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.

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.

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.

Tracking down of laryngo-pharyngeal metastasis.

BACKGROUND: In Romania, the most optimistic statistics give a 5 years survival rate in approximately 33% of laryngo-pharyngeal cancer patients. Considering that a cell carrying the viral DNA is originating from primary tumor, we have tested whether HPV DNA could be detected in the blood cell of patients with laryngeal cancer as a marker of disease progression and metastases. METHODS: The study was performed on 85 patients (59 +/- 8.7 age) with laryngo-pharyngeal cancer. HPV DNA was detected in tumor using nested PCR with consensus primers, and also in local lymph nodes and/or blood cells from patients HPV positive in primary tumor. RESULTS: HPV DNA was detected in 75.29% of analyzed tumours, and all HPV16 positive samples were confirmed by mRNA E6 expression. 56.3% of patients presented HPV DNA in peripheral circulation as confirmed by PCR with E6 HPV16 specific primers followed by Southern Blot. CONCLUSION: Our results sustain that the detection of HPV DNA in blood is a "surrogate marker" of metastasis when extension of metastasis cannot be estimated, this observation is very important for management of cancer patients with laryngopharyngeal localization.