Mesenchymal stromal/stem cells promote intestinal epithelium regeneration after chemotherapy-induced damage.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for leukemia and a range of non-malignant disorders. The success of the therapy is hampered by occurrence of acute graft-versus-host disease (aGvHD); an inflammatory response damaging recipient organs, with gut, liver, and skin being the most susceptible. Intestinal GvHD injury is often a life-threatening complication in patients unresponsive to steroid treatment. Allogeneic mesenchymal stromal/stem cell (MSC) infusions are a promising potential treatment for steroid-resistant aGvHD. Data from our institution and others demonstrate rescue of approximately 40-50% of aGvHD patients with MSCs in Phase I, II studies and minor side effects. Although promising, better understanding of MSC mode of action and patient response to MSC-based therapy is essential to improve this lifesaving treatment. METHODS: Single cell human small intestine organoids were embedded in Matrigel, grown for 5 days and treated with busulfan for 48 h. Organoids damaged by treatment with busulfan or control organoids were co-cultured with 5000, 10,000, and 50,000 MSCs for 24 h, 48 h or 7 days and the analyses such as surface area determination, proliferation and apoptosis assessment, RNA sequencing and proteomics were performed. RESULTS: Here, we developed a 3D co-culture model of human small intestinal organoids and MSCs, which allows to study the regenerative effects of MSCs on intestinal epithelium in a more physiologically relevant setting than existing in vitro systems. Using this model we mimicked chemotherapy-mediated damage of the intestinal epithelium. The treatment with busulfan, the chemotherapeutic commonly used as conditioning regiment before the HSCT, affected pathways regulating epithelial to mesenchymal transition, proliferation, and apoptosis in small intestinal organoids, as shown by transcriptomic and proteomic analysis. The co-culture of busulfan-treated intestinal organoids with MSCs reversed the effects of busulfan on the transcriptome and proteome of intestinal epithelium, which we also confirmed by functional evaluation of proliferation and apoptosis. CONCLUSIONS: Collectively, we demonstrate that our in vitro co-culture system is a new valuable tool to facilitate the investigation of the molecular mechanisms behind the therapeutic effects of MSCs on damaged intestinal epithelium. This could benefit further optimization of the use of MSCs in HSCT patients.

Prognostic importance of nutritional assessment in patients with acute ischemic stroke undergoing endovascular thrombectomy.

OBJECTIVE: The prevalence of malnutrition in patients with acute ischemic stroke (AIS) can range from 8% to 34%. It has been shown that prognostic nutritional index (PNI) and control nutritional status (CONUT) scores can provide an opportunity to make prognostic predictions in some disease groups. Previous studies have shown a close relationship between malnutrition scores and stroke prognosis. We evaluated the effect of nutritional scores on in-hospital and long-term mortality in AIS patients undergoing endovascular therapy (EVT). PATIENTS AND METHODS: 219 patients who underwent EVT for the AIS were included in this retrospective design and cross-sectional study. The primary endpoint of the study was accepted as all-cause death including in-hospital death, 1-year death, and 3-years death. RESULTS: A total of 57 patients died in the hospital. In-hospital mortality rate was higher in the high CONUT group [36 (49.3%), 10 (13.7%), 11 (15.1%), p<0.001]. A total of 78 patients died within one year, and 1-year mortality was higher in the high CONUT group [43 (58.9%), 21 (28.8), 14 (19.2), p<0.001]. At the end of the 3-year follow-up, 90 patients had died, and the 3-year mortality rate was significantly higher in groups with a high CONUT score than in those with a low CONUT score (p<0.001). CONCLUSIONS: A higher CONUT score, calculated easily by simple scoring with parameters studied from peripheral blood before the EVT procedure, is an independent predictor of in-hospital, 1-year, and 3-years all-cause mortality.

Global longitudinal strain score predicts all cause death in patients with chronic total occlusion with preserved ejection fraction.

OBJECTIVE: Change in LVEF is one of the most important indicators of prognosis in CTO cases. Studies in patients with CTO have shown improvement in LVEF approximately at 3 and 6 months after successful PCI. It has been shown that LV global longitudinal strain (GLS) starts to improve even 1 day after CTO-PCI. We aimed at investigating the effect of subclinical echocardiographic involvement on all-cause mortality in the group with CTO and preserved ejection fraction by evaluating the LV GLS score. PATIENTS AND METHODS: Patients with LVEF ≥ 50% were considered to have preserved ejection fraction and were included in the study. The endpoint of the study was all-cause death. For this retrospective study, 1,171 patients with coronary angiography who had had CTO in any of their vessels were screened. RESULTS: A total of 86 consecutive patients were reviewed in the study. The optimum GLS score cut-off value (≥ 14.18) for predicting mortality was determined using receiver operating characteristic (ROC) curve analysis (AUC: 0.897, sensitivity 87.5%, specificity 81.5% p<0.001). At a mean follow-up of 49 months, a significant difference was found between the two groups in all-cause mortality determined by the GLS score [2 (3.4%) vs. 14 (51.9%), p<0.001]. A significant difference in mortality was observed between the group with a low GLS score and the group with a high GLS score, according to Kaplan-Meier analysis. The effect of GLS score in predicting all-cause mortality was demonstrated in multivariate cox regression analysis (Low GLS score; OR: 6.36 95%CI (1.039-39.013), p=0.045). Cox regression multivariate analysis and the effect of GLS score in predicting mortality were observed [Low GLS score; OR: 6.368 95%CI (1.039-39.013), p=0.045]. CONCLUSIONS: As a predictor, GLS may be a valuable marker of cardiac subclinical dysfunction for all caused mortality in CTO patients.

Long-Term Follow-Up on Systemic Bevacizumab Treatment in Recurrent Respiratory Papillomatosis.

OBJECTIVES/HYPOTHESIS: Recurrent respiratory papillomatosis (RRP) is a primarily benign disease affecting the entire respiratory tract. Treatment is challenging and usually involves surgical interventions and adjuvant medications. Previously, promising results on systemic administration of bevacizumab have been reported. However, experience on long-term systemic use in patients with RRP is not yet available. Here, we present our long-term follow-up on RRP patients undergoing systemic bevacizumab treatment. STUDY DESIGN: Case series. METHODS: To describe experience on long-term systemic bevacizumab administration, we performed the underlying investigation. Clinical, radiological, and bronchoscopy data were collected. RESULTS: To date, a total of n = 5 patients has been treated with systemic bevacizumab at Muenster University Hospital. With a median follow-up since first systemic bevacizumab administration of 95.5 months long-term follow-up is illustrated. Following bevacizumab treatment partial remission or very good partial remission were achieved in all patients. After papilloma recurrence/progression due to bevacizumab discontinuation, further response was documented in all patients in whom bevacizumab was started again. In one patient, bevacizumab was discontinued due to loss of efficacy. Lung cancer developed in one patient with pulmonary papillomatosis prior to bevacizumab administration whereas three patients suffered from malignant transformation during bevacizumab treatment. Systemic bevacizumab led to long-term reduction in surgical interventions in all patients. Except from mild proteinuria and hypertension in two patients therapy was well tolerated. CONCLUSIONS: Systemic bevacizumab represents a promising long-term treatment option for aggressive forms of papillomatosis. Rate of malignant transformation under bevacizumab treatment, optimal treatment schedule, and influence on survival should be further evaluated in clinical trials. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1926-E1933, 2021.

Endothelial tip cells in vitro are less glycolytic and have a more flexible response to metabolic stress than non-tip cells.

Formation of new blood vessels by differentiated endothelial tip cells, stalk cells, and phalanx cells during angiogenesis is an energy-demanding process. How these specialized endothelial cell phenotypes generate their energy, and whether there are differences between these phenotypes, is unknown. This may be key to understand their functions, as (1) metabolic pathways are essentially involved in the regulation of angiogenesis, and (2) a metabolic switch has been associated with angiogenic endothelial cell differentiation. With the use of Seahorse flux analyses, we studied metabolic pathways in tip cell and non-tip cell human umbilical vein endothelial cell populations. Our study shows that both tip cells and non-tip cells use glycolysis as well as mitochondrial respiration for energy production. However, glycolysis is significantly lower in tip cells than in non-tip cells. Additionally, tip cells have a higher capacity to respond to metabolic stress. Finally, in non-tip cells, blocking of mitochondrial respiration inhibits endothelial cell proliferation. In conclusion, our data demonstrate that tip cells are less glycolytic than non-tip cells and that both endothelial cell phenotypes can adapt their metabolism depending on microenvironmental circumstances. Our results suggest that a balanced involvement of metabolic pathways is necessary for both endothelial cell phenotypes for proper functioning during angiogenesis.

Prostate specific membrane antigen (PSMA) expression in non-small cell lung cancer.

OBJECTIVES: PSMA (prostate-specific membrane antigen) is overexpressed in prostate cancer cells and is reported to be a promising target for antibody-based radioligand therapy in patients with metastasized prostate cancer. Since PSMA expression is not restricted to prostate cancer, the underlying study investigates PSMA expression in non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: Immunohistochemistry was used to identify PSMA expression in n = 275 samples of NSCLC tissue specimens. By means of CD34 co-expression, the level of PSMA expression in tumor associated neovasculature was investigated. The impact of PSMA expression on clinicopathologic parameters and prognosis was evaluated. RESULTS: PSMA tumor cell expression in NSCLC is as low as 6% and was predominantly found in squamous cell carcinoma (p = 0.002). Neovascular PSMA expression was found in 49% of NSCLC. High neovascular PSMA expression was associated with higher tumor grading (G3/G4) (p < 0.001). Neither for PSMA tumor cell expression, nor for PSMA neovascular cell expression prognostic effects were found for the investigated NSCLC cases. CONCLUSION: Here, we report on the expression of PSMA in NSCLC tissue samples. Against the background of a potential treatment with radiolabeled PSMA ligands, our data might serve for the future identification of patients who could benefit from this therapeutic option.

Progressive Multifocal Leukoencephalopathy after Ibrutinib Therapy for Chronic Lymphocytic Leukemia.

Progressive multifocal leukoencephalopathy (PML) is a devastating neurological disease observed nearly exclusively in immunocompromised patients. Recently, the introduction of monoclonal antibodies significantly inhibiting the immune system such as rituximab has led to an increase in PML cases. Although rituximab-based immunochemotherapy remains the standard of treatment for chronic lymphocytic leukemia (CLL), the importance of Bruton's tyrosine kinase inhibitors such as ibrutinib is steadily increasing. However, long-term experiences regarding possible side effects of these new substances are rare. Here, we report the development of eventually fatal PML possibly associated with ibrutinib therapy for CLL after multiple prior treatment lines, including rituximab. To the best of our knowledge, this is the first study to report such findings. Since the last course of rituximab was applied over 3 years ago, it is conceivable that the strong B cell inhibition by ibrutinib led to PML. With increased awareness of this potential side effect, further clinical studies are certainly warranted to evaluate this possible association.

Progressive Multifocal Leukoencephalopathy after Ibrutinib Therapy for Chronic Lymphocytic Leukemia / Journal of the Korean Cancer Association, 대한암학회지

Progressive multifocal leukoencephalopathy (PML) is a devastating neurological disease observed nearly exclusively in immunocompromised patients. Recently, the introduction of monoclonal antibodies significantly inhibiting the immune system such as rituximab has led to an increase in PML cases. Although rituximab-based immunochemotherapy remains the standard of treatment for chronic lymphocytic leukemia (CLL), the importance of Bruton’s tyrosine kinase inhibitors such as ibrutinib is steadily increasing. However, long-term experiences regarding possible side effects of these new substances are rare. Here, we report the development of eventually fatal PML possibly associated with ibrutinib therapy for CLL after multiple prior treatment lines, including rituximab. To the best of our knowledge, this is the first study to report such findings. Since the last course of rituximab was applied over 3 years ago, it is conceivable that the strong B cell inhibition by ibrutinib led to PML. With increased awareness of this potential side effect, further clinical studies are certainly warranted to evaluate this possible association.

Total pulmonary vein diameter is a strong predictor of atrial fibrillation after coronary artery bypass graft surgery.

OBJECTIVE: Recent studies have shown that the pulmonary veins are important in atrial fibrillation (AF). This study evaluated the relationship between total pulmonary vein diameter and postoperative AF in on-pump coronary artery bypass graft (CABG) patients. PATIENTS AND METHODS: Our study enrolled 149 patients undergoing on-pump CABG. The primary endpoint was defined as postoperative new-onset in-hospital AF. All patients underwent preoperative non-contrast tomography to measure pulmonary vein diameter. RESULTS: The patients who developed AF had significantly greater total pulmonary vein diameters than those who remained in sinus rhythm. Logistic multivariate regression analysis revealed that only total pulmonary vein diameter was an independent predictor of the development of new-onset AF. CONCLUSIONS: To our knowledge, this is the first report of an association between total pulmonary vein diameter and the development postoperative AF. The identification of high-risk patients using pulmonary vein diameters should facilitate preventive measures.

Overcoming the blood-brain tumor barrier for effective glioblastoma treatment.

Gliomas are the most common primary brain tumors. Particularly in adult patients, the vast majority of gliomas belongs to the heterogeneous group of diffuse gliomas, i.e. glial tumors characterized by diffuse infiltrative growth in the preexistent brain tissue. Unfortunately, glioblastoma, the most aggressive (WHO grade IV) diffuse glioma is also by far the most frequent one. After standard treatment, the 2-year overall survival of glioblastoma patients is approximately only 25%. Advanced knowledge in the molecular pathology underlying malignant transformation has offered new handles and better treatments for several cancer types. Unfortunately, glioblastoma multiforme (GBM) patients have not yet profited as although numerous experimental drugs have been tested in clinical trials, all failed miserably. This grim prognosis for GBM is at least partly due to the lack of successful drug delivery across the blood-brain tumor barrier (BBTB). The human brain comprises over 100 billion capillaries with a total length of 400 miles, a total surface area of 20 m(2) and a median inter-capillary distance of about 50 µm, making it the best perfused organ in the body. The BBTB encompasses existing and newly formed blood vessels that contribute to the delivery of nutrients and oxygen to the tumor and facilitate glioma cell migration to other parts of the brain. The high metabolic demands of high-grade glioma create hypoxic areas that trigger increased expression of VEGF and angiogenesis, leading to the formation of abnormal vessels and a dysfunctional BBTB. Even though the BBTB is considered 'leaky' in the core part of glioblastomas, in large parts of glioblastomas and, even more so, in lower grade diffuse gliomas the BBTB more closely resembles the intact blood-brain barrier (BBB) and prevents efficient passage of cancer therapeutics, including small molecules and antibodies. Thus, many drugs can still be blocked from reaching the many infiltrative glioblastoma cells that demonstrate 'within-organ-metastasis' away from the core part to brain areas displaying a more organized and less leaky BBTB. Hence, drug delivery in glioblastoma deserves explicit attention as otherwise new experimental therapies will continue to fail. In the current review we highlight different aspects of the BBTB in glioma patients and preclinical models and discuss the advantages and drawbacks of drug delivery approaches for the treatment of glioma patients. We provide an overview on methods to overcome the BBTB, including osmotic blood-brain barrier disruption (BBBD), bradykinin receptor-mediated BBTB opening, inhibition of multidrug efflux transporters, receptor-mediated transport systems and physiological circumvention of the BBTB. While our knowledge about the molecular biology of glioma cells is rapidly expanding and is, to some extent, already assisting us in the design of tumor-tailored therapeutics, we are still struggling to develop modalities to expose the entire tumor to such therapeutics at pharmacologically meaningful quantities. Therefore, we must expand our knowledge about the fundamentals of the BBTB as a step toward the design of practical and safe devices and approaches for enhanced drug delivery into the diseased brain area.