Prolonged air leak (PAL) is often associated with pain and immobilization and is a major limiting factor for discharge from the hospital. The efficacy of 2 surgical patches was investigated in the ...treatment of air leak following open surgery.
Forty-five patients were randomized in a 1:1 ratio either to treatment with Neoveil (polyglycolic acid) (n = 22) or TachoSil (collagen sponge) (n = 23). Air leak was monitored at 2, 4, 8, 12 and 24 h after surgery and then daily at 8 am and 6 pm, using a digital recording system. The primary outcome was the time to air leak closure. Secondary outcomes were incidence, air leak intensity, incidence of PAL and incidence of pneumonia.
Air leak 2 h after surgery was observed in 11/22 (50%) vs 14/23 (61%) patients treated with polyglycolic acid, respectively, with collagen sponge. On average, air loss within the first 24 h after surgery was lower and declined faster in patients treated with polyglycolic acid. Time to pulmonary air leak closure was somewhat shorter with polyglycolic acid (median interquartile range 10 2, 52 h) compared to collagen sponge (19 2, 141 h). However, the difference was not statistically significant (P = 0.35, Wilcoxon rank-sum test). PAL occurred in 3/22 (14%) vs 6/23 (26%) patients, and pneumonia occurred in 2/22 (9%) vs 3/23 (13%) patients treated with polyglycolic acid, respectively, collagen sponge.
Both systems are effective in the treatment of air leak. Our results suggest a possible superiority of Neoveil over TachoSil in post-surgery air leak control.
NCT04065880.
Tumor-specific T cells are frequently exhausted by chronic antigenic stimulation. We here report on a human antigen-specific ex vivo model to explore new therapeutic options for T cell ...immunotherapies. T cells generated with this model resemble tumor-infiltrating exhausted T cells on a phenotypic and transcriptional level. Using a targeted pooled CRISPR-Cas9 screen and individual gene knockout validation experiments, we uncover sorting nexin-9 (SNX9) as a mediator of T cell exhaustion. Upon TCR/CD28 stimulation, deletion of SNX9 in CD8 T cells decreases PLCγ1, Ca
, and NFATc2-mediated T cell signaling and reduces expression of NR4A1/3 and TOX. SNX9 knockout enhances memory differentiation and IFNγ secretion of adoptively transferred T cells and results in improved anti-tumor efficacy of human chimeric antigen receptor T cells in vivo. Our findings highlight that targeting SNX9 is a strategy to prevent T cell exhaustion and enhance anti-tumor immunity.
Kohn and Movshon Kohn, A., & Movshon, J. (2003). Neuronal adaptation to visual motion in area MT of the macaque.
Neuron, 39, 681–691; Kohn, A., & Movshon, J. A. (2004). Adaptation changes the ...direction tuning of macaque MT neurons.
Nature Neuroscience, 7(7), 764–772 measured the contrast response functions of single neurons in MT (V5) before and after adaptation to high contrast gratings. They found that when gratings were smaller than the MT receptive field, so that adapting and test regions could be either co-localised or non-overlapping, adaptation was spatially specific. This led to the hypothesis that grating adaptation occurs in V1, where receptive fields are small and retinotopically organized, and that MT merely inherits this adaptation. We predicted that spatial specificity would be less for dot stimuli that probably adapt MT cells directly. Also, given recent contradictory claims that hMT primarily exhibits both spatiotopy d’Avossa, G., Tosetti, M., Crespi, S., Biagi, L., Burr, D., & Morrone, M. (2006). Spatiotopic selectivity of BOLD responses to visual motion in human area MT.
Nature Neuroscience, 10, 249–255 and retinotopy Gardner, J. L., Merriam, E. P., Movshon, J. A., & Heeger, D. J. (2008). Maps of visual space in human occipital cortex are retinotopic, not spatiotopic.
The Journal of Neuroscience, 28, 3988–3999, we were interested in producing relevant psychophysical evidence using the direction aftereffect. In three experiments, we measured direction aftereffects (DAEs) induced and tested either with drifting gratings or drifting dots when stimulus location was changed both retinotopically and spatiotopically between adaptation and test; when retinotopic location only was changed; and when spatiotopic location only was changed. We predicted and found that spatial specificity was greater for gratings than for dots. We also found very small spatiotopic effects that call into question some recent claims that area MT exhibits a high degree of spatiotopicity.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
BackgroundThe costimulatory receptor 4-1BB (CD137, TNFRSF9) plays an important role in sustaining effective T cell immune responses and is investigated as target for cancer therapy. Systemic 4-1BB ...directed therapies elicit toxicity or low efficacy, which significantly hampered advancement of 4-1BB-based immunotherapy. Therefore, targeted delivery of 4-1BB agonist to the tumor side is needed for eliciting antitumor efficacy while avoiding systemic toxicity.MethodsWe analyzed the immunostimulatory properties of a fibroblast activation protein (FAP)-targeted 4-1BB agonist (FAP-4-1BBL) by assessing tumor-infiltrating lymphocytes’ (TIL) activity from patients with non-small cell lung cancer and epithelial ovarian cancer.ResultsCombination treatment with FAP-4-1BBL and T cell receptor stimulation by either anti-CD3 or T cell bispecific antibodies significantly enhanced TIL activation and effector functions, including T cell proliferation, secretion of proinflammatory cytokines and cytotoxicity. Notably, costimulation with FAP-4-1BBL led to de novo secretion of interleukin (IL)−13. This was associated with cytokine-mediated tumor cell apoptosis, which was partially dependent on IL-13 alpha 1/2 receptors and STAT6 phosphorylation.ConclusionsOur study provides mechanistic insights into T cell stimulation induced by FAP-4-1BBL in primary human tumors and supports the investigation of FAP-4-1BBL compound in early clinical trials.
Several technical points for postoperative lung hernia repair are still not fully elucidated. We present an original technical solution to deal with this complication. In a 68-year-old female, the ...lung hernia was confirmed 5 months after the partial left-sided chest wall and scapula angle resection with primary Mersilene mesh reconstruction for elastofibroma. The patient refused the proposed surgical correction, being only slightly limited in daily activities. The symptoms persisted under analgetic therapy till the moment when patient’s daily activities became critically limited, 22 months after surgery. The repeated chest CT showed a slight increase in hernia size with no signs of tumour recurrence, so that reoperation was planned. After the exposure of the mesh region, a lung protrusion (4×3 cm) along the anterolateral edge of the mesh was confirmed. By careful dissection, the mesh was separated from a firmly adherent lung and removed. After adhaesiolysis and complete lung liberation, a wedge resection of the afunctional lung tissue of the lingula was done, just in the region of contact with the mesh. After the chest tube insertion, the chest wall defect was reconstructed by using a Mersilene mesh, and the final chest wall stabilization was done by the fixation of two Synthes plates (DePuy Synthes J&J) over the 5th and 6th ribs. The postoperative course was uneventful. One year after the operation, the patient was in good general condition, without the need for analgesics. To the best of our knowledge, the described technique is the original way of dealing with postoperative lung hernia. We find it efficient as a prevention of potential serious hernia-related complications.
Full text
Available for:
DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
BackgroundNext-generation cancer immunotherapies are designed to broaden the therapeutic repertoire by targeting new immune checkpoints including lymphocyte-activation gene 3 (LAG-3) and T cell ...immunoglobulin and mucin-domain containing-3 (TIM-3). Yet, the molecular and cellular mechanisms by which either receptor functions to mediate its inhibitory effects are still poorly understood. Similarly, little is known on the differential effects of dual, compared with single, checkpoint inhibition.MethodsWe here performed in-depth characterization, including multicolor flow cytometry, single cell RNA sequencing and multiplex supernatant analysis, using tumor single cell suspensions from patients with cancer treated ex vivo with novel bispecific antibodies targeting programmed cell death protein 1 (PD-1) and TIM-3 (PD1-TIM3), PD-1 and LAG-3 (PD1-LAG3), or with anti-PD-1.ResultsWe identified patient samples which were responsive to PD1-TIM3, PD1-LAG3 or anti-PD-1 using an in vitro approach, validated by the analysis of 659 soluble proteins and enrichment for an anti-PD-1 responder signature. We found increased abundance of an activated (HLA-DR+CD25+GranzymeB+) CD8+ T cell subset and of proliferating CD8+ T cells, in response to bispecific antibody or anti-PD-1 treatment. Bispecific antibodies, but not anti-PD-1, significantly increased the abundance of a proliferating natural killer cell subset, which exhibited enrichment for a tissue-residency signature. Key phenotypic and transcriptional changes occurred in a PD-1+CXCL13+CD4+ T cell subset, in response to all treatments, including increased interleukin-17 secretion and signaling toward plasma cells. Interestingly, LAG-3 protein upregulation was detected as a unique pharmacodynamic effect mediated by PD1-LAG3, but not by PD1-TIM3 or anti-PD-1.ConclusionsOur in vitro system reliably assessed responses to bispecific antibodies co-targeting PD-1 together with LAG-3 or TIM-3 using patients’ tumor infiltrating immune cells and revealed transcriptional and phenotypic imprinting by bispecific antibody formats currently tested in early clinical trials.
Cancer immunotherapy with antibodies targeting immune checkpoints such as the PD-1/PD-L1 pathway have emerged as breakthrough treatment for multiple solid tumors with high response rates and durable ...remissions. Despite the benefit for patients and encouraging safety profile, severe inflammatory reactions are observed in some patients. Such immune-related adverse events (irAEs) frequently lead to temporary or permanent cessation of the treatment and require systemic immunosuppression yet underlying mechanisms of irAEs are not known in detail. Here, we describe the T cell-mediated immune reaction in irAE lesions of four patients that developed pneumonitis during therapy with a PD-1 blocking antibody. Immunohistochemical analysis was performed to map the environment of the inflammatory lesions. Tumor infiltrating T cell clones were identified by sequencing the T cell receptor, and comparison with clones from peripheral blood or secondary lymphoid organs. A significant overlap of clones infiltrating irAE lesions and tumors was found. The most prevalent clones were also expanded in peripheral blood, but only a minor fraction of clonal overlap was found. Our findings suggest that irAE lesions in patients under PD-1 blockade are infiltrated by T cells with similar specificity as tumor-infiltrating T cells. These results raise the possibility that the immune response is elicited in these patients against antigens shared by the tumor and distant organs affected by irAEs.
Duncker (1929/1955, Source Book of Gestalt Psychology, pp 161–172) demonstrated a laboratory version of induced motion. He showed that, when a stationary spot of light in a dark laboratory is ...enclosed in an oscillating rectangular frame, the frame is perceived as stationary and the dot appears to move in the direction opposite the true motion of the frame. Zivotofsky (2004, Investigative Ophthalmology & Visual Science 45 2867–2872) studied a more complex variant of the Duncker illusion, in which both the inducing and the test stimuli moved: a single red test dot moved horizontally left or right while a dense background set of black dots on a white background moved vertically up or down. When the background inducing dots moved up (down), the truly horizontally translating test dot appeared to drift at an angle down (up) from the horizontal. In experiment 1, we used two methods to measure the complete angular function of the Zivotofsky effect and found it to peak with an inducer-test direction separation of approximately 30°, similar to the inducing angle that has been found to maximise other direction illusions. Experiment 2 tested and confirmed predictions regarding the effects of relative test and inducer speeds based on the vectorial subtraction of the inducing velocity from the test velocity.
Full text
Available for:
NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Evidence from mouse chronic viral infection models suggests that CD8
T cell subsets characterized by distinct expression levels of the receptor PD-1 diverge in their state of exhaustion and potential ...for reinvigoration by PD-1 blockade. However, it remains unknown whether T cells in human cancer adopt a similar spectrum of exhausted states based on PD-1 expression levels. We compared transcriptional, metabolic and functional signatures of intratumoral CD8
T lymphocyte populations with high (PD-1
), intermediate (PD-1
) and no PD-1 expression (PD-1
) from non-small-cell lung cancer patients. PD-1
T cells showed a markedly different transcriptional and metabolic profile from PD-1
and PD-1
lymphocytes, as well as an intrinsically high capacity for tumor recognition. Furthermore, while PD-1
lymphocytes were impaired in classical effector cytokine production, they produced CXCL13, which mediates immune cell recruitment to tertiary lymphoid structures. Strikingly, the presence of PD-1
cells was strongly predictive for both response and survival in a small cohort of non-small-cell lung cancer patients treated with PD-1 blockade. The characterization of a distinct state of tumor-reactive, PD-1-bright lymphocytes in human cancer, which only partially resembles that seen in chronic infection, provides potential avenues for therapeutic intervention.
Objective
To investigate the diagnostic value of whole-body magnetic resonance imaging (MRI) including diffusion-weighted imaging with background signal suppression (DWIBS) for preoperative ...assessment of non-small-cell lung cancer (NSCLC) in comparison to
18
F-fluorodeoxyglucose
18
FDG) positron emission tomography/computed tomography (PET/CT).
Methods
Thirty-three patients with suspected NSCLC were enrolled. Patients were examined before surgery with PET/CT and whole-body MRI including T1-weighted turbo spin echo (TSE), T2-weighted short tau inversion recovery (STIR) and DWIBS sequences (b = 0/800). Histological or cytological specimens were taken as standard of reference.
Results
Whole-body MRI with DWIBS as well as PET/CT provided diagnostic image quality in all cases. Sensitivity for primary tumour detection: MRI 93%, PET/CT 98%. T-staging accuracy: MRI 63%, PET/CT 56%. N-staging accuracy: MRI 66%, PET/CT 71%. UICC staging accuracy: MRI 66%, PET/CT 74%. Sensitivity for metastatic involvement of individual lymph node groups: MRI 44%, PET/CT 47%. Specificity for individual non-metastatic lymph node groups: MRI 93%, PET/CT 96%. Assessment accuracy for individual lymph node groups: MRI 85%, PET/CT 88%. Observer agreement rate for UICC staging: MRI 74%, PET/CT 90%.
Conclusion
Whole-body MRI with DWIBS provides comparable results to PET/CT in staging of NSCLC, but shows no superiority. Most relevant challenges for both techniques are T-staging accuracy and sensitivity for metastatic lymph node involvement.
Key Points
•
Numerous radiological methods are available for the crucial staging of lung cancer
•
Whole-body DWIBS MRI provides comparable results to PET/CT in NSCLC staging.
•
No evident superiority of whole-body DWIBS over PET/CT in NSCLC staging.
•
Challenges for both techniques are T-staging and detection of small metastases.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
PDF
