A review of NTRK fusions in cancer.

The family of the neurotrophic tropomyosin kinase receptors (NTRK or TRK) is a part of the transmembrane tyrosine kinases responsible for neuronal development. The members of this receptor family are TRKA, TRKB and TRKC and they are encoded by the genes NTRK1, NTRK2 and NTRK3. Alterations of NTRK genes can induce carcinogenesis both in neurogenic and non-neurogenic cells. The prevalence of NTRK gene fusion is under 1% in solid tumors, but is highly encountered in rare tumors. The presence of NTRK 1 gene fusion is associated, in some types of neoplasia, with a favorable evolution, but the presence of NTRK 2 may be associated with a poor prognosis. The identification of cancer patients harboring NTRK gene fusions is constantly growing, especially with the advent of NTRK inhibitors. This has promisingly provided a rationale for personalized therapeutics that improved outcomes in settings with this signature.

Is There a Place for PD-1-PD-L Blockade in Acute Myeloid Leukemia?

Checkpoint inhibitors were a major breakthrough in the field of oncology. In September 2014, based on the KEYNOTE-001 study, the Food and Drug Administration (FDA) approved pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, for advanced or unresectable melanoma. Up until now, seven PD-1/PD-ligand(L)-1 inhibitors are approved in various solid cancers and hundreds of clinical studies are currently ongoing. In hematology, PD-1 inhibitors nivolumab and pembrolizumab were approved for the treatment of relapsed/refractory (R/R) classic Hodgkin lymphoma, and later pembrolizumab was approved for R/R primary mediastinal large B-cell lymphoma. In acute myeloid leukemia (AML), the combination of hypomethylating agents and PD-1/PD-L1 inhibitors has shown promising results, worth of further investigation, while other combinations or single agent therapy have disappointing results. On the other hand, rather than in first line, these therapies could be useful in the consolidation or maintenance setting, for achieving minimal residual disease negativity. Furthermore, an interesting application could be the use of PD-1/PD-L1 inhibitors in the post allogeneic hematopoietic stem cell transplantation relapse. There are several reasons why checkpoint inhibitors are not very effective in treating AML, including the characteristics of the disease (systemic, rapidly progressive, and high tumor burden disease), low mutational burden, and dysregulation of the immune system. We here review the results of PD-1/PD-L1 inhibition in AML and discuss their potential future in the management of this disease.

Macrophage Polarization in Chronic Lymphocytic Leukemia: Nurse-Like Cells Are the Caretakers of Leukemic Cells.

Macrophages are terminally differentiated innate immune cells. Through their activation, they can be polarized towards the pro-inflammatory M1 type or the wound healing-associated, anti-inflammatory M2 type macrophages. In the tumor microenvironment (TME), M2 is the dominant phenotype and these cells are referred to as tumor-associated macrophages (TAMs). TAMs secrete cytokines and chemokines, exerting an antiapoptotic, proliferative and pro-metastatic effect on the tumor cells. TAMs can be found in many cancers, including chronic lymphocytic leukemia (CLL), where they are called nurse-like cells (NLCs). Despite the generally indolent behavior of CLL, the proportion of treatment-refractory patients is significant. As with the majority of cancers, despite significant recent progress, CLL pathogenesis is poorly understood. The emerging role of the TME in nurturing the neoplastic process warrants the investigation of macrophages as a significant pathogenetic element of tumors. In this paper, we review the current knowledge on the role of stromal macrophages in CLL.

Are Community Acquired Respiratory Viral Infections an Underestimated Burden in Hematology Patients?

Despite a plethora of studies demonstrating significant morbidity and mortality due to community-acquired respiratory viral (CRV) infections in intensively treated hematology patients, and despite the availability of evidence-based guidelines for the diagnosis and management of respiratory viral infections in this setting, there is no uniform inclusion of respiratory viral infection management in the clinical hematology routine. Nevertheless, timely diagnosis and systematic management of CRV infections in intensively treated hematology patients has a demonstrated potential to significantly improve outcome. We have briefly summarized the recently published data on CRV infection epidemiology, as well as guidelines on the diagnosis and management of CRV infections in patients intensively treated for hematological malignancies. We have also assessed available treatment options, as well as mentioned novel agents currently in development.

A Review of Macrophage MicroRNAs' Role in Human Asthma.

There is an imbalance in asthma between classically activated macrophages (M1 cells) and alternatively activated macrophages (M2 cells) in favor of the latter. MicroRNAs (miRNAs) play a critical role in regulating macrophage proliferation and differentiation and control the balance of M1 and M2 macrophage polarization, thereby controlling immune responses. Here we review the current published data concerning miRNAs with known correlation to a specific human macrophage phenotype and polarization, and their association with adult asthma. MiRNA-targeted therapy is still in the initial stages, but clinical trials are under recruitment or currently running for some miRNAs in other diseases. Regulating miRNA expression via their upregulation or downregulation could show potential as a novel therapy for improving treatment efficacy in asthma.

Traumatic Diaphragmatic Lesions - Considerations Over a Series of 15 Consecutive Cases.

Introduction: Diaphragmatic injuries are produced by blunt or penetrating thoracoabdominal trauma. They are potentially life-threatening due to the herniation of abdominal organs into the pleural cavities and severe associated lesions. The aim of this retrospective study was to analyse the clinical presentation and management of patients admitted with diaphragmatic rupture in our institution. Material and Method: We performed a 5-year retrospective study of patients admitted with acute blunt or penetrating diaphragmatic rupture in the Department of General Surgery of "Bagdasar- Arseni" Emergency Hospital. We have studied sex, age, mechanism of trauma, side-location, timeto-diagnosis, concomitant injuries, surgical treatment and outcome. Results: Fifteen patients (8 males, 7 females, mean age: 42 years) with diaphragmatic rupture (left-side: 13, right-side: 2) following blunt (8 patients) or penetrating (7) trauma were included. Patients with blunt diaphragmatic injury had larger tears and abdominal viscera herniation was observed in 6of these cases. A direct suture was performed for all 15 patients. Laparotomy was the surgical approach preferred in most of the cases. Mortality rate was 20%, mainly caused by severe associated lesions. Conclusion: Although traumatic diaphragmatic lesions are frequently associated with severe cerebral and thoraco-abdominal trauma that is also the main cause of death, a prompt diagnosis and treatment can lead to good outcome.

Imbalance between Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases Promotes Invasion and Metastasis of Head and Neck Squamous Cell Carcinoma.

BACKGROUND: The balance between collagenolysis and its inhibition is critical during extracellular matrix remodeling in head and neck squamous cell carcinoma (HNSCC). An imbalance between matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) plays a critical role in the development of tumor cell invasion and metastasis. The purpose of the study was to determine MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios in the sera of patients with HNSCC in relation to clinicopathological parameters. METHODS: Serum samples from seventy patients with HNSCC were measured by ELISA, before and 2 days after surgery. Forty healthy volunteers were selected as controls. RESULTS: Preoperative MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios were significantly higher in HNSCC patients than in the control group (p < 0.001 and p = 0.002, respectively). Changes in MMP-9 concentration and MMP9/TIMP-1 ratio after surgery had a negative correlation with lymph node involvement (r = - 0.35, p = 0.021 and r = - 0.37, p = 0.013), while changes in TIMP-1 had a positive one (r = 0.45, p = 0.006). Histological grade was positively correlated with the changes in circulating TIMP-2 level (r = 0.39, p = 0.021). No significant correlation was discovered between MMP-2/TIMP-2 ratio and tumor grade or any clinicopathological variables. CONCLUSIONS: Our results suggest that an imbalance between MMP-9 and TIMP-1 could play an important role in metastatic spread via lymphatic pathways of HNSCC cells. MMP-9/TIMP-1 ratio and, in particular, MMP-9, TIMP-1, TIMP-2, may represent suitable biomarkers for early diagnosis and detection of disease progression and dissemination in HNSCC patients.

Immune checkpoint blockade: the role of PD-1-PD-L axis in lymphoid malignancies.

The co-inhibitory receptor programmed cell death (PD)-1, expressed by immune effector cells, is credited with a protective role for normal tissue during immune responses, by limiting the extent of effector activation. Its presently known ligands, programmed death ligands (PD-Ls) 1 and 2, are expressed by a variety of cells including cancer cells, suggesting a role for these molecules as an immune evasion mechanism. Blocking of the PD-1-PD-L signaling axis has recently been shown to be effective and was clinically approved in relapsed/refractory tumors such as malignant melanoma and lung cancer, but also classical Hodgkin's lymphoma. A plethora of trials exploring PD-1 blockade in cancer are ongoing. Here, we review the role of PD-1 signaling in lymphoid malignancies, and the latest results of trials investigating PD-1 or PD-L1 blocking agents in this group of diseases. Early phase studies proved very promising, leading to the clinical approval of a PD-1 blocking agent in Hodgkin's lymphoma, and Phase III clinical studies are either planned or ongoing in most lymphoid malignancies.

Cortical modulation of cardiac autonomic activity in ischemic stroke patients.

The cardiovascular system is regulated by the autonomic nervous system, under cortical modulation. Stroke can induce cardiac autonomic imbalance, therefore, causing secondary cardiovascular complications. Heart rate variability (HRV) analysis is a simple method to appraise the autonomic nervous function. The purpose of this study was to investigate the cardiac autonomic activity in patients that suffered an ischemic stroke in middle cerebral artery (MCA) territory. Using Biopac Acquisition System, we monitored ECG in rest condition and during Ewing's tests. From these measurements, HRV parameters (using time and frequency domain analysis) were determined in 20 right MCA and 20 left MCA ischemic stroke patients, in the first 6 months after the acute event. Data were compared with 20 age- and sex-matched healthy controls. All the patients were right handed. In ischemic stroke patients, HRV parameters were significantly modified compared to controls (p < 0.05) and we found asymmetric responses to different stimulation autonomic tests between right and left hemisphere. Parameters illustrating the parasympathetic predominance in time domain (RMSSD) and frequency domain (HF) analysis were higher in left hemisphere stroke compared to right hemisphere stroke patients (p < 0.01) in resting state. From Ewing's battery test, patients with left hemisphere ischemic stroke showed predominance of parasympathetic activity to deep breathing (p < 0.01), while HRV parameters in right hemisphere ischemic stroke patients described a reduced cardiac parasympathetic innervation (p < 0.01). Cardiac autonomic imbalance occurs more often after right hemisphere ischemic stroke. HRV study may highlight cardiac dysfunctions that increase the risk of cardiovascular complications and portends a poor long-term outcome.

Serum Level of Matrix Metalloproteinase-9 in Patients with Head and Neck Squamous Cell Carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is characterized by the upregulation of a large number of matrix metalloproteinases (MMPs). The aim of the study was to investigate the level of MMP-9 in the sera of HNSCC patients and its relationship to clinicopathological features. METHODS: Serum samples from sixty-five patients (56M/9F, 59.11 ± 9.02 years) with HNSCC were quantitatively measured by ELISA assay, before and two days after surgery. Forty healthy volunteers served as controls (29M/ 11F, 56.21 ± 12.13 years). RESULTS: Median serum concentrations of MMP-9 were consistently upregulated in HNSCC patients both preoperatively (1593.0 ng/mL, IQR: 833.0 - 1942.0 ng/mL) and postoperatively (1382.0 ng/mL, IQR: 778.6 - 2062.0 ng/mL) in comparison to healthy controls (291.3 ng/mL, IQR: 223.8 - 330.5 ng/mL) (p < 0.001). Pretreatment levels of MMP-9 were related to the size of primary tumor (p = 0.018) and lymph node involvement (p = 0.045). No statistically significant association was found between serum MMP-9 concentrations and clinical stage or degree of differentiation of the tumor cells. CONCLUSIONS: Serum MMP-9 level could be used as a diagnostic tool for early detection of HNSCC and for determining prognosis. Moreover, our results suggest that MMP-9 might be a good marker in evaluating the size of the primary tumor and lymph node involvement. Further studies are needed to show whether MMP-9 could serve as a marker for recurrence.

Cerebrolysin and Recovery After Stroke (CARS): A Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial.

BACKGROUND AND PURPOSE: The aim of this trial was to investigate whether stroke patients who receive Cerebrolysin show improved motor function in the upper extremities at day 90 compared with patients who receive a placebo. METHODS: This study was a prospective, randomized, double-blind, placebo-controlled, multicenter, parallel-group study. Patients were treated with Cerebrolysin (30 mL/d) or a placebo (saline) once daily for 21 days, beginning at 24 to 72 hours after stroke onset. The patients also participated in a standardized rehabilitation program for 21 days that was initiated within 72 hours after stroke onset. The primary end point was the Action Research Arm Test score on day 90. RESULTS: The nonparametric effect size on the Action Research Arm Test score on day 90 indicated a large superiority of Cerebrolysin compared with the placebo (Mann-Whitney estimator, 0.71; 95% confidence interval, 0.63-0.79; P<0.0001). The multivariate effect size on global status, as assessed using 12 different outcome scales, indicated a small-to-medium superiority of Cerebrolysin (Mann-Whitney estimator, 0.62; 95% confidence interval, 0.58-0.65; P<0.0001). The rate of premature discontinuation was <5% (3.8%). Cerebrolysin was safe and well tolerated. CONCLUSIONS: Cerebrolysin had a beneficial effect on function and global outcome in early rehabilitation patients after stroke. Its safety was comparable with that of the placebo, suggesting a favorable benefit/risk ratio. Because this study was exploratory and had a relatively small sample size, the results should be confirmed in a large-scale, randomized clinical trial. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrialsregister.eu. Unique identifier: 2007-000870-21.

Influence of Staphylococcus aureus attachment to the herpes simplex virus infected cells.

The purpose of this study was to investigate the response of HeLa cells to the interaction with inactivated Staphylococcus aureus cells and live challenge with herpes simplex virus (HSV).The results of this study are indicating that the interaction between the HeLa cells and S. aureus inactivated whole cells could modulate the host cell apoptosis and cytokine production, and therefore, influence the progression of HSV infection. The pre-treatment of HeLa cells with heat inactivated bacterial whole cells protects them from the occurrence of HSV mediated cytopathic effect, while the post viral infection treatment with bacterial cells prevents the high activation of bax/bcl-2 apoptotic pathway, a process that could change the fate of the infectious process triggered by the virus, and eventually reduce its multiplication rate. The pre-treatment of HeLa monolayer with inactivated bacterial cells 24 hours before the viral infection is increasing the expression level of TNF-a, IL-6 and IL-8 pro-inflammatory cytokines genes, also suggesting that bacterial antigens could contribute to the decrease of viral multiplication rate.

Mirror therapy enhances upper extremity motor recovery in stroke patients.

The purpose of this study was to evaluate the effects of mirror therapy program in addition with physical therapy methods on upper limb recovery in patients with subacute ischemic stroke. 15 subjects followed a comprehensive rehabilitative treatment, 8 subjects received only control therapy (CT) and 7 subjects received mirror therapy (MT) for 30 min every day, five times a week, for 6 weeks in addition to the conventional therapy. Brunnstrom stages, Fugl-Meyer Assessment (upper extremity), the Ashworth Scale, and Bhakta Test (finger flexion scale) were used to assess changes in upper limb motor recovery and motor function after intervention. After 6 weeks of treatment, patients in both groups showed significant improvements in the variables measured. Patients who received MT showed greater improvements compared to the CT group. The MT treatment results included: improvement of motor functions, manual skills and activities of daily living. The best results were obtained when the treatment was started soon after the stroke. MT is an easy and low-cost method to improve motor recovery of the upper limb.

Fluorescence analysis of apoptosis induced by Pseudomonas aeruginosa in endothelial cells.

Intracellular invasion of professional phagocytic cells like monocytes and macrophages by a pathogen usually triggers the apoptosis of the host cells. The aim of this study was to evaluate if Pseudomonas aeruginosa, although not considered a classic intracellular pathogen, could adhere to endothelial cell surface, invade the intracellular compartment and subsequently induce apoptosis of the cells. The adherence and invasion capacity of P. aeruginosa to endothelial cells was monitored using Cravioto's adapted method. The apoptotic cells were evidenced by staining with Acridine orange/Ethidium bromide. The qualitative assay of bacterial adherence to the cellular substrate revealed that all tested strains adhered to endothelial cells surface, exhibiting a diffuse, aggregative or mixed (diffuse-aggregative or localized-aggregative) pattern and 20-70% adherence rates. The adherence of P. aeruginosa induced the reorganization of cytoskeleton filaments and formation of endocytic membrane expansions. Cell free P. aeruginosa culture supernatants did not induce any cell death response, as noticed in case of whole bacterial culture, showing the capacity to induce apoptosis of endothelial cells. The fluorescence microscopy examination revealed chromatin condensation, fragmented nuclei, and membrane blebbing and apoptotic bodies in pathogen invaded cells.

Seasonal migrations of North Atlantic minke whales: novel insights from large-scale passive acoustic monitoring networks.

BACKGROUND: Little is known about migration patterns and seasonal distribution away from coastal summer feeding habitats of many pelagic baleen whales. Recently, large-scale passive acoustic monitoring networks have become available to explore migration patterns and identify critical habitats of these species. North Atlantic minke whales (Balaenoptera acutorostrata) perform seasonal migrations between high latitude summer feeding and low latitude winter breeding grounds. While the distribution and abundance of the species has been studied across their summer range, data on migration and winter habitat are virtually missing. Acoustic recordings, from 16 different sites from across the North Atlantic, were analyzed to examine the seasonal and geographic variation in minke whale pulse train occurrence, infer information about migration routes and timing, and to identify possible winter habitats. RESULTS: Acoustic detections show that minke whales leave their winter grounds south of 30° N from March through early April. On their southward migration in autumn, minke whales leave waters north of 40° N from mid-October through early November. In the western North Atlantic spring migrants appear to track the warmer waters of the Gulf Stream along the continental shelf, while whales travel farther offshore in autumn. Abundant detections were found off the southeastern US and the Caribbean during winter. Minke whale pulse trains showed evidence of geographic variation, with longer pulse trains recorded south of 40° N. Very few pulse trains were recorded during summer in any of the datasets. CONCLUSION: This study highlights the feasibility of using acoustic monitoring networks to explore migration patterns of pelagic marine mammals. Results confirm the presence of minke whales off the southeastern US and the Caribbean during winter months. The absence of pulse train detections during summer suggests either that minke whales switch their vocal behaviour at this time of year, are absent from available recording sites or that variation in signal structure influenced automated detection. Alternatively, if pulse trains are produced in a reproductive context by males, these data may indicate their absence from the selected recording sites. Evidence of geographic variation in pulse train duration suggests different behavioural functions or use of these calls at different latitudes.

Non-Hodgkin's Malignant Lymphoma with Aggressive Development.

ABSTRACT: Non-Hodgkin's malignant lymphoma is a hematologic malignant disease which usually responds to the polychemotherapy. We present a clinical case report of a 50 years old patient who develops an aggressive type of lymphoma. Patient develops a nodal Non-Hodgkin's malignant lymphoma who present at hospital admission as a huge tumor at the right side of the neck. Any type of treatment was a failure, the patient having a particularly aggressive form of lymphoma, resistant to all three chemotherapy regimens tested. Death occurs quickly, about one year after diagnosis and initiation of therapy.

Orbital complications of fungal pan-sinusitis in uncontrolled diabetes.

ABSTRACT: The purpose of our clinical case presentation is to emphasize the role of ear, nose and throat specialist in early recognition and urgent treatment of mucormycosis, which is a rare infection caused by fungus belonging to the order Mucorales. They are known opportunistic organisms, which potentially invade and infect a host with depressed immunity. In our paper we present a case of an uncontrolled diabetic male with orbital complications caused by a fungal pan-sinusitis. The typical presentation of rhino-orbital fungal infection is that of anterior orbital inflammation, severe visual loss, external ophthalmoplegia and fever. Our diagnostic was based on an otolaryngological, ophthalmological, imagistic but especially biopsy exam, which is the only one that can make the certain diagnostic in this case. We followed the standard treatment for these situations. Early recognition and treatment with urgent surgical debridement and systemic antifungal therapy is the key to the management of rhino-orbital mucormycosis and is necessary to limit the spread of infection, which can lead to high morbidity and mortality. Therefore, health practitioners should be familiar with the signs and symptoms of the disease.The authors certify that they do not have any financial or personal relationships that might bias the content of this work.

Multiple cancers of the head and neck.

Multiple head and neck cancers are not rare entities and according to studies in the literature, their incidence is increasing. The emergence of multiple cancers is explained by the phenomenon of "field cancerization". Patients with cancer of the upper digestive and respiratory tract develop most often a second malignancy, usually in the upper aero-digestive tract and among them, those with larynx cancer ranks first among patients with multiple cancers. In the literature and in practice, we met rare combination of multiple cancers, associations that appear to be "random", cannot be explained by any of the hypotheses developed: exposure to carcinogens, genetic susceptibility, and immunodeficiency or cancer treatments after index tumor. Follow-up of patients who have had a head and neck cancer and periodic control are important for early detection of multiple cancers.

Investigation of Th1/Th2 cytokine profiles in patients with laryngo-pharyngeal, HPV-positive cancers.

The aim of this study was to reveal the relationships between the features of the primary tumour, the degree of tumour stage, the presence of human papillomaviruses (HPV) in blood and the severity of Th1/Th2 serum cytokine imbalance in patients with laryngo-pharyngeal cancer. The study was performed on 50 patients (47 men and 3 women), with age ranging from 40 to 83 years (the mean of the patients' ages was 58.4 ± 9.43 years, with a median of 60 years). A control group was represented by age-matched healthy patients (with no clinical diseases). The viral DNA was detected by PCR; the cytokine levels were determined by ELISA. A clear switch from cytokine Th1 to cytokine Th2 in cancer patients, low levels of IL-2 and IFNγ in advanced stages, as well as a positive correlation of increased levels of both IL-2 and IL-12 with the early stages of laryngo-pharyngeal cancer was observed. Loco-regional metastases were correlated with increased levels of IL-8 and IL-10 and drastic decrease of IFNγ. In advanced cancer stages, we found that the most affected were IL-2 and IFNγ correlated with increased levels of Th2 cytokines. Patients with HPV present in both primary tumours and blood showed increased values of IL-4:IL-2 ratio as compared with patients with HPV-positive primary tumours only, demonstrating the aggravation of the immunosuppressive state. The most important finding of our study is that for a correct evaluation of the Th1 to Th2 switch in cancer patients, it is necessary to establish not only the negative/positive correlations between different Th1 and Th2 type cytokines, but also the ratio between them. These parameters allowed us to state that the presence of HPV DNA in blood was associated with the most severe immunological imbalance that could potentially lead to a poor prognosis of these patients. Our findings encourage us to consider that the ratio between different Th1 and Th2 cytokines could represent a useful marker for clinical and pathological evaluation of cancer patients.

Methods of investigating metastatic lymph nodes in head and neck cancer.

ABSTRACT: When dealing with patients who have head and neck cancer - squamous cell carcinoma and have clinically N0 neck disease it is very difficult to assess the real extension of the malignant proccess. This is why several techniques are curently in use to determine the actual TNM clasiffication for each patient in order to apply best suited therapy management. Up until today the staging of the neck has been done by using a combination of the physical exam and conventional imaging studies. Recent studies and research have tried to determine weather the use of sentinel lymph node biopsy is a more reliable tool in predicting occult metastasis in cancer patients with clinically N0 neck disease. There are no guidelines in this matter and as such the use of the sentinel lymph node detection technique is yet to be used on a routine basis. The authors are trying to assess the benefits of different paraclinical investigation regarding the improvement of overall survival rates in patients with T1/T2 squamous cell carcinoma of the head and neck and N0 neck disease.