PD-1/CTLA-4 Blockade Leads to Expansion of CD8+PD-1int TILs and Results in Tumor Remission in Experimental Liver Cancer.

Background: Checkpoint inhibitors act on exhausted CD8+ T cells and restore their effector function in chronic infections and cancer. The underlying mechanisms of action appear to differ between different types of cancer and are not yet fully understood. Methods: Here, we established a new orthotopic HCC model to study the effects of checkpoint blockade on exhausted CD8+ tumor-infiltrating lymphocytes (TILs). The tumors expressed endogenous levels of HA, which allowed the study of tumor-specific T cells. Results: The induced tumors developed an immune-resistant TME in which few T cells were found. The few recovered CD8+ TILs were mostly terminally exhausted and expressed high levels of PD-1. PD-1/CTLA-4 blockade resulted in a strong increase in the number of CD8+ TILs expressing intermediate amounts of PD-1, also called progenitor-exhausted CD8+ TILs, while terminally exhausted CD8+ TILs were almost absent in the tumors of treated mice. Although transferred naïve tumor-specific T cells did not expand in the tumors of untreated mice, they expanded strongly after treatment and generated progenitor-exhausted but not terminally exhausted CD8+ TILs. Unexpectedly, progenitor-exhausted CD8+ TILs mediated the antitumor response after treatment with minimal changes in their transcriptional profile. Conclusion: In our model, few doses of checkpoint inhibitors during the priming of transferred CD8+ tumor-specific T cells were sufficient to induce tumor remission. Therefore, PD-1/CTLA-4 blockade has an ameliorative effect on the expansion of recently primed CD8+ T cells while preventing their development into terminally exhausted CD8+ TILs in the TME. This finding could have important implications for future T-cell therapies.

[Which patients from routine care use the new insulin analogue glargine U300 compared to patients with glargine U100 : A multicenter analysis of 14,123 patients with insulin glargine from die diabetes registries DPV and DIVE]. / Welche Patienten aus der Routinebetreuung verwenden das neue Insulin-Analogon Glargin U300 im Vergleich zu Patienten mit Glargin U100? : Eine multizentrische Analyse von 14.123 Patienten mit Insulin Glargin aus den Diabetesregistern DPV und DIVE.

BACKGROUND: Glargine U300 (Gla-300) is a further development of glargine U100 (Gla-100). Since 2015, Gla-300 has been available in Germany and Austria. We compared patients initiating therapy with Gla-300 with patients starting with Gla-100. Moreover, it was investigated whether patients from real-life diabetes care differ from patients participating in the EDITION clinical study program. METHODS: Data are based on the diabetes registries DPV and DIVE. Patients started/switched to Gla-100 or Gla-300 in 2015 were included. Linear regression was applied for bodyweight (BW), BMI, HbA1C, daily total and basal insulin dose/kgBW and negative binomial regression for severe hypoglycemia. Data were adjusted for age, sex, and diabetes duration. RESULTS: 14,123 patients were identified (Gla-100: 11,397; Gla-300: 2726). Gla-300 patients with T1D were older, T2D patients younger compared to subjects using Gla-100 (both p < 0.0001). In Gla-300 subjects, diabetes duration was longer (both p < 0.0001). Patients started/switched to Gla-300 had a higher BW, a higher BMI and a lower baseline HbA1C. The rate of severe hypoglycemia was comparable. Total and basal insulin doses/kgBW were higher in patients with Gla-300. DPV/DIVE subjects were older, had a lower BW, and were more frequently male compared to EDITION patients. HbA1C was higher in T1D patients from DPV/DIVE. CONCLUSION: Data from the diabetes registries DPV/DIVE indicate differences between Gla-300 and Gla-100 patients at the onset of insulin therapy. This analysis provides additional information to the EDITION clinical study program.

Lean diabetes in middle-aged adults: A joint analysis of the German DIVE and DPV registries.

AIMS: To assess differences in demographics, treatment and outcome of lean (LD) compared to overweight and obese people with diabetes clinically classified as type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: We combined data from the German DIVE (Diabetes Versorgungs-Evaluation) and DPV (Diabetes-Patienten-Verlaufsdokumentation) databases to produce a large cohort of people with T2DM. The characteristics of people with Body Mass Index (BMI) <25 kg/m2, ≥25-30 kg/m2 and ≥30 kg/m2 aged 30 to 50 years were compared, including demographics, cardiovascular (CV) risk factors, comorbidities and outcomes. RESULTS: A total of 37,870 people were included in the analysis, 3,191 of these (8.4%) had a BMI < 25 kg/m2. LD reported more nicotine (41.6% of 2,070 vs. 38.1% of 6,070 and 33.4% of 16,823; P<0.001)and alcohol consumption (12.0% of 1,282, 10.3% of 3,594 and 6.6% of 9,418; P<0.001)compared to overweight and obese people. More LD were treated with insulin in comparison to the other subgroups (short acting insulin 33.1% of 3,191 vs. 28.4% of 9,234 and 28.0% of 25,445; P <0.001; long acting insulin 31.3% of 3,191 vs. 28.9% of 9,234 and 29.3% of 25,445; P = 0.043). Regression models adjusted for age, gender and diabetes duration showed a 2.50 times higher odds ratio (OR) for hypoglycemia and a 2.52 higher OR for mortality in LD compared to the BMI subgroup ≥30 kg/m2. CONCLUSIONS: LD is associated with an increased risk of hypoglycaemia and death. Patients are characterized by male gender, lifestyle habits as smoking and alcohol consumption while cardiovascular comorbidities are less important. In comparison to patients of the other weight groups they are treated with insulin more often and considerably less with metformin.

Real-life experience of patients starting insulin degludec. A multicenter analysis of 1064 subjects from the German/Austrian DPV registry.

BACKGROUND: The long-acting insulin analogue degludec is a therapeutic option for patients with type 1 (T1D) or type 2 diabetes (T2D). Aim of this analysis was to investigate differences in clinical characteristics of patients before and after initiating degludec use in a cohort of German/Austrian patients. METHODS: 1064 subjects with T1D/T2D and documented degludec use from the Diabetes-Patient-Follow-Up (DPV) registry were included. The follow-up cohort (n=421) comprised patients with available data before and 3-15months after switching to degludec. A t-test for paired values was implemented to compare rates of severe hypoglycaemia, and mean values for HbA1C, BMI, basal insulin dose/kg bodyweight/day, and the number of basal insulin injections/day before and after switching to degludec Results were stratified by type of diabetes. In T1D, subgroup analyses were conducted (age, sex, basal insulin used before switching). P<0.05 was considered significant. FINDINGS: In T1D (n=360), basal insulin dose (0.43±0.17 to 0.38±0.13IU) and the number of basal injections/day (1.7±0.6 to 1.1±0.3) decreased whereas BMI increased from 23.2±4.8 to 24.0±5.0kg/m2 (all p<0.0001) after switching to degludec. No significant changes were observed regarding rates of severe hypoglycaemia or HbA1C-values. Findings were comparable for subgroups. In T2D (n=61), basal insulin dose (0.41±0.23 to 0.38±0.21; p=0.1730) and the number of basal injections/day (1.3±0.4 to 1.1±0.3; p=0.0097) decreased after switching to degludec. HbA1C improved from 7.9±1.6 to 7.1±1.5% (p<0.0001). CONCLUSIONS: The DPV registry provides data from real-life diabetes care. Our analysis predominantly confirmed results from clinical trials and provides additional information complementing the clinical study program of degludec.

Liver regeneration: the emergence of new pathways.

The present overview summarizes important knowledge having accumulated during the last years. The liver maintains a steady mass which is basically controlled by a delicate balance between cell gain and cell loss. However, reconstitution of the organ after tissue loss does not only involve replacement of target cells, but also complex remodeling processes resulting in the reconstruction of the typical tissue architecture. Most information in liver regeneration refers to hepatocytes. It is important to note that hepatocytes are not terminally differentiated cells, but cells situated in the G0 phase that can undergo proliferation upon appropriate stimulation. In most situations, hepatic stem cells are not significantly involved in this response. Hepatocyte regeneration is accomplished by a sequence of distinct phases: an initiation phase, rendering cells in a state of replicative competence; a proliferation phase, where expansion of the cell population occurs; and a termination phase, where cell growth is suppressed to terminate regeneration at a set point. These three phases are regulated by a whole group of factors, mainly cytokines, the significance of which has in part been defined by use of animal models with target gene deletions (gene knockouts). It seems that several mechanisms are capable to sense the critical cell mass which has to be achieved. Hepatocyte regeneration is accompanied by a complex remodeling of hepatic tissue, with a transient breakdown of the lobular architecture. In contrast to hepatocytes, less is known for the the regenerative replacement of bile ducts, blood vessels and hepatic stellate cells.