Infiltration of regulatory T (Treg) cells, an immunosuppressive population of CD4+ T cells, into solid cancers represents a barrier to cancer immunotherapy. Chemokine receptors are critical for Treg ...cell recruitment and cell-cell interactions in inflamed tissues, including cancer, and thus are an ideal therapeutic target. Here, we show in multiple cancer models that CXCR3+ Treg cells were increased in tumors compared with lymphoid tissues, exhibited an activated phenotype, and interacted preferentially with CXCL9-producing BATF3+ dendritic cells (DCs). Genetic ablation of CXCR3 in Treg cells disrupted DC1-Treg cell interactions and concomitantly increased DC-CD8+ T cell interactions. Mechanistically, CXCR3 ablation in Treg cells increased tumor antigen-specific cross-presentation by DC1s, increasing CD8+ T cell priming and reactivation in tumors. This ultimately impaired tumor progression, especially in combination with anti-PD-1 checkpoint blockade immunotherapy. Overall, CXCR3 is shown to be a critical chemokine receptor for Treg cell accumulation and immune suppression in tumors.
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•CXCR3 is elevated on Treg cells within draining lymph nodes and tumors•CXCR3+ Treg cells co-localize with CXCL9-producing type 1 DCs in tumors•Disrupting CXCR3 in Tregs increases tumor antigen cross-presentation by DC1s in tumors•Loss of CXCR3 in Treg cells boosts tumor CD8+ T cells and slows cancer progression
Regulatory T (Treg) cell accumulation in tumors suppresses antitumor immunity, but the mechanisms are incompletely understood. Here, Moreno Ayala et al. show that CXCR3 expression on Treg cells puts them in close proximity to CXCL9-producing dendritic cells in tumors, where they suppress tumor antigen presentation and impede the antitumor CD8+ T cell response.
A 22-year old female with type 1 diabetes (T1DM) presented with generalized rash. She was diagnosed at the age of 9 years and is treated with insulin pump and CGMS (continues glucose monitoring ...sensors), her recent HbA1c was 7.4%. Four weeks prior to her rash presentation she started a low carbohydrate diet (50 gr of carbs per day) in order to improve her glycemic control. Pruritic erythematous papules, papulovesicular, and vesicles appeared on her axillary region, upper back and groins. Lesions were associated with severe pruritus and negatively affected her quality of life. Various therapies were initiated by dermatologist as: antifungal agent, Itraconazole, and Betamethasone Esters, without any improvement. Her serum beta-hydroxybutyrate levels were between 1.1-1.2 mmol/l. Prurigo pigmentosa, a rare pruritic inflammatory dermatosis secondary to her high ketones levels was diagnosed. Her condition resolved after she increased her carbohydrate intake to 75 gr per day. Beta-hydroxybutyrate level decreased concomitantly to 0.1-0.2 mmol/l. When carbohydrate restriction was rechallenged, she again entered ketosis, followed by recurrence of the pruritic lesions. Carbohydrate intake was increased and subsequently all lesions resolved with remaining reticular hyperpigmentation. During the last few years low carb diets have gained popularity among patients with T1DM. This case illustrates the rare side effect of high ketones body levels. Health care providers should be familiar with this side effect.
Disclosure
N. levran: None. K. Mazor-Aronovitch: None. S. Grenberger: None. N. Levek: None. B. Sher: None. E. Mauda: None. Z. Landau: None. E. Monsonego-Ornan: None. O. Pinhas-Hamiel: None.
Abstract
Background
VB-111 is a non-replicating adenovirus carrying a Fas-chimera transgene, leading to targeted apoptosis of tumor vascular endothelium and induction of a tumor-specific immune ...response. This phase I/II study evaluated the safety, tolerability, and efficacy of VB-111 with and without bevacizumab in recurrent glioblastoma (rGBM).
Methods
Patients with rGBM (n = 72) received VB-111 in 4 treatment groups: subtherapeutic (VB-111 dose escalation), limited exposure (LE; VB-111 monotherapy until progression), primed combination (VB-111 monotherapy continued upon progression with combination of bevacizumab), and unprimed combination (upfront combination of VB-111 and bevacizumab). The primary endpoint was median overall survival (OS). Secondary endpoints were safety, overall response rate, and progression-free survival (PFS).
Results
VB-111 was well tolerated. The most common adverse event was transient mild-moderate fever. Median OS time was significantly longer in the primed combination group compared with both LE (414 vs 223 days; hazard ratio HR, 0.48; P = 0.043) and unprimed combination (414 vs 141.5 days; HR, 0.24; P = 0.0056). Patients in the combination phase of the primed combination group had a median PFS time of 90 days compared with 60 in the LE group (HR, 0.36; P = 0.032), and 63 in the unprimed combination group (P = 0.72). Radiographic responders to VB-111 exhibited characteristic, expansive areas of necrosis in the areas of initial enhancing disease.
Conclusions
Patients with rGBM who were primed with VB-111 monotherapy that continued after progression with the addition of bevacizumab showed significant survival and PFS advantage, as well as specific imaging characteristics related to VB-111 mechanism of action. These results warrant further assessment in a randomized controlled study.
Aim
To examine the effectiveness and safety over a 12-month period of a telemedicine intervention in adults with type 1 diabetes (T1D) treated with insulin pumps.
Methods
74 T1D patients on insulin ...pumps for at least 1 year (mean 19.5 11.5 years) and HbA1
c
≥ 6.5% (≥ 48 mmol/mol) were randomized to the telemedicine (
n
= 37) or the standard care group (
n
= 37). The intervention group was instructed to download data from insulin pumps and glucometers monthly. They received immediate phone feedback and recommendations for insulin dose adjustment; and face-to-face visits once in 6 months, compared to once every 3 months for the standard care group. Satisfaction with treatment, quality of life and frequency of hypoglycemic events was evaluated.
Results
The mean changes in HbA1c adjusted to baseline were − 0.08% (0.25 mmol/mol) vs. − 0.01% (0.03 mmol/mol), in the intervention and control groups, respectively (
p
= 0.18) at 12 months, without an increased frequency of hypoglycemia. Patients in the intervention group felt satisfied and interested in continuing with the treatment (
p
= 0.04). The quality of life scores were similar in both groups. Direct total costs were 24% less in the intervention group, and indirect total costs decreased by 22% compared to the year preceding the study.
Conclusions
Internet-based insulin dose adjustment is as effective and safe as routine care in adults with type 1 diabetes treated by insulin pumps. For suitable patients, some of the time-consuming routine visits may be replaced by user-friendly digital medicine.
Clinical trial registration
Clinical Trial.gov Identifier NCT01887431.
The necessity and timing of early postoperative imaging (POI) are debated in many studies. Despite the consensus that early POI does not change patient management, these examinations are routinely ...performed. This is the first prospective study related to POI. Our aims were to assess the necessity of early POI in asymptomatic patients and to verify accuracy of the presented algorithm.
This was an algorithm-based prospective single-center study. The algorithm addressed preoperative, perioperative, and postoperative considerations, including estimated pathology type, device placement, and postoperative neurologic change. Early computed tomography scans were obtained in all patients, but if postoperative algorithm indications did not recommend a scan, the treating team was blinded to them, and patient management was conducted based on clinical examinations alone. A neuroradiologist and study-independent neurosurgeon reviewed all the scans.
Of 103 enrolled patients, 88 remained asymptomatic, and 15 experienced symptoms postoperatively. Pathology was present on POI in 1% of the asymptomatic patients and 53% of the symptomatic patients (P < 0.001). In the asymptomatic group, no treatment modifications were made postoperatively. Blinding of the surgical team was not removed, and 20% of the symptomatic patients returned to the operating room because of imaging and neurologic findings. The goal of <5% algorithm failure was reached with statistical significance.
In asymptomatic postoperative patients in whom early imaging is not performed for oncologic indications, device placement verification, or similar reasons, POI is unnecessary and does not change the management of these patients.
To investigate the effect of repetitive magnetic stimulation (RMS) on corneal epithelial permeability in a rabbit model of exposure keratopathy.
61 female New Zealand White (NZW) rabbits were treated ...on one eye with repetitive magnetic stimulation (RMS) at a frequency of 20 Hz for 15 min. The other eye was untreated. Rabbit eyes were kept open for 2 h to induce acute corneal desiccation. The extent of fluorescein corneal staining was evaluated using EpiView software and the concentration of fluorescein in the anterior chamber was determined by a fluorometer. Safety was evaluated by electroretinogram, spectral domain optical coherence tomography (SD-OCT) and histopathology. Expression pattern of corneal cell markers was determined by immunofluorescence.
A significant decrease in fluorescein concentration in the anterior chamber (54 ± 8.4 ng/ml vs. 146.5 ± 18.6 ng/ml, p = 0.000001) and in corneal surface fluorescein staining score (1.7 ± 0.2 vs. 4.6 ± 0.6, p = 0.00001) was obtained in RMS-treated eyes compared with control eyes, respectively. RMS treatment reduced by nearly 4 fold the percentage of corneal area with epithelial erosions by anterior segment SD-OCT. The therapeutic effect was maintained for at least 3 months. Increased expression of epithelial tight junction protein Zo-1 was observed in treated eyes. SD-OCT and histopathology analysis revealed no pathological changes in the treated or non-treated eyes.
RMS treatment decreases epithelial corneal erosions in a rabbit model of exposure keratopathy, with no indication of pathological changes. RMS may present a novel treatment for protection of corneal epithelium from desiccation.
To evaluate the potential use of anterior segment spectral domain optical coherence tomography (AS-SD-OCT) combined with an automated grading of fluorescein staining for assessment of corneal ...erosions in a rabbit short-term dry eye model.
Twenty-one New Zealand white rabbits were anesthetized and eyes were kept open for 140 minutes to induce acute corneal desiccation. Rectangular scans of the cornea were performed using Spectralis AS-SD-OCT. Total corneal thickness, corneal epithelial thickness, and the percentage of epithelial erosion area (PEEA) were evaluated. Corneas were stained with fluorescein and graded automatically using EpiView and semi-automatically using ImageJ. Spearman's rank-order correlations were calculated to compare the AS-SD-OCT PEEA and the two corneal staining scores.
Eye desiccation resulted in corneal epithelium erosions that covered 0.67% to 14.2% of the central cornea (mean ± SD: 3.95% ± 3.2%) by AS-SD-OCT. The percentage of corneal area positively stained with fluorescein ranged from 0.24% to 38.01% (mean ± SD: 12.24% ± 9.7%) by using ImageJ, correlating with the AS-SD-OCT PEEA (Spearman's ρ, 0.574;
= 0.007). The EpiView score ranged from 0.5 to 10.17 and was better correlated with the AS-SD-OCT PEEA score (Spearman's ρ, 0.795;
= 0.000017).
Our study suggests that multimodal analysis of AS-SD-OCT and grading of fluorescein staining using EpiView software may enable quantitative assessment of corneal epithelial erosions in a rabbit short-term dry eye model.
This multimodal imaging analysis may be applied for evaluation of superficial punctate keratitis associated with dry eye.
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