Adjuvant Approach Research Articles

Evidence in support of using a neurochemistry approach to identify therapy for both epilepsy and associated depression.

The present study aimed to develop a neurochemistry-based single or adjuvant therapy approach for comprehensive management of epilepsy and associated depression employing pentylenetetrazole-kindled animals. Kindling was induced in two-month-old male Swiss albino mice by administering a subconvulsant pentylenetetrazole dose (35mg/kg, i.p.) at an interval of 48±2h. These kindled animals were treated with saline and sodium valproate (300mg/kg/day, i.p.) for 15days. Except for the naïve group, all other groups were challenged with pentylenetetrazole (35mg/kg, i.p.) on days 5, 10, and 15 to evaluate the seizure severity. Depression was evaluated in all experimental groups after normalization of locomotor activity, using tail suspension and forced swim test on days 1, 5, 10, and 15. Four hours after behavioral evaluations on day 15, all animals were euthanized to collect their serum and discrete brain parts. Corticosterone levels were estimated in all the experimental groups as a marker of a dysregulated hypothalamus pituitary adrenal axis. Neurochemical alterations (norepinephrine, dopamine, tryptophan, kynurenine, serotonin, glutamate, GABA, and total nitrate levels) were also estimated in the cortical and hippocampal areas of the mouse brain. Results revealed that saline-treated kindled animals were associated with significant depression and altered neurochemical milieu in comparison with naïve animals. Chronic valproate treatment in kindled animals significantly reduced seizure severity score bud did not ameliorate associated depression or completely restore altered biochemical and neurochemical milieu. Based on the observation of neurochemical changes in all the groups, we propose that restoration of altered neurochemical milieu, elevated indoleamine 2,3-dioxygenase enzyme activity, and corticosterone levels using pharmacological tools with/out valproic acid may be explored for management of both epilepsy and comorbid depression.

Diabetes Educators' Intended and Reported Use of Common Diabetes-Related Technologies: Discrepancies and Dissonance.

Technology provides adjuvant and/or alternative approaches to care and may promote self-care, communication, and engagement with health care services. Common recent technologies for diabetes include continuous subcutaneous insulin infusions (insulin pumps), continuous glucose monitoring systems, smartphone and tablet applications, and telehealth (video conferencing). This study reports Australian diabetes educators' intentions and reported professional use of these technologies for people with type 1 diabetes, and factors predictive of this. An anonymous, web-based questionnaire based on the technology acceptance model was distributed to members of the Australian Diabetes Educators Association through their electronic newsletter. Exploratory factor analysis revealed a 5-factor solution comprising confidence and competence, improving clinical practice, preparation (intentions and training), ease of use, and subjective norms. Logistic regression analyses identified factors predicting intention and use of technology. Respondents (n = 228) had high intentions to use technology. The majority reported using continuous subcutaneous insulin infusions, continuous glucose monitoring systems, and applications with patients, but usage was occasional. Confidence and competence independently predicted both intentions and use of all 4 technologies. Preparation (intentions and training) independently predicted use of each technology also. Discrepancies and dissonance appear between diabetes educators' intentions and behavior (intentions to use and reported technology use). Intentions were higher than current use, which was relatively low and not likely to provide significant support to people with type 1 diabetes for disease management, communication, and engagement with health care services. Continuing education and experiential learning may be key in supporting diabetes educators to align their intentions with their practice.

Clinicopathologic analysis and prognostic factors for survival in early stage patients with ampullary carcinoma.

e15666Background: In this study we aimed to evaluate the possible important clinicopathological features and adjuvant treatment approaches in terms of prognosis in patient with early stage ampullar...

Cabazitaxel operates anti-metastatic and cytotoxic via apoptosis induction and stalls brain tumor angiogenesis.

Taxanes target microtubules and are clinically established chemotherapeutic agents with proven efficacy in human cancers. Cabazitaxel (XRP-6258, Jevtana®) is a second generation semisynthetic taxane with high chemotherapeutic potential in prostate cancer. There, cabazitaxel can overcome docetaxel-resistant prostate cancer. Here, we tested the effects of cabazitaxel on glioma cells, and non-transformed cells such as neurons and astrocytes. Cabazitaxel operates highly toxic in various human glioma cells at nanomolar concentrations. In contrast, primary astrocytes and neurons are not affected by this agent. Cabazitaxel disrupts cytoskeletal F-actin fibers and induces apoptotic cell death in gliomas. Moreover, cabazitaxel displayed highest efficacy in inhibiting glioma cell migration and invasion. Here we demonstrate that cabazitaxel inhibited tumor migration already at 1 nM. We also tested cabazitaxel in the ex vivo VOGiM assay. Cabazitaxel stalled glioma growth and at the same time inhibited tumor-induced angiogenesis. In summary, we found that cabazitaxel operates as an apoptosis-inducing gliomatoxic agent with strongest effects on migration and invasive growth. Thus, our report uncovered cabazitaxel actions on gliomas and on the brain tumor microenvironment. These data reveal novel aspects for adjuvant approaches when applied to brain tumor patients.

HSP70 Inhibition Limits FAK-Dependent Invasion and Enhances the Response to Melanoma Treatment with BRAF Inhibitors.

The stress-inducible chaperone protein HSP70 (HSPA1) is implicated in melanoma development, and HSP70 inhibitors exert tumor-specific cytotoxic activity in cancer. In this study, we documented that a significant proportion of melanoma tumors express high levels of HSP70, particularly at advanced stages, and that phospho-FAK (PTK2) and BRAF are HSP70 client proteins. Treatment of melanoma cells with HSP70 inhibitors decreased levels of phospho-FAK along with impaired migration, invasion, and metastasis in vitro and in vivo Moreover, the HSP70 inhibitor PET-16 reduced levels of mutant BRAF, synergized with the BRAF inhibitor PLX4032 in vitro, and enhanced the durability of response to BRAF inhibition in vivo Collectively, these findings provide strong support for HSP70 inhibition as a therapeutic strategy in melanoma, especially as an adjuvant approach for overcoming the resistance to BRAF inhibitors frequently observed in melanoma patients. Cancer Res; 76(9); 2720-30. ©2016 AACR.

Adenosine-mediated immunosuppression in patients with squamous cell carcinoma of the head and neck.

This review article describes the potential role of ectonucleotidase activity, adenosine metabolism, and the adenosinergic signaling pathway in the suppression of the host immune system in patients with head and neck cancer. Identifying such mechanisms leads to abetter understanding of immunosuppressive mechanisms in this patient population. Further, potential targets for immunotherapy in an adjuvant approach to treating squamous cell carcinoma of the head and neck in the future might be identified and improve the prognosis of these patients.

Gaps between Evidence and Practice in Postoperative Radiotherapy for Prostate Cancer: Focus on Toxicities and the Effects on Health-Related Quality of Life.

Adjuvant radiotherapy (ART) after prostatectomy for patients with high-risk features [extracapsular extension (ECE), seminal vesicle invasion (SVI), and positive margin] has been shown to be associated with improved biochemical disease-free survival in three large randomized trials and with improved overall survival in one. Similarly, salvage radiotherapy (SRT) can effectively achieve biochemical control in a significant proportion of patients with a rising PSA after surgery. Nonetheless, both approaches of postoperative RT remain highly underutilized. This might be partly due to concerns with overtreatment inherent to adjuvant approaches, and/or hesitance about causing radiation toxicities and their subsequent effects on the patient’s quality of life. Herein, we review the literature lending evidence to these arguments. We show recent series of ART/SRT and their low rates of acute and long-term toxicities, translating only in transient decline in quality-of-life (QoL) outcomes. We conclude that concerns with side effects should not preclude the recommendation of an effective and curative-intent therapy for men with prostate cancer initially treated with radical surgery.

A novel approach to the management of carotid blowout syndrome: the use of thrombin in a case of failed covered stenting

Acute hemorrhage relating to an expanding pseudoaneurysm of the carotid artery is referred to as carotid blowout syndrome (CBS). CBS is associated with a high morbidity and mortality. We describe...

A novel multi-drug metronomic chemotherapy significantly delays tumor growth in mice.

BackgroundThe tumor immunosuppressive microenvironment represents a major obstacle to an effective tumor-specific cellular immune response.MethodsIn the present study, the counterbalance effect of a novel metronomic chemotherapy protocol on such an immunosuppressive microenvironment was evaluated in a mouse model upon sub-cutaneous ectopic implantation of B16 melanoma cells. The chemotherapy consisted of a novel multi-drug cocktail including taxanes and alkylating agents, administered in a daily metronomic fashion. The newly designed strategy was shown to be safe, well tolerated and significantly efficacious.ResultsTreated animals showed a remarkable delay in tumor growth and prolonged survival as compared to control group. Such an effect was directly correlated with CD4+ T cell reduction and CD8+ T cell increase. Furthermore, a significant reduction in the percentage of both CD25+FoxP3+ and CD25+CD127low regulatory T cell population was found both in the spleens and in the tumor lesions. Finally, the metronomic chemotherapy induced an intrinsic CD8+ T cell response specific to B16 naturally expressed Trp2 TAA.ConclusionThe novel multi-drug daily metronomic chemotherapy evaluated in the present study was very effective in counterbalancing the immunosuppressive tumor microenvironment. Consequently, the intrinsic anti-tumor T cell immunity could exert its function, targeting specific TAA and significantly containing tumor growth. Overall, the results show that this represents a promising adjuvant approach to significantly enhance efficacy of intrinsic or vaccine-elicited tumor-specific cellular immunity.

Salivary proteomics: A new adjuvant approach to the early diagnosis of familial juvenile systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic multisystemic disease characterized by autoimmune inflammatory disturbance. Pleomorphic manifestations are present and a potentially progressive and debilitating course can be detected. SLE rarely manifests before age 5, and its onset peaks is around puberty. Although clinical manifestations, immunological alterations and treatment do not differ between juvenile and adult SLE, children tend to present with a more aggressive disease course than adults. Hence, autoimmune rheumatic diseases are the most common cause of morbidity and mortality in pediatric populations. Blood serum analysis plays an especially important role in the detection and monitoring of autoantibodies in SLE. However, since blood sampling is an uncomfortable procedure, especially in children, novel less invasive techniques and approaches are of utmost importance to evaluate pediatric subjects. In this regard, saliva samples have several advantages, such as: easy access, fast collection, painless and riskless procedure. Saliva has antimicrobial, immunomodulatory and anti-inflammatory properties, as well as several other relevant features. The whole saliva is a complex mixture of major and minor salivary gland secretion, gingival crevicular fluid, transudates plasma protein, keratinocyte products and oral microbiota. This biological fluid reflects the physiological state of the body, including the emotional condition, and endocrine, nutritional and metabolic changes. Therefore, salivary proteomics is becoming increasingly used for the early diagnosis of several diseases such as breast cancer, oral cancer, Sjögren’s syndrome, diffuse systemic sclerosis, rheumatoid arthritis, among others. Considering the detection of some potential markers related to SLE in serum and urine, this study aims to conduct an initial evaluation of the possible presence of such biomarkers in saliva. Furthermore, it is expected to track down new salivary proteins that could be correlated with the disease. As such, it is important to evaluate whether the analysis of the salivary proteome of children whose mothers have SLE may help identify biomarkers for the early detection and monitoring of the condition.

Biomarkers of residual disease after neoadjuvant therapy for breast cancer.

Nowadays, the decision of which adjuvant treatment should be given to patients with residual breast cancer after neoadjuvant therapy is based on the initial, pretreatment breast cancer molecular subtype and on the estimated residual tumour burden after neoadjuvant therapy. Substantial biological differences exist, however, between treatment-naive breast cancer and the residual tissue that remains after neoadjuvant therapy. In addition, the evaluation of relapse risk in patients is subject to a lack of uniformity in pathological qualification and quantification of remnant breast cancer following neoadjuvant treatment. In this Review, we present the recent recommendations for standardized evaluation of response to neoadjuvant therapy in patients with breast cancer, followed by a comprehensive overview of the pathobiological features of the residual disease after neoadjuvant therapy, which could serve as prognostic biomarkers or guide the choice of targeted adjuvant approaches. These biomarker candidates are at different stages of development, but some already have demonstrated superior prognostic value compared with biomarkers derived from pretreatment breast-cancer characteristics. The evidence presented herein indicates that further research on the biology of breast cancer that persists after neoadjuvant therapy is necessary to improve the management of this disease.

Cancer Vaccines: A Brief Overview.

Vaccine approaches for cancer differ from traditional vaccine approaches for infectious disease in tending to focus on clearing active disease rather than preventing disease. In this review, we provide a brief overview of different types of vaccines and adjuvants that have been investigated for the purpose of controlling cancer burdens in patients, some of which are approved for clinical use or in late-stage clinical trials, such as the personalized dendritic cell vaccine sipuleucel-T (Provenge) and the recombinant viral prostate cancer vaccine PSA-TRICOM (Prostvac-VF). Vaccines against human viruses implicated in the development and progression of certain cancers, such as human papillomavirus in cervical cancer, are not considered here. Cancers express "altered self" antigens that tend to induce weaker responses than the "foreign" antigens expressed by infectious agents. Thus, immune stimulants and adjuvant approaches have been explored widely. Vaccine types considered include autologous patient-derived immune cell vaccines, tumor antigen-expressing recombinant virus vaccines, peptide vaccines, DNA vaccines, and heterologous whole-cell vaccines derived from established human tumor cell lines. Opportunities to develop effective cancer vaccines may benefit from seminal recent advances in understanding how immunosuppressive barricades are erected by tumors to mediate immune escape. In particular, targeted ablation of these barricades with novel agents, such as the immune checkpoint drug ipilimumab (anti-CTLA-4) approved recently for clinical use, may offer significant leverage to vaccinologists seeking to control and prevent malignancy.

Malignant and borderline phyllodes tumor of breast treated with a multi-modality approach in a tertiary cancer care centre in North India

Background:Phyllodes tumor (PT) of the breast can be categorized into benign, borderline and malignant subgroups depending on various histopathological factors. Although malignant PTs may be indolent and controlled by local excision, they frequently show local and distant relapses. Literature reveals local recurrence to be the predominant pattern of failure and thus emphasizes the importance of adjuvant radiation in these tumors. The role of systemic chemotherapy has remained doubtful.Materials and Methods:We have analyzed details of all patients of PT (n = 33) treated with adjuvant multi-modality approach in our institute since 1994–2009. The demographic data, treatment details, recurrence patterns and salvage treatment options were documented.Results:All patients received adjuvant radiation. Seven patients received adjuvant chemotherapy. The mean survival of the entire cohort was 150.618 months. There was a trend for better overall survival with borderline grade (193.6 vs. 160.2 months; P = 0.08, log rank). The disease free survival (DFS) favored borderline grade (193.6 months vs. 82.9 months for high grade; P = 0.02, log rank). The DFS was significantly better in tumors having negative margins on postoperative histopathological examination (DFS rate at 5 years being 100% vs. 69.2% for positive or close margins; P = 0.015). The mode of surgery did not have any impact on survival.Conclusion:Adjuvant Radiation should be discussed taking into account surgical margins, size and various pathological factors of the primary. Adjuvant radiation may be utilized in high risk patients to enhance loco-regional control. Systemic chemotherapy is an option, worth exploring, in cases of systemic failure.

Zinc Chloride Protects against Streptozotocin-Induced Diabetic Nephropathy in Rats

Diabetes mellitus (DM) is a health problem affecting millions of individuals worldwide. Diabetic nephropathy (DN), as a significant complication of DM, has become the most common cause of endstage renal failure. Oxidative stress constitutes the key and common events in the pathogenesis of DN and antioxidants may play a beneficial role in its prevention. This study was conducted to investigate the effect of Zinc Chloride on streptozotocin-induced diabetic nephropathy in rats compared to Gliclazide, a reference antidiabetic agent. Results showed that Zinc Chloride was able to control STZ-induced DN in rats as it normalized the elevated blood pressure, the increased insulin release, and the decreased blood glucose level. Zinc Chloride also improved kidney function as determined by the restoration of blood urea and creatinine level. Finally, Zinc Chloride was able to boost the antioxidant defenses of the kidney by increasing the reduced glutathione content and decreasing lipid peroxides content in addition to significantly decreasing kidney nitric oxide content compared to diabetic control rats. These results suggest that exposure to Zinc Chloride can protect from diabetic nephropathy and can be used as an adjuvant approach to treatment and prevention of renal damage.

HNF1β drives glutathione (GSH) synthesis underlying intrinsic carboplatin resistance of ovarian clear cell carcinoma (OCCC).

Chemoresistance to platinum-based antineoplastic agents is a consistent feature among ovarian carcinomas; however, whereas high-grade serous carcinoma (OSC) acquires resistance during chemotherapy, ovarian clear cell carcinoma (OCCC) is intrinsically resistant. The main objective of this study was to explore, in vitro and in vivo, if hepatocyte nuclear factor 1β (HNF1β) and glutaminolysis contribute for the resistance of OCCC to carboplatin through the intrinsically increased GSH bioavailability. To disclose the role of HNF1β, experiments were also performed in an OSC cell line, which does not express HNF1β. Metabolic profiles, GSH quantification, HNF1β, and γ-glutamylcysteine ligase catalytic subunit (GCLC) and modifier subunit (GCLM) expression, cell cycle, and death were assessed in ES2 cell line (OCCC) and OVCAR3 cell line (OSC); HNF1β knockdown was performed in ES2 and murine model of subcutaneous and peritoneal OCCC tumors was established to test buthionine sulphoxamine (BSO), as a sensitizer to carboplatin. Glutaminolysis is activated in ES2 and OVCAR3, though ES2 exclusively synthesizes amino acids and GSH. ES2 cells are more resistant to carboplatin than OVCAR3 and the abrogation of GSH production by BSO sensitizes ES2 to carboplatin. HNF1β regulates the expression of GCLC, but not GCLM, and consequently GSH production in ES2. In vivo, BSO prior to carboplatin reduces dramatically subcutaneous tumor size and GSH levels, as well as peritoneal dissemination. Our study discloses HNF1β as the mediator of intrinsic OCCC chemoresistance and sheds a light to re-explore a cancer adjuvant therapeutic approach using BSO to overcome the lack of efficient therapy in OCCC.

Effects of combining robot-assisted therapy with neuromuscular electrical stimulation on motor impairment, motor and daily function, and quality of life in patients with chronic stroke: a double-blinded randomized controlled trial.

BackgroundRobot-assisted therapy (RT) is a widely used intervention approach to enhance motor recovery in patients after stroke, but its effects on functional improvement remained uncertain. Neuromuscular electrical stimulation (NMES) is one potential adjuvant intervention approach to RT that could directly activate the stimulated muscles and improve functional use of the paretic hand.MethodsThis was a randomized, double-blind, sham-controlled study. Thirty-nine individuals with chronic stroke were randomly assigned to the RT combined with NMES (RT + ES) or to RT with sham stimulation (RT + Sham) groups. The participants completed the intervention 90 to 100 minutes/day, 5 days/week for 4 weeks. The outcome measures included the upper extremity Fugl-Meyer Assessment (UE-FMA), modified Ashworth scale (MAS), Wolf Motor Function Test (WMFT), Motor Activity Log (MAL), and Stroke Impact Scale 3.0 (SIS). All outcome measures were assessed before and after intervention, and the UE-FMA, MAL, and SIS were reassessed at 3 months of follow-up.ResultsCompared with the RT + Sham group, the RT + ES group demonstrated greater improvements in wrist flexor MAS score, WMFT quality of movement, and the hand function domain of the SIS. For other outcome measures, both groups improved significantly after the interventions, but no group differences were found.ConclusionRT + ES induced significant benefits in reducing wrist flexor spasticity and in hand movement quality in patients with chronic stroke.Trial registrationClinicalTrials.gov. NCT01655446

Adjuvant therapy and interdisciplinary follow-up care of conjunctival melanoma

Despite microscopically controlled tumor excision, malignant melanomas of the conjunctiva have a propensity for local recurrence, lymphatic spread and distant metastases. This review outlines the options of adjuvant therapy as well as the structure of interdisciplinary follow-up care for patients with conjunctival melanoma. The study provides a PubMed literature review and own clinical results. In conjunctival melanoma complete tumor excision using a minimal touch technique should always be combined with adjuvant therapy, such as cryotherapy, radiotherapy, topical chemotherapy and/or immunotherapy. For locally circumscribed lesions of the bulbar conjunctiva adjuvant brachytherapy can be supplemented and for non-bulbar, extensive, diffuse or multilocular tumor growth, complementary adjuvant topical mitomycin C therapy or proton radiotherapy can be used. Novel adjuvant approaches include topical interferon alpha-2b immunotherapy, topical vascular endothelial growth factor (VEGF) inhibitors or in cases of BRAF mutations personalized therapy using selective BRAF inhibitors or in combination with mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK), MAPK/ERK (MEK) inhibitors. All patients should be integrated into an interdisciplinary follow-up care program including quarter yearly checkups in the first 5 years and psycho-oncological healthcare. Following microscopically controlled tumor excision, adjuvant treatment using cryotherapy, radiotherapy, topical chemotherapy and/or immunotherapy as well as interdisciplinary follow-up care are mandatory for the modern management of patients with conjunctival melanoma.

Appendiceal Goblet Cell Carcinoids: Management Considerations from a Reference Peritoneal Tumour Service Centre and ENETS Centre of Excellence

Background: Appendix goblet cell carcinoids are known to share histological features of adenocarcinoma and neuroendocrine tumours. Due to their low incidence, quality evidence is lacking for the management of these patients. Methods: We performed a single-centre retrospective study of patients with a confirmed diagnosis of appendiceal goblet cell carcinoid (GCC; 1996-2014). Patients were divided into curative intent (CI) and palliative intent (PI) cohorts. Our primary end point was overall survival (OS). Results: Seventy-four patients were eligible; 76% were treated with CI [surgery only (36%), cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy (HIPEC; 36%), adjuvant chemotherapy (20%) and a combination of CRS and HIPEC followed by adjuvant chemotherapy (9%)], and 23% had advanced-stage disease amenable to palliative treatment (chemotherapy or supportive care) only. Completion right hemicolectomy, performed in 64% of the CI cohort, did not impact on the relapse rate or disease-free survival. FOLFOX chemotherapy was used in both the adjuvant and palliative settings; safety was as expected, and we observed a high rate (60%) of disease control in the palliative cohort. The estimated median OS (all patients), disease-free survival (CI patients) and progression-free survival (PI patients) were 52.1 (95% CI 29.4-90.3), 75.9 (26.6-not reached) and 5.3 (0.6-5.7) months, respectively. Age and stage were independent factors associated with OS in the multivariable analysis. Tang classification showed a trend for impact on OS. No benefit from specific adjuvant approach was identified; however, selection bias for treatment approach was observed. Conclusion: Prospective trials are needed to define optimal approaches in GCC. All GCC patients should be managed by specialized centres due to their esoteric behaviour; we provide management considerations based on our experience and conclusions.

Extracellular Vesicles Improve Post-Stroke Neuroregeneration and Prevent Postischemic Immunosuppression.

Although the initial concepts of stem cell therapy aimed at replacing lost tissue, more recent evidence has suggested that stem and progenitor cells alike promote postischemic neurological recovery by secreted factors that restore the injured brain's capacity to reshape. Specifically, extracellular vesicles (EVs) derived from stem cells such as exosomes have recently been suggested to mediate restorative stem cell effects. In order to define whether EVs indeed improve postischemic neurological impairment and brain remodeling, we systematically compared the effects of mesenchymal stem cell (MSC)-derived EVs (MSC-EVs) with MSCs that were i.v. delivered to mice on days 1, 3, and 5 (MSC-EVs) or on day 1 (MSCs) after focal cerebral ischemia in C57BL6 mice. For as long as 28 days after stroke, motor coordination deficits, histological brain injury, immune responses in the peripheral blood and brain, and cerebral angiogenesis and neurogenesis were analyzed. Improved neurological impairment and long-term neuroprotection associated with enhanced angioneurogenesis were noticed in stroke mice receiving EVs from two different bone marrow-derived MSC lineages. MSC-EV administration closely resembled responses to MSCs and persisted throughout the observation period. Although cerebral immune cell infiltration was not affected by MSC-EVs, postischemic immunosuppression (i.e., B-cell, natural killer cell, and T-cell lymphopenia) was attenuated in the peripheral blood at 6 days after ischemia, providing an appropriate external milieu for successful brain remodeling. Because MSC-EVs have recently been shown to be apparently safe in humans, the present study provides clinically relevant evidence warranting rapid proof-of-concept studies in stroke patients. Transplantation of mesenchymal stem cells (MSCs) offers an interesting adjuvant approach next to thrombolysis for treatment of ischemic stroke. However, MSCs are not integrated into residing neural networks but act indirectly, inducing neuroprotection and promoting neuroregeneration. Although the mechanisms by which MSCs act are still elusive, recent evidence has suggested that extracellular vesicles (EVs) might be responsible for MSC-induced effects under physiological and pathological conditions. The present study has demonstrated that EVs are not inferior to MSCs in a rodent stroke model. EVs induce long-term neuroprotection, promote neuroregeneration and neurological recovery, and modulate peripheral post-stroke immune responses. Also, because EVs are well-tolerated in humans, as previously reported, the administration of EVs under clinical settings might set the path for a novel and innovative therapeutic stroke concept without the putative side effects attached to stem cell transplantation.

Significance of Echocardiography in the Assessment of Left Ventricular Function in Patients Receiving Combined Adjuvant Treatment with Anthracyclines and Trastuzumab / Značaj ehokardiografije u proceni funkcije leve komore kod bolesnica na adjuvantnoj terapji (kombinovana terapija antraciklinima i trastuzumabom)

Abstract The application of anthracycline and trastuzumab in adjuvant breast cancer treatment approach has significantly improved the survival of patients, but also carries the risk of cardiotoxicity that is manifested by reducing the ejection fraction of the heart. The aim of the study was to investigate the effect of cumulative anthracycline dose in combination therapy with trastuzumab on the left ventricular ejection fraction, and the influence of the time interval for starting the treatment with trastuzumab. The study included a group of 80 breast cancer patients (aged 28 to 75 years) who underwent the therapy with anthracyclines (IV-VI cycles) with the continuation of trastuzumab therapy for a period of one year. Ejection fraction at the end of completing the treatment period (VI anthracycline cycles and trastuzumab) was significantly lower in 68 (93%) patients compared to the value at the beginning of the study (68.2% ± 6.06 to 62.1 ± 6.1%; p <0.0001; difference 6.1%). In five patients (anthracyclines and trastuzumab IV cycles) a decrease of 7.1% EF; p = 0.0043 was registered compared to the baseline values. The reduction in the ejection fraction was highest in patients in whom the trastuzumab therapy was initiated one month after the last anthracycline therapy (7.33%), and lowest in the subgroup who started receiving the therapy after three months (5.31%). In patients on cytostatic therapy, echocardiography proves the reduction in the left ventricular ejection fraction, which is cumulative and dose-dependent, and it also proves that the shorter time interval between the last cycle of anthracycline and the initial trastuzumab treatment the more it is associated with a marked decrease in the left ventricular ejection fraction.