
In this prospective, multicenter, randomized, controlled trial, we assigned, in a 2:1 ratio, patients age 22 years and older with Eustachian tube dilatory dysfunction refractory to medical therapy to undergo balloon dilation of the Eustachian tube with balloon catheter in conjunction with medical management or medical management alone.
Methods
The primary endpoint was normalization of tympanogram at 6 weeks. Additional endpoints were normalization of Eustachian Tube Dysfunction Questionaire‐7 symptom scores, positive Valsalva maneuver, mucosal inflammation, and safety.
Results
Primary efficacy results demonstrated superiority of balloon dilation of the Eustachian tube with balloon catheter + medical management compared to medical management alone. Tympanogram normalization at 6‐week follow‐up was observed in 51.8% (72/139) of investigational patients versus 13.9% (10/72) of controls (P < .0001). Tympanogram normalization in the treatment group was 62.2% after 24 weeks. Normalization of Eustachian Tube Dysfunction Questionaire‐7 Symptom scores at 6‐week follow‐up was observed in 56.2% (77/137) of investigational patients versus 8.5% (6/71) controls (P < .001). The investigational group also demonstrated substantial improvement in both mucosal inflammation and Valsalva maneuver at 6‐week follow‐up compared to controls. No device‐ or procedure‐related serious adverse events were reported for those who underwent balloon dilation of the Eustachian tube.
Conclusions
This study demonstrated superiority of balloon dilation of the Eustachian tube with balloon catheter + medical management compared to medical management alone to treat Eustachian tube dilatory dysfunction in adults.
Level of Evidence
1b. Laryngoscope, 128:1200–1206, 2018
While researchers have extensively studied the growth in the number of small farms between 1982 and 2012 reported in the Census of Agriculture (COA), there has been little discussion of trends among ...farm operators who do not sell any agri-cultural products. Using previously unreleased COA data collected between 1982 and 2012, this research empirically examines these “zero-sales farmers” for the first time. There was a large increase in the number of zero-sales farmers from 104,000 in 1982 to 466,000 in 2012, as well as a remarkable rise in their share of the farming popu-lation, from 5 percent in 1982 to 22 percent in 2012. Women and minority farmers were dispro-portionately likely to be zero-sales operators: at least 30 percent of women, Native American, and black farmers reported no sales in 2012. Older and beginning farmers were also more likely to report zero sales in 2012 than younger and experienced ones, respectively. Zero-sales farmers dramatically influenced recent census data on farm income, farm size, and operator age, among other results, due to their substantial share of the overall population. In order to effectively utilize COA data, practitioners, policymakers, and researchers should include zero-sales farms in their analyses. There are several steps the U.S. Department of Agriculture (USDA) can take to make information about zero-sales farmers more readily available and widely understood, such as introducing a zero-sales category in the census results.
Preparations highly enriched in Golgi complex membranes, synaptosomes, and synaptic plasma membranes (SPM) by marker enzyme analysis and electron microscopic morphology were made from the brains of ...28-day-old rats. These were incubated with cytidine 5'-monophosphate-N-acetyl14Cneuraminic acid (CMP-NeuAc) in a physiologic buffer, without detergents. Glycolipid sialosyltransferase activities (SATs) were measured by analyzing incorporation of radiolabeled NeuAc into endogenous membrane gangliosides. Golgi SAT was diversified in producing all the various molecular species of labeled gangliosides 2.64 pmol of NeuAc transferred (mg of protein)-1 h-1. Synaptosomal SAT exhibited a lower activity 0.66 pmol (mg of protein)-1 h-1, but it was highly specific in its labeling pattern, with a marked preference for labeling NeuAc alpha 2---8NeuAc alpha 2---3Gal beta 1---4Glc beta 1---1 Cer (GD3 ganglioside). SPM prepared from the synaptosomes retained the GD3-related SAT (or SAT-2), and the total specific activity increased 1.41 pmol (mg of protein)-1 h-1, which suggests that the location of the synaptosomal activity is in the SPM. These results indicate that SAT activity in Golgi membranes differs from that in synaptosomes with regard to endogenous acceptor substrate specificity and SAT activity of synaptosomes should be located in the synaptosomal plasma membrane. This SAT could function as an ectoenzyme in concert with ecto-sialidase to modulate the GD3 and other ganglioside population in situ at the SPM of the central nervous system.
This volume undertakes the examination and appraisal of the economic controls employed by the British Labor Government in attempting to regulate the output of the building industry in the years ...immediately following the Second World War.
Early Age Robotics (EAR) education has become extremely popular throughout the world. It has proven to be not only interesting and enjoyable, but also effective at helping even the youngest of ...children (aged 4–7) develop skills and reap educational benefits. But what about their families? Are parents as happy with EAR programs as are the children? What are their attitudes and beliefs regarding it? In this novel empirical study, we seek to answer these questions and succeed in refuting some commonly held beliefs. This study is based on a unique EAR program running since 2016 for over 2000 children. Using qualitative and quantitative research methods, we analyzed interviews with 29 parents and surveys submitted to 203 parents whose children (aged 4–7) studied technology and robotics as a compulsory component of their curriculum. We uncovered an interesting phenomenon of parents becoming transformed from being passive consumers of the educational system into new, twenty-first-century parents, more confident about their ability to learn and to help promote their children’s abilities. They are more motivated and involved, and ready to invest in both their own and their children’s learning. Also encouraging is the gender equality found in this technological area. We recommend introducing a new PEAR (Parents in EAR) model, offering practical proposals for enhancing and expanding robotics education. The study confirms parents’ satisfaction with technology, their willingness to learn more about robotics, and their satisfaction with their children’s participation in an EAR program. This transformation should be considered by EAR stakeholders.
A common theme across multiple successful immunotherapies for cancer is the recognition of tumor-specific mutations (neoantigens) by T cells. The rapid discovery of such antigen responses could lead ...to improved therapies through the adoptive transfer of T cells engineered to express neoantigen-reactive T cell receptors (TCRs). Here, through CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing) and TCR-seq of non-small cell lung cancer (NSCLC) tumor-infiltrating lymphocytes (TILs), we develop a neoantigen-reactive T cell signature based on clonotype frequency and CD39 protein and CXCL13 mRNA expression. Screening of TCRs selected by the signature allows us to identify neoantigen-reactive TCRs with a success rate of 45% for CD8+ and 66% for CD4+ T cells. Because of the small number of samples analyzed (4 patients), generalizability remains to be tested. However, this approach can enable the quick identification of neoantigen-reactive TCRs and expedite the engineering of personalized neoantigen-reactive T cells for therapy.
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•T cells in fresh NSCLC tumor were analyzed by CITE-seq with TCR-seq•Neoantigen-reactive T cells are CD39 protein+, CXCL13+, and high-frequency clonotype•The signature can identify both CD4 and CD8 neoantigen-reactive T cells•This method can expedite the personalized neoantigen-reactive T cell therapy
The discovery of T cell receptors (TCRs) that recognize tumor-specific neoantigens can lead to improved therapies through the adoptive transfer of T cells engineered to express these TCRs. Here, Hanada et al. design a signature of neoantigen-reactive T cells that enables the rapid identification of both CD4 and CD8 neoantigen-reactive TCRs.
Gene therapy of human cancer using genetically engineered lymphocytes is dependent on the identification of highly reactive T-cell receptors (TCRs) with antitumor activity. We immunized transgenic ...mice and also conducted high-throughput screening of human lymphocytes to generate TCRs highly reactive to melanoma/melanocyte antigens. Genes encoding these TCRs were engineered into retroviral vectors and used to transduce autologous peripheral lymphocytes administered to 36 patients with metastatic melanoma. Transduced patient lymphocytes were CD45RA− and CD45RO+ after ex vivo expansion. After infusion, the persisting cells displayed a CD45RA+ and CD45RO− phenotype. Gene-engineered cells persisted at high levels in the blood of all patients 1 month after treatment, responding patients with higher ex vivo antitumor reactivity than nonresponders. Objective cancer regressions were seen in 30% and 19% of patients who received the human or mouse TCR, respectively. However, patients exhibited destruction of normal melanocytes in the skin, eye, and ear, and sometimes required local steroid administration to treat uveitis and hearing loss. Thus, T cells expressing highly reactive TCRs mediate cancer regression in humans and target rare cognate–antigen-containing cells throughout the body, a finding with important implications for the gene therapy of cancer. This trial was registered at www.ClinicalTrials.gov as NCI-07-C-0174 and NCI-07-C-0175.
OBJECTIVETo test the hypothesis that transcranial magnetic resonance–guided focused ultrasound (tcMRgFUS) thalamotomy is effective, durable, and safe for patients with medication-refractory essential ...tremor (ET), we assessed clinical outcomes at 3-year follow-up of a controlled multicenter prospective trial.
METHODSOutcomes were based on the Clinical Rating Scale for Tremor, including hand combined tremor–motor (scale of 0–32), functional disability (scale of 0–32), and postural tremor (scale of 0–4) scores, and total scores from the Quality of Life in Essential Tremor Questionnaire (scale of 0–100). Scores at 36 months were compared with baseline and at 6 months after treatment to assess for efficacy and durability. Adverse events were also reported.
RESULTSMeasured scores remained improved from baseline to 36 months (all p < 0.0001). Range of improvement from baseline was 38%–50% in hand tremor, 43%–56% in disability, 50%–75% in postural tremor, and 27%–42% in quality of life. When compared to scores at 6 months, median scores increased for hand tremor (95% confidence interval CI 0–2, p = 0.0098) and disability (95% CI 1–4, p = 0.0001). During the third follow-up year, all previously noted adverse events remained mild or moderate, none worsened, 2 resolved, and no new adverse events occurred.
CONCLUSIONSResults at 3 years after unilateral tcMRgFUS thalamotomy for ET show continued benefit, and no progressive or delayed complications. Patients may experience mild degradation in some treatment metrics by 3 years, though improvement from baseline remains significant.
CLINICALTRIALS.GOV IDENTIFIERNCT01827904.
CLASSIFICATION OF EVIDENCEThis study provides Class IV evidence that for patients with severe ET, unilateral tcMRgFUS thalamotomy provides durable benefit after 3 years.
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