PD-1+ natural killer cells in human non-small cell lung cancer can be activated by PD-1/PD-L1 blockade.

Natural killer (NK) cells are critically involved in anti-tumor immunity by targeting tumor cells. In this study, we show that intratumoral NK cells from NSCLC patients expressed elevated levels of the immune checkpoint receptor PD-1 on their cell surface. In contrast to the expression of activating receptors, PD-1+ NK cells co-expressed more inhibitory receptors compared to PD-1- NK cells. Intratumoral NK cells were less functional compared to peripheral NK cells, and this dysfunction correlated with PD-1 expression. Tumor cells expressing PD-L1 inhibited the functionality of PD-1+ NK cells in ex vivo models and induced PD-1 clustering at the immunological synapse between NK cells and tumor cells. Notably, treatment with PD-1 blockade was able to reverse PD-L1-mediated inhibition of PD-1+ NK cells. Our findings highlight the therapeutic potential of PD-1+ NK cells in immune checkpoint blockade and could guide the development of NK cell-stimulating agents in combination with PD-1 blockade.

Signal enhancement ratio imaging of the lung parenchyma with ultra-fast steady-state free precession MRI at 1.5T.

BACKGROUND: Lung perfusion MRI after i.v. gadolinium (Gd) contrast administration is commonly based on spoiled gradient-echo acquisitions, such as volume-interpolated breath-hold examinations (VIBE), suffering from low signal-to-noise in the parenchyma. PURPOSE: To investigate the lung signal enhancement ratio (SER) with ultra-fast steady-state free precession (ufSSFP) after Gd-administration. STUDY TYPE: Retrospective. SUBJECTS: Ten subjects with healthy lungs; nine patients with pulmonary diseases (chronic obstructive pulmonary disease [COPD], lung cancer, pulmonary fibrosis, lung contusion). FIELD STRENGTH/SEQUENCE: VIBE and ufSSFP imaging of the chest was performed at 1.5T before and 3 minutes after i.v. gadobenate dimeglumine. ASSESSMENT: A workflow including deformable image registration and median filtering was used to compute 3D SER maps. SER was analyzed in the lung, blood pool, liver, muscles, and fat. The artifacts were assessed by a radiologist. In the COPD patients, ufSSFP-SER was compared to 99m Tc-MAA-SPECT/CT by visual scoring of lung enhancement deficits. STATISTICAL TESTS: Mean signal, standard deviation (SD), intersubject SD, and coefficient of variation (CV) were calculated for SER. Statistical significance of differences in signal and artifacts were determined using Wilcoxon signed-rank paired test. Intermodality agreement between ufSSFP-SER and SPECT/CT was calculated by Cohen's kappa (κq ). RESULTS: In healthy lungs, ufSSFP-SER (99% ± 23%, mean ± pooled intrasubject SD, CV = 23%) was significantly higher (P < 10-3 ) and more homogeneous (P < 10-3 ) than VIBE (47% ± 26%, CV = 57%). UfSSFP-SER was significantly higher (P < 10-3 ) for the lungs (99% ± 9%, mean ± intersubject SD) than for the blood (81% ± 7%) and other tissues (liver 33% ± 8%, muscle 26% ± 5%, fat 2% ± 1%). In the lung ufSSFP-SER exhibits homogeneity on iso-gravitational planes, and an anterior-posterior gradient. In COPD patients, ufSSFP-SER was reduced and less homogeneous compared to the control group (73% ± 33%, mean ± pooled intrasubject SD, CV = 42%). ufSSFP-SER had moderate intermodality agreement with SPECT/CT (κq = 0.64). DATA CONCLUSION: UfSSFP-SER of the lung is a rapid and simple method. Our preliminary data show plausible results in different pulmonary diseases, motivating further evaluation in larger cohorts. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018.

An unexpected cause for cavitary pneumonia and empyema.

Tularemia is an emerging zoonotic disease mainly of the Northern Hemisphere caused by the Gram-negative coccobacillus Francisella tularensis. It is affecting a wide range of animals and causes human disease after insect and tick bites, skin contact, ingestion and inhalation. A 66-year-old man presented to our clinic with cavitary pneumonia and distinct pleural effusion. After failure of empiric antibiotic therapy, thoracoscopic assisted decortication and partial excision of the middle lobe were conducted. Conventional culture methods and broad-range bacterial PCR including RipSeqMixed analysis were performed from the excised biopsies. Culture results remained negative but broad-range PCR targeting the first half of the 16S rRNA gene revealed F. tularensis DNA. This result was confirmed by F. tularensis-specific PCR and by serology. The source of infection could not be explored. To conclude, we report the rare clinical picture of a community-acquired pneumonia followed by pleural effusion and empyema due to F. tularensis. Broad range bacterial PCR proved to be a powerful diagnostic tool to detect the etiologic organism.

An unexpected cause of diffuse alveolar hemorrhage in a kidney transplant patient.

Diffuse alveolar hemorrhage (DAH) is a life-threatening condition requiring urgent treatment. There are many different treatment-relevant causes of DAH, making the diagnostic approach to these patients complex and necessitating a multidisciplinary team. We report the case of a kidney transplant recipient in whom all diagnostic efforts did not reveal the cause of DAH, and only autopsy was able to establish an unexpected diagnosis.

Perioperative intravenous lidocaine in thoracoscopic surgery for improved postoperative pain control: a randomized, placebo-controlled, double-blind, superiority trial.

Background: Pain, including associated pain management, remains a burden on patients after thoracic surgery. Our objective was to investigate whether perioperative intravenous administration of lidocaine reduces postoperative morphine consumption and pain intensity after video-assisted thoracoscopic surgery (VATS). Methods: In this double-blind, placebo-controlled superiority trial, patients undergoing VATS with a planned duration of ≤90 minutes were randomized within an intention-to-treat setting. Patients received either intravenous lidocaine or placebo as a bolus of 1.5 mg/kg 30 minutes before incision, followed by a continuous infusion of 3.0 mg/kg/hour until 2 hours after skin closure. Pain and morphine consumption were evaluated when resting and when coughing 1, 2, 4, 8, 16, 24, and 48 hours after skin closure and in a follow-up 14, 90, and 180 days postoperatively. Results: Twenty-eight patients were included in the lidocaine group, 24 in the placebo group. Patients' characteristics and preoperative pain scores were similar in both groups. When coughing, patients of the lidocaine group had less pain within 24 hours after skin closure than the placebo group (4.60±1.64 vs. 5.52±1.65; P=0.02). Morphine consumption was not statistically significantly lower in lidocaine group (18.22±12.87 vs. 21.26±9.39 mg; P=0.26). There were no significant differences between groups in secondary outcomes. Conclusions: Our results suggest that perioperative intravenous lidocaine administration reduces pain scores after VATS. The beneficial clinical effects are limited. Nevertheless, intravenous lidocaine may be helpful as part of a multimodal analgesia protocol or with patients in whom the use of other analgesics is contraindicated. Trial Registration: ClinicalTrials.gov NCT03677817.

Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy.

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, Ca2+, 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.

Preoperative staging of non-small-cell lung cancer: comparison of whole-body diffusion-weighted magnetic resonance imaging and 18F-fluorodeoxyglucose-positron emission tomography/computed tomography.

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.

Chest wall stabilization and rib fixation using a nitinol screwless system in selected patients after blunt trauma: long-term results in a single-centre experience.

OBJECTIVES: First experiences with rib fixation using nitinol, in terms of reliability and morbidity, influence on pain control and quality of life (QOL), in a large series of selected patients after blunt chest trauma. METHODS: Data of all patients who had undergone rib fixation by the use of nitinol were retrospectively analysed in terms of indications, morbidity and in-hospital mortality. Pain status and health-related QOL were assessed preoperatively, when possible, at discharge and at 1, 3, 6 and 12 months post-surgery using visual analogous scale and short form 12 questionnaires. RESULTS: From September 2017 to April 2019, 70 patients underwent rib fixation using the nitinol device, of which 47 (67%) had dislocated, painful fractures, 6 (8.5%) had flail chest injuries, 6 (8.5%) were emergencies with haemodynamical instability and 11 (16%) had pseudoarthrosis. Morbidity was 21% without wound infection; in-hospital mortality was 3%. Fracture of the material occurred in 6% of the patients during the first year, but removal of the material was not required. Analysis of the pain score showed a statistically significant decrease in pain for both the whole collective and the group with a series of dislocated and painful fractured ribs (P < 0.001, Tukey contrast on the linear mixed-effects models). Assessment of health-related QOL revealed a significant improvement in the physical score for the mid- and long-term analysis. CONCLUSIONS: Our results suggest that rib fixation using the nitinol device is reliable, associated with an acceptable morbidity, while significantly decreasing pain and improving health-related QOL.

Neoveil versus TachoSil in the treatment of pulmonary air leak following open lung surgery: a prospective randomized trial.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION NUMBER: NCT04065880.

Role of 18F-FDG PET/CT in the postoperative follow-up in patients with stage I-III NSCLC: A retrospective single-institution study.

BACKGROUND: The optimal surveillance strategy in patients with resected non-small cell lung cancer (NSCLC) is unknown. Early detection of recurrences by follow-up imaging might improve survival and whole-body 18F-FDG-PET/CT might be the optimal imaging modality given its high accuracy in preoperative staging. MATERIAL AND METHODS: Data from a single-center cohort of 205 patients with resected stage I-III NSCLC and FDG-PET/CT surveillance was retrospectively collected. Patients had preoperative FDG-positive tumors and FDG-PET/CT at 6, 12, 24 months, chest CT at 18 months. Thereafter, annual chest CT was performed for stage I-II, annual FDG-PET/CT for stage III. RESULTS: With a median follow-up of 26.3 months (range, 4.1-60.6), the rate for recurrence and secondary primary lung cancer (SPLC) was 22 % and 8 %, respectively. Associated symptoms were present in 48 % (recurrence) and 18 % (SPLC) of patients. Overall, 83 % of recurrences, and 65 % of SPLC were detected on FDG-PET/CT. 82 % of recurrences were detected in one of the first two follow-up PET/CT scans. Second curatively intended treatment (SCIT) was possible in 37 % of patients with recurrence and 100 % with SPLC. The 2-year recurrence-free survival rate after SCIT for recurrence was 53 % [95 %CI; 31-91 %]. Non-malignant FDG-positive findings occurred in 25 % of patients (71 % possible infections). CONCLUSION: In our cohort of patients, more than 80% of all recurrences were identified in one of the three FDG-PET/CTs performed as part of our imaging protocol during the first two years after resection. Nearly all patients with non-distant recurrence qualified for a SCIT. Further studies are needed to identify patients who might benefit from an even more intensive surveillance strategy.

Deciphering molecular and cellular ex vivo responses to bispecific antibodies PD1-TIM3 and PD1-LAG3 in human tumors.

BACKGROUND: Next-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. METHODS: We 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. RESULTS: We 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. CONCLUSIONS: Our 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.

Reconstruction of the chest wall with a latissimus dorsi muscle flap after an infection of alloplastic material: a case report.

Alloplastic material is often used for thoracic wall reconstruction following extended resection bringing the risk of infection, especially after chemotherapy and/or radiation. We present the case of a 66-year-old male with lung adenocarcinoma of the right lower lobe. After extended lobectomy, a partial resection of the sixth to eighth ribs followed by chest wall reconstruction with Mersilene mesh and osteosynthesis for sixth and seventh rib was performed. One month postoperatively, he developed pleural empyema. The alloplastic material was removed, extensive surgical debridement was performed and a latissimus dorsi muscle flap was used to cover the chest wall defect and fill out the remnant space supradiaphragmatically. Three years later, the patient has fully recovered with no local pain or relapse of the tumour. This case shows that rigid chest wall reconstruction with a soft autologous muscle flap is a valuable salvage option in case of infection, making alloplastic material highly risky.

Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer.

BACKGROUND: The 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. METHODS: We 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. RESULTS: Combination 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. CONCLUSIONS: Our 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.

Surgical Repair of the Postoperative Lung Hernia by Combining Mesh Interposition and Chest Wall Stabilization by Using Synthes Plates: A Novel Technique.

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.

Retinotopic encoding of the direction aftereffect.

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.

The T cell repertoire in tumors overlaps with pulmonary inflammatory lesions in patients treated with checkpoint inhibitors.

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.

A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade.

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-1T), intermediate (PD-1N) and no PD-1 expression (PD-1-) from non-small-cell lung cancer patients. PD-1T T cells showed a markedly different transcriptional and metabolic profile from PD-1N and PD-1- lymphocytes, as well as an intrinsically high capacity for tumor recognition. Furthermore, while PD-1T 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-1T 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.

The different mechanisms of the motion direction illusion and aftereffect.

Direction repulsion is the illusory expansion of the angle between two directions of motion, and may occur when the two directions are presented simultaneously (an illusion) or successively (an aftereffect). Here we demonstrate that the motion direction illusion (DI) and aftereffect (DAE) have different mechanisms. Two experiments show that when the two interacting stimuli are presented to different eyes, the DI is greatly reduced but the DAE is obtained at near to full strength. These results suggest that different populations of cells within the visual pathway produce the DI and DAE.

Unexpected collateral impact after out of hospital resuscitation using LUCAS system.

BACKGROUND: Mechanical chest compression using a piston device during reanimation is often the only way to ensure stable chest compression at a constant rate and force. However, its use can be associated with severe fractures of the thoracic rib cage and endanger the clinical course of the patient. Thus, the usage of such a piston device during the reanimation has currently been classified as a mere Class IIB indication. CASE PRESENTATION: We present a case of a 66-year-old male who underwent emergent CABG surgery after receiving out-of-hospital resuscitation as a result of myocardial infarction using the LUCAS system. Due to severe bilateral rib fractures a concomitant emergency chest-wall stabilization surgery had to be performed to ensure uncompromised graft flow to obtain stable cardiac function and hemodynamics. CONCLUSIONS: Reanimation using LUCAS-System might enable stable resuscitation conditions. However, it is crucial not to underestimate potential collateral damage which can in turn aggravate patient's clinical condition.

The Spatial Relationship between Apparent Diffusion Coefficient and Standardized Uptake Value of 18F-Fluorodeoxyglucose Has a Crucial Influence on the Numeric Correlation of Both Parameters in PET/MRI of Lung Tumors.

The minimum apparent diffusion coefficient (ADCmin) derived from diffusion-weighted MRI (DW-MRI) and the maximum standardized uptake value (SUVmax) of FDG-PET are markers of aggressiveness in lung cancer. The numeric correlation of the two parameters has been extensively studied, but their spatial interplay is not well understood. After FDG-PET and DW-MRI coregistration, values and location of ADCmin- and SUVmax-voxels were analyzed. The upper limit of the 95% confidence interval for registration accuracy of sequential PET/MRI was 12 mm, and the mean distance (D) between ADCmin- and SUVmax-voxels was 14.0 mm (average of two readers). Spatial mismatch (D > 12 mm) between ADCmin and SUVmax was found in 9/25 patients. A considerable number of mismatch cases (65%) was also seen in a control group that underwent simultaneous PET/MRI. In the entire patient cohort, no statistically significant correlation between SUVmax and ADCmin was seen, while a moderate negative linear relationship (r = -0.5) between SUVmax and ADCmin was observed in tumors with a spatial match (D ≤ 12 mm). In conclusion, spatial mismatch between ADCmin and SUVmax is found in a considerable percentage of patients. The spatial connection of the two parameters SUVmax and ADCmin has a crucial influence on their numeric correlation.