The role of <Superscript>18</Superscript>F-FDG PET/CT in the assessment of suspected recurrent gastric cancer after initial surgical resection: can the results of FDG PET/CT influence patients’ treatment decision making?

Purpose  

¹⁸F-fluorodeoxyglucose (FDG) PET/CT has been widely used for staging, re-staging and for monitoring therapy-induced changes and response to therapy in patients with various types of cancer, but its utilization for gastric cancer has been limited. The purpose of this study was to evaluate the clinical role of FDG PET/CT in the detection of gastric cancer recurrence as compared with diagnostic CT and to assess the impact of FDG PET/CT results on patients’ treatment planning.     

Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility

Multiple sclerosis (MS) is an inflammatory disease of the CNS that is characterized by BBB dysfunction and has a much higher incidence in females. Compared with other strains of mice, EAE in the SJL mouse strain models multiple features of MS, including an enhanced sensitivity of female mice to disease; however, the molecular mechanisms that underlie the sex- and strain-dependent differences in disease susceptibility have not been described. We identified sphingosine-1-phosphate receptor 2 (S1PR2) as a sex- and strain-specific, disease-modifying molecule that regulates BBB permeability by destabilizing adherens junctions. S1PR2 expression was increased in disease-susceptible regions of the CNS of both female SJL EAE mice and female patients with MS compared with their male counterparts. Pharmacological blockade or lack of S1PR2 signaling decreased EAE disease severity as the result of enhanced endothelial barrier function. Enhanced S1PR2 signaling in an in vitro BBB model altered adherens junction formation via activation of Rho/ROCK, CDC42, and caveolin endocytosis-dependent pathways, resulting in loss of apicobasal polarity and relocation of abluminal CXCL12 to vessel lumina. Furthermore, S1PR2-dependent BBB disruption and CXCL12 relocation were observed in vivo. These results identify a link between S1PR2 signaling and BBB polarity and implicate S1PR2 in sex-specific patterns of disease during CNS autoimmunity.     

Histological and Biochemical Effects of Dexmedetomidine on Liver during an Inflammatory Bowel Disease

Inflammation in the liver is an extraintestinal manifestation that is frequently seen during inflammatory bowel diseases (IBD). The authors investigated histopathologycal, ultrastructural and antioxidant effects of dexmedetomidine (Dex) on liver during trinitrobenzene sulfonic acid (TNBS)-induced inflammatory bowel disease. Thirty-two BALB/c mice were divided (n?=?8) as follows: control; Dex (dexmedetomidine) (30?μg/kg) for 6 days; TNBS 150?μL, TNBS?+?ethanol (50% w/v) intrarectally; TNBS?+?Dex. The histopathological and ultrastructural changes were evaluated. The levels of malondialdehyde (MDA), activity of antioxidant enzymes (GPx and SOD) were measured in liver tissue. Induction of colitis induced histopathological and ultrastructural changes of damage in liver. Those changes were markedly reduced in the TNBS?+?Dex group and that reduction was even significant in comparison to the TNBS group. MDA levels were significantly higher in the TNBS group and dexmedetomidine significantly elevated SOD levels in the TNBS?+?Dex group. These results suggest that the administration of dexmedetomidine reduces the histopathological and ultrastructural damage and increases the defense capacity against oxidative damage on liver in this IBD mice model.     

Discarded Livers Find a New Life: Engineered Liver Grafts Using Hepatocytes Recovered From Marginal Livers

Treatment for end‐stage liver failure is restricted by the critical shortage of donor organs; about 4000 people die in the USA while waiting for a transplantable organ. This situation has been a major driving force behind the rise of tissue engineering to build artificial tissues/organs. Recent advancements in creating transplantable liver grafts using decellularized liver scaffolds bring the field closer to clinical translation. However, a source of readily available and highly functional adult hepatocytes in adequate numbers for regenerative liver therapies still remains unclear. Here, we describe a new method to utilize discarded livers to make transplantable new liver grafts. We show that marginal donor livers damaged due to warm ischemia could be treated with machine perfusion to yield 39 million viable hepatocytes per gram of liver, similar to fresh livers, and these cells could be used to repopulate decellularized liver matrix (DLM) scaffolds to make transplantable liver grafts. The hepatocytes from recovered livers sustained their characteristic epithelial morphology while they exhibited slightly lower protein synthesis functions both in plate cultures and in recellularized liver grafts. The dampened protein synthesis was attributed to residual endoplasmic reticulum stress found in recovered cells. The results here represent a unique approach to reengineer transplantable liver grafts solely from discarded organs.     

Altered expression of methylenetetrahydrofolate reductase modifies response to methotrexate in mice

OBJECTIVE: Folates provide one-carbon units for nucleotide synthesis and methylation reactions. A common polymorphism (677C-->T) in methylenetetrahydrofolate reductase (MTHFR) encodes an enzyme with reduced activity. Response to the antifolate methotrexate (MTX) may be modified in 677TT individuals because MTHFR converts nonmethylated folates, used for thymidine and purine synthesis, to 5-methyltetrahydrofolate, used in homocysteine remethylation to methionine. To study potential interactions between MTHFR activity and MTX, we examined the impact of decreased and increased MTHFR expression on MTX response in mice. METHODS: Mthfr-deficient (Mthfr and Mthfr) and wild-type (Mthfr) mice were injected with MTX or saline and assessed for hematological parameters (hematocrit, hemoglobin, red, and white blood cell numbers), plasma homocysteine, nephrotoxicity, hepatotoxicity, and splenic 2'-deoxyuridine 5'-triphosphate/2'-deoxythymidine 5'-triphosphate ratios. MTHFR-overexpressing transgenic mice (MTHFR-Tg) were generated, metabolites and folate distributions were measured, and response to MTX was assessed. RESULTS: MTX-treated Mthfr and Mthfr mice displayed hyperhomocysteinemia and decreased hematocrit, hemoglobin, and red blood cell numbers compared with wild-type animals. Mthfr mice also showed increased nephrotoxicity and hepatotoxicity. MTHFR-Tg mice were generated and confirmed to have increased levels of MTHFR with altered distributions of folate and thiols in a tissue-specific manner. After MTX treatment, MTHFR-Tg mice exhibited the same decreases in hematological parameters as Mthfr-deficient mice, and significantly decreased thymidine synthesis (higher 2'-deoxyuridine 5'-triphosphate/2'-deoxythymidine 5'-triphosphate ratios) compared with wild-type mice, but they were protected from MTX-induced hyperhomocysteinemia. CONCLUSION: Underexpression and overexpression of Mthfr/MTHFR increase MTX-induced myelosuppression but have distinct effects on plasma homocysteine and nephrotoxicity. Pharmacogenetic analysis of polymorphisms in folate-dependent enzymes may be useful in optimization of MTX therapy.     

Which questionnaires should we use to evaluate quality of life in patients with chronic graft-vs-host disease?

AimTo investigate the ability of two standard quality of life (QOL) questionnaires – The Short Form (36-item) Health Survey (SF-36) and The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ C30) to evaluate QOL in patients with chronic graft-vs-host disease (cGVHD) graded according to National Institutes of Health (NIH) consensus criteria.MethodsIn this cross-sectional study, QOL was assessed in patients who underwent allogeneic stem cell transplantation (allo-SCT) at the University Hospital Centre Zagreb and were alive and in complete remission for more than one year after allo-SCT.ResultsThe study included 58 patients, 38 patients with cGVHD and 20 controls, patients without cGVHD. Patients with cGVHD scored according to the NIH criteria had significantly lower scores of global health status and lower QOL on all SF-36 subscales and most of QLQ C30 functional subscales (P < 0.050 for all comparisons). Furthermore, patients with active cGVHD had significantly lower QOL scores than patients with inactive cGVHD, and this difference was most evident in physical functioning subscale of SF-36 (P = 0.0007) and social functioning subscale of QLQ C30 (P = 0.009).ConclusioncGVHD scored according to the NIH criteria is correlated with patient-reported QOL, particularly in the physical domains as detected by SF-36. QLQ C30 questionnaire adds more information on social functioning and should be used as a valuable tool in the evaluation of social domains in cGVHD patients.Although it is potentially lifesaving for a variety of hematological malignant and non-malignant disorders, allogeneic stem cell transplantation (allo-SCT) carries a significant risk of acute and late post-transplant complications. Improvements in transplantation techniques and supportive care have resulted in a reduction of early transplant-related mortality (1,2). However, the burden of late complications remains high, and two thirds of long-term allo-SCT survivors experience at least one chronic health condition (3). These complications occur due to treatment exposures before and during allo-SCT, cause substantial mortality, and severely impair patients’ functional status and quality of life (QOL). This is why today the aim of the treatment is not just to cure the primary hematological disease, but to facilitate the recovery of the physical and emotional functioning and improve QOL and social reintegration in family and work environment.Health-related QOL is now considered to be one of the relevant treatment outcomes because it provides a broader understanding of the patient’s status beyond simple disease-free survival. It is a multi-dimensional construct comprised of several related domains including physical, emotional, social, and role functioning, as well as a person''s overall evaluation of his or her well-being and ability to function (4,5). Better understanding of QOL in long-term survivors is necessary to provide adapted pre-transplant counseling and recommendations for post-transplant follow-up.With a cumulative incidence of 40%-70% and significant mortality, chronic GVHD (cGVHD) represents the most important late complication following allo-SCT (6,7). Moreover, it seems that the incidence of cGVHD in the recent years has been increasing, probably due to the fact that much older patients undergo allo-SCT, as well as due to the increased use of peripheral blood stem cell grafts and matched unrelated donors, all known risk factors for cGVHD (8). In a series of publications originating from 2005 National Institutes of Health (NIH) Consensus Conference, investigators proposed means to standardize diagnosis, scoring, histopathology, biomarkers, response assessment, and research in cGVHD (9-14). These criteria were developed to advance clinical trials and consequently improve the management of cGVHD and long-term survivorship after allo-SCT.As one of the important treatment outcomes, QOL is increasingly being subjected to the same degree of rigorous study as other significant allo-SCT outcomes. Most of the studies so far have reported a negative, significant association between cGVHD and QOL after allo-SCT (15-20). However, some of the studies have found no association (21-25), and this relationship still needs to be elucidated. The awareness of the relationship between QOL and cGVHD is necessary to further facilitate the prevention and treatment of cGVHD.The aim of this study was to examine the effect of cGVHD on QOL in our cohort of long-term allo-SCT survivors with the use of two standard QOL questionnaires; The Short Form (36-item) Health Survey (SF-36) and The EORTC Quality of Life Questionnaire (QLQ C30). Furthermore, we assessed QOL according to cGVHD severity and activity defined by the NIH consensus criteria.     

Current Practice in Vitamin D Management in Allogeneic Hematopoietic Stem Cell Transplantation: A Survey by the Transplant Complications Working Party of the European Society for Blood and Marrow Transplantation

Beyond its impact on bone health, numerous studies have investigated the immune-regulatory properties of vitamin D and shown how its deficiency can affect outcomes in allogeneic hematopoietic stem cell transplantation (HSCT), particularly in acute or chronic graft-versus-host disease. This survey, carried out by the Transplant Complications Working Party of the European Society for Blood and Marrow Transplantation (EBMT), describes the current clinical practice discrepancies across the EBMT HSCT programs. We therefore recommend the development of evidence-based guidelines to standardize evaluation criteria and to harmonize the management of vitamin D deficiency in patients undergoing allogeneic HSCT.     

Comparison of different cryopreservation protocols for human umbilical cord tissue as source of mesenchymal stem cells

The main purpose of this study is to establish an effective cryopreservation protocol for the umbilical cord tissue as a source of mesenchymal stem cells (MSCs). In this context, it was aimed to use a cryoprotectant that could be an alternative to dimethyl sulfoxide (DMSO) which is commonly used despite the toxic side effects. Therefore, two different cryopreservation solutions were prepared using 10% DMSO and 10% 1,2 propanediol (PrOH). The fresh tissue group that was not performed cryopreservation was used as the control group. Following the cryopreservation step, MSCs were isolated from all groups and compared with each other to assess the efficiency of the cryopreservation solutions. The comparison was performed in terms of followings: morphology, immunophenotypes, growth kinetics, differentiation, and ultrastructural features. Based on the results, there were no significant morphological and immunophenotypic differences between the MSCs isolated from cryopreserved tissue groups and the MSCs isolated from the fresh tissue group. According to the growth kinetic analysis, the cells isolated from the PrOH group had a lower proliferation rate than the cells isolated from the fresh tissue. However, there was no significant difference between the cryopreserved groups in this respect. Osteogenic and adipogenic differentiation was observed in all groups. Upon comparison of the cryopreserved groups, PrOH group was discovered to hold a minor superiority in terms of these modes of differentiation. These results suggest that PrOH, which is considered as a cryoprotectant with low toxicity, could be used as a preferred cryoprotectant instead of DMSO concerning the process of cryopreservation of the umbilical cord.