Trends in pediatric CNS tumors in Armenia: a multicenter retrospective study.

PURPOSE: Central nervous system (CNS) tumors are the most common solid malignancies in children worldwide, including in Armenia. The current study aims to analyze epidemiological data, treatment, and outcomes of children and young adults (≤25 years) with CNS tumors in Armenia during the last 26 years. METHODS: We collected data from pediatric and young adult patients treated in selected sites in Armenia from 1st January 1995 to 31st December 2020. Incidence by sex, age at diagnosis, time from first complaints to diagnosis, histopathology results, treatment strategies, complications, and overall survival (OS) rates were calculated. RESULTS: The multicenter data analysis revealed 149 patients with diagnosed primary CNS tumors over 26 years. Among them, 84 (56.4%) were male. The median age at diagnosis was 7 years (range, 3 months to 25 years), and the median time from the first complaints to diagnosis was 2 months (range, 1 week to 70 months). Medulloblastomas and other embryonal tumors (47), low-grade gliomas (32), and high-grade gliomas (22) were the most commonly diagnosed malignancies. Ependymomas, craniopharyngiomas, germ cell tumors, and other malignancies were observed in 22 patients. For 26 patients, no histopathological or radiological diagnosis was available. Follow-up information was available for 98 (65.8%) patients. The 5-year OS rate for the whole study group was 67.7%. CONCLUSION: Consistent with international data, embryonal tumors, and gliomas were the most commonly diagnosed CNS malignancies in Armenia. Multimodal treatment was often not available in Armenia during the study period, especially for early cases.

Opsoclonus-Myoclonus-Associated Neuroblastoma With Bone Marrow Metastases: What Would Be the Best Treatment Option?

A 1.9-year-old girl was presented to the hospital with dancing eye movements, ataxia, and behavioral disorders. The MRI showed a retroperitoneal tumor (transversal size: 3.9 x 2.5 cm, craniocaudal size: 4.6 cm) extending from T12 to L3 vertebral bodies (Figure), which was suspicious for neuroblastoma. Afterwards, biopsy of the lesion and bone marrow was performed. The initial pathological evaluation (CD56+, PHOX2B+, NKX2-, Ki67 50%-55%, NSE+, CD99-) of the tumor and bone marrow confirmed the diagnosis of poorly differentiated, high-risk neuroblastoma.

The emergence of a texas collaboration to improve well-being in learning health systems.

Prior models of well-being have focused on resolving issues at different levels within a single institution. Changes over time in medicine have resulted in massive turnover and reduced clinical hours that portray a deficit-oriented system. As developments to improve purpose and professional satisfaction emerge, the Texas Medical Association Committee on Physician Health and Wellness (PHW) is committed to providing the vehicle for a statewide collaboration and illuminating the path forward.To describe the existing health and wellness resources in Texas academic medical centers and understand the gaps in resources and strategies for addressing the health and wellness needs in the medical workforce, and in student and trainee populations.Various methods were utilized to gather information regarding health and wellness resources at Texas academic medical centers. A survey was administered to guide a Think Tank discussion during a PHW Exchange, and to assess resources at Texas academic medical centers. Institutional representatives from all Texas learning health systems were eligible to participate in a poster session to share promising practices regarding health and wellness resources, tools, and strategies.Survey responses indicated a need for enhancing wellness program components such as scheduled activities promoting health and wellness, peer support networks, and health and wellness facilities in academic medical centers. Answers collected during the Think Tank discussion identified steps needed to cultivate a culture of wellness and strategies to improve and encourage wellness.The Texas Medical Association Committee on Physician Health and Wellness and PHW Exchange provided a forum to share best practices and identify gaps therein, and has served as a nidus for the formation of a statewide collaboration for which institutional leaders of academic medical centers have affirmed the need to achieve the best result.

Overview of Cancer Control in Armenia and Policy Implications.

Cancer is the second leading cause of death in Armenia. Over the past two decades, the country has seen a significant rise in cancer morbidity and mortality. This review aims to provide up-to-date info about the state of cancer control in Armenia and identify priority areas of research. The paper analyzes published literature and local and international statistical reports on Armenia and similar countries to put numbers into context. While cancer detection, diagnosis, and treatment are improving, the prevalence of risk factors is still quite high and smoking is widespread. Early detection rates are low and several important screening programs are absent. Diagnosis and treatment methods are not standardized; there is a lack of treatment accessibility due to insufficient government coverage and limited availability of essential medicines. Overall, there is room for improvement in this sector, as research is limited and multidisciplinary approaches to the topic are rare.

Incidence patterns and review of Hodgkin lymphoma in the Republic of Armenia.

Hodgkin lymphoma (HL) accounts for roughly 10% of all lymphomas and 0.6% of all malignant tumours analysed worldwide yearly. Data regarding HL in developing world are exceptionally constrained. The main objective of this research is to investigate the incidence patterns of HL within the Republic of Armenia and to portray disease distribution according to age and sex. There is a very strict evidence on the frequency of HL in Armenia. The results of our research find out that the frequency of HL in Armenia has not changed altogether over the past 15 years and is comparable to that detailed from the USA and Europe.

Impact of the coronavirus disease 2019 (COVID-19) pandemic on pediatric oncology care in the Middle East, North Africa, and West Asia region: A report from the Pediatric Oncology East and Mediterranean (POEM) group.

BACKGROUND: Childhood cancer is a highly curable disease when timely diagnosis and appropriate therapy are provided. A negative impact of the coronavirus disease 2019 (COVID-19) pandemic on access to care for children with cancer is likely but has not been evaluated. METHODS: A 34-item survey focusing on barriers to pediatric oncology management during the COVID-19 pandemic was distributed to heads of pediatric oncology units within the Pediatric Oncology East and Mediterranean (POEM) collaborative group, from the Middle East, North Africa, and West Asia. Responses were collected on April 11 through 22, 2020. Corresponding rates of proven COVID-19 cases and deaths were retrieved from the World Health Organization database. RESULTS: In total, 34 centers from 19 countries participated. Almost all centers applied guidelines to optimize resource utilization and safety, including delaying off-treatment visits, rotating and reducing staff, and implementing social distancing, hand hygiene measures, and personal protective equipment use. Essential treatments, including chemotherapy, surgery, and radiation therapy, were delayed in 29% to 44% of centers, and 24% of centers restricted acceptance of new patients. Clinical care delivery was reported as negatively affected in 28% of centers. Greater than 70% of centers reported shortages in blood products, and 47% to 62% reported interruptions in surgery and radiation as well as medication shortages. However, bed availability was affected in <30% of centers, reflecting the low rates of COVID-19 hospitalizations in the corresponding countries at the time of the survey. CONCLUSIONS: Mechanisms to approach childhood cancer treatment delivery during crises need to be re-evaluated, because treatment interruptions and delays are expected to affect patient outcomes in this otherwise largely curable disease.

Availability of Essential Medicines for Pediatric Oncology in Armenia

Background: One of the main contributors in low survival rate in LMIC is the lack of availability of cancer medications for curative, supportive and palliative care. In many developing countries access to cytotoxic medicine is a major challenge. The information about the availability of essential medicines for pediatric cancer in the country is not known. The main objective of this study was to determine whether the medications used during the treatment of pediatric cancer are available in Armenia. Methods: In summer 2016 we conducted a survey in the 3 main pharmacies in Yerevan, which import pediatric cancer medications to Armenia to evaluate whether medications used during cancer treatment are officially registered and available in the country. In addition, the information on official registration was cross-checked with the Ministry of Health of the Republic of Armenia (MOH). Simultaneously, detailed information about the drugs, on type of produced drug company, doses and price intervals was confined from the price lists of the national drug importer companies. Results: The survey included 64 agents in three classes of medication: anti-neoplastics, anti-microbials, and drugs used in supportive care. All of these medications were included in the recent version of the WHO model list of essential medicines. From 30 anti-neoplastic medications on the essential medicines list 22 (73%) were officially registered in Armenia; from 19 anti-microbial drugs all were registered except caspofungin and from 15 supportive care agents 13 (87%) were registered. From registered anti-neoplastic drugs 18% and from antimicrobial drugs 33% were not available in the drug stores. Conclusion: This study showed that not all the drugs from the SIOP PODC Essential Medication list for pediatric oncology are officially registered and available in Armenia, and effective drug regulation focusing on the childhood cancer care medicine is needed for improving the situation in the country.

Younger age and previous exposure to radiation therapy are correlated with the severity of chemotherapy-induced thrombocytopenia.

BACKGROUND: Chemotherapy-induced thrombocytopenia (CIT) is a significant complication of cancer therapy. Data on the optimal management approaches of this morbidity in children and young adults are still limited. AIM: The aim of the study is to estimate the frequency and severity of CIT and associated clinically significant bleeding in children and young adults with solid tumours and haematologic malignancies. METHODS: For this retrospective, hospital-based study, children (0-18 y) and young adults (19-40 y) with different types of solid tumours and haematologic malignancies who received chemotherapy at the Muratsan Hospital Complex of Yerevan State Medical University were identified from the patients' database and included in the study (overall 122 patients). Thrombocytopenia was defined as a decrease of platelet count below <100 × 109/L. For assessing bleeding, WHO scale had been used. RESULTS: Overall, the whole group of patients received 430 chemotherapy cycles. During 131 (31.6%) chemotherapy cycles, patients developed CIT. The study revealed a statistically significant inversely proportional correlation between the age and the severity of CIT. Another important finding of the study was that the patients, who previously were exposed to radiation therapy, were more likely to develop CIT, than those who have not received radiation therapy (68% and 28.7%, p = 0.001). From 430 cycles of chemotherapy, 31 (7.2%) cycles reported to have bleeding events. CONCLUSION: Our study showed that clinically significant thrombocytopenia and bleeding are quite rare among children and young adults. Younger age and previous exposure to radiation therapy are positively correlated with the severity of thrombocytopenia. Larger studies are needed to investigate these findings.

Acute and chronic brucellosis eleven-year audit from a tertiary hospital in Armenia.

INTRODUCTION: The incidence of brucellosis in Armenia in 2010 was twice as high as in other countries of the Caucasian region and has almost doubled over the last three decades. This study aimed to investigate factors associated with acute or chronic forms of presentation of human brucellosis. METHODOLOGY: Retrospective study using data from medical records of 455 patients hospitalized for the first time at the Nork Republican Infectious Disease Referral Hospital in Yerevan, Armenia between the years 2006 and 2016. We undertook descriptive analysis of cases, compared acute and chronic cases, and identified factors associated with acute and chronic cases using regression. RESULTS: The majority of brucellosis cases had acute case presentation (73.0%), were males (70.3%), between the ages of 20-60 years (66.2%) and unemployed (89.9%). About two-thirds of cases reported a history of consumption of raw unpasteurized milk. The multivariate analysis revealed that factors associated with the form of brucellosis were age, symptom duration preadmission, fever, antibody titer, and hospitalization outcomes. CONCLUSION: This study revealed that brucellosis is unevenly distributed across different age groups, as well as regions of Armenia. Affected individuals did not seek medical attention after the onset of the symptoms for about 2 months. Therefore, the targeted educational campaigns could be of crucial importance to prevent the disease in humans, contribute to its early diagnosis and treatment.

P190RhoGAP prevents mitotic spindle fragmentation and is required to activate Aurora A kinase at acentriolar poles.

Assembly of the mitotic spindle is essential for proper chromosome segregation during mitosis. Maintenance of spindle poles requires precise regulation of kinesin- and dynein-generated forces, and improper regulation of these forces disrupts pole integrity leading to pole fragmentation. The formation and function of the mitotic spindle are regulated by many proteins, including Aurora A kinase and the motor proteins Kif2a and Eg5. Here, we characterize a surprising role for the RhoA GTPase-activating protein, p190RhoGAP, in regulating the mitotic spindle. We show that cells depleted of p190RhoGAP arrest for long periods in mitosis during which cells go through multiple transitions between having bipolar and multipolar spindles. Most of the p190RhoGAP-depleted cells finally achieve a stable bipolar attachment and proceed through anaphase. The multipolar spindle phenotype can be rescued by low doses of an Eg5 inhibitor. Moreover, we show that p190RhoGAP-depleted multipolar cells localize Aurora A to all the poles, but the kinase is only activated at the two centriolar poles. Overall, our data identify an unappreciated connection between p190RhoGAP and the proteins that control spindle poles including Aurora A kinase and Eg5 that is required to prevent or correct spindle pole fragmentation.

Denosumab treatment for progressive skull base giant cell tumor of bone in a 14 year old female - a case report and literature review.

BACKGROUND: Giant cell tumor of bone (GCT) is a rare primary bone tumor, which can metastasize and undergo malignant transformation. The standard treatment of GCT is surgery. In patients with unresectable or metastatic disease, additional therapeutic options are available. These include blocking of the receptor activator of NF-kappa B ligand (RANKL) signaling pathway, which plays a role in the pathogenesis of GCT of bone, via the anti-RANKL monoclonal antibody denosumab. CASE PRESENTATION: Herein we report on a female teenager who presented in a very poor clinical condition (cachexia, diplopia, strabismus, dysphonia with palsy of cranial nerves V, VI, VIII, IX, X, XI and XII) due to progressive disease, after incomplete resection and adjuvant radiotherapy, of a GCT which affected the cervical spine (C1 and C2) as well as the skull base; and who had an impressive clinical response to denosumab therapy. To the best of our knowledge, this is the youngest patient ever reported with a skull base tumor treated with denosumab. CONCLUSION: In situations when surgery can be postponed and local aggressiveness of the tumor does not urge for acute surgical intervention, upfront use of denosumab in order to reduce the tumor size might be considered. Principally, the goal of denosumab therapy is to reduce tumor size as much as possible, with the ultimate goal to make local surgery (or as in our case re-surgery) amenable. However, improvement in quality of life, as demonstrated in our patient, is also an important aspect of such targeted therapies.

Ethanol-Induced Alterations of T Cells and Cytokines after Surgery in a Murine Infection Model.

BACKGROUND: Interactions between alcohol, infection, and surgery and their effect on differentiation and functionality of T helper cells are not yet completely understood. We hypothesized that alcohol and surgery disturb differentiation of T helper cells and contribute to an impaired immune response. METHODS: Mice were treated with alcohol for two weeks. Saline treatment served as control. Clinical performance and weight were assessed. On day 14, a median laparotomy was performed and animals were challenged with Klebsiella pneumoniae intranasally. Bacterial load was determined in lungs and blood. T helper cell subpopulations and the released cytokines were assessed in lungs, spleens, and plasma. Key transcription factors of T cell differentiation were evaluated. RESULTS: Alcohol significantly impaired clinical appearance and body weight of animals with postsurgical infection (p < 0.05). Bacterial load was significantly higher after alcohol treatment (p < 0.05). T helper cell subsets and released cytokine levels were significantly altered in lung, but not in spleen. Expression of transcription factors of T helper cell lineage commitment did not translate into different counts of T helper cells. CONCLUSIONS: Alcohol and surgery lead to significant cellular and functional modulations of T helper cells during postsurgical infection. These effects may contribute to an impaired immune response after surgery.

Treating Adults with Hodgkin Lymphoma in the Developing World: a Hospital-Based Cohort Study from Armenia.

BACKGROUND: With advances in diagnostics and treatment approaches, patients with Hodgkin's lymphoma (HL) in developed countries can nowadays expect to have excellent outcomes. However, information about the characteristics and outcomes in the developing world is very scarce, and this is important given the fact that there are several reports about differences of disease characteristics depending on geographic location and the development level of the country. MATERIALS AND METHODS: In this retrospective study we assessed the features of 36 adult (≥18 years old) patients with HL and their diagnosis and treatment and outcomes in the Clinic of Chemotherapy of Muratsan University Hospital of Yerevan State Medical University, Armenia, between 2008- 2014. RESULTS: All patients had classic HL and among them 19 (53%) had nodular sclerosis subtype, 8 (22%) mixed cellularity and 9 (25%) lymphocyte-rich. 16 (44.5%) patients were at stage II, 13 (36%) stage III and 7 (19.5%) stage IV. Median follow-up time was 24.5 months (range 1-71 months) and during the whole follow- up period only two relapses (early) were documented and there were no deaths. Twenty-three (64%) patients received a BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) regimen, and 13 (36%) ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) regimen. A total of 25 (69.5%) patients received radiation in addition to chemotherapy. CONCLUSIONS: Although the number of patients involved in the study is small and the median follow-up time was just two years, this retrospective study shows that treatment of HL can be successfully organized in a resource-limited setting.

Proof of principle: hydration by low-osmolar mannitol-glucose solution alleviates undesirable renal effects of an iso-osmolar contrast medium in rats.

OBJECTIVE: Saline infusion is widely used to prevent contrast media (CM)-induced acute kidney injury, because it fosters diuresis. Osmodiuretics have a stronger diuretic effect than saline, yet previous trials indicate that osmodiuretic mannitol tends to promote rather than to prevent CM-induced acute kidney injury. However, these studies used hypertonic mannitol solutions that will result in rebound volume contraction. We hypothesize that combining the osmodiuretic effects of a nonhypertonic mannitol solution with sustained volume expansion alleviates undesirable renal effects of CM. MATERIALS AND METHODS: Forty-four anesthetized rats were studied by 4 protocols. Urine flow rate, urine viscosity, and glomerular filtration rate (GFR) were measured. Intravenous infusions of hydration solutions were initiated 60 minutes before CM administration and continued throughout the observation period. Hydration by a 3.2% mannitol and 3.2% glucose solution infused at 12 mL/kg per hour (Mannit-Gluc regimen) was compared with a standard regimen of isotonic saline at 4 mL/kg per hour (NaCl regimen); greater infusion rates are required for the Mannit-Gluc regimen because of the profound diuretic effect of mannitol. Two CM were studied: iso-osmolar iodixanol (320 mg I/mL) and low-osmolar iopromide (370 mg I/mL), they were administered as 1.5-mL bolus injection into the thoracic aorta. RESULTS: The Mannit-Gluc regimen resulted in higher urine flow rates than the standard NaCl regimen, yet maintained a good volume status. By virtue of its stronger diuretic effect, the Mannit-Gluc regimen greatly diminished the increase in urine viscosity and completely prevented the transient decrease in GFR caused by iodixanol with the NaCl regimen. After iopromide, the differences between the hydration regimens were much less, as iopromide increased urine flow rates much more than iodixanol, thus resulting in a much smaller increase in viscosity than iodixanol and no decrease in GFR even with the NaCl regimen. CONCLUSION: This proof of principle study shows that a hydration regimen that combines the osmodiuretic effect of a low-osmolar mannitol-glucose solution with sustained volume expansion is effective in reducing high urine viscosity and preventing GFR reduction caused by iso-osmolar iodixanol. For low-osmolar CM, the beneficial effects seem negligible, because these compounds per se exert greater osmodiuretic action.

Renal effects of bicarbonate versus saline infusion for iso- and lowosmolar contrast media in rats.

OBJECTIVE: Hydration is widely accepted as an effective measure to prevent contrast media (CM)-induced acute kidney injury (AKI). Whether bicarbonate (NaHCO3) infusion has a greater effect than saline is disputed. Effective prevention of CM-induced AKI by NaHCO3 has been found by several clinical trials. However, others found either no effect or an enhanced incidence of CM-induced AKI after giving NaHCO3. Because of their different tubular resorption, NaHCO3 and saline may have a different capacity to flush the nephron. In this study, we compare the magnitudes by which NaHCO3 and saline can enhance urinary flow, prevent a decline in glomerular filtration rate (GFR), and limit an increase in urine viscosity, as caused by CM administration. MATERIALS AND METHODS: Prewarmed (37°C) CM were administered as 1.5 mL bolus into the thoracic aorta of anesthetized rats. Following 2 CM were studied: iso-osmolar iodixanol (320 mg I/mL) and low-osmolar iopromide (370 mg I/mL). Four protocols (n = 7 rats per protocol) were followed: (1) saline + iodixanol, (2) saline + iopromide, (3) NaHCO3 + iodixanol, and (4) NaHCO3 + iopromide. Isotonic saline or NaHCO3 were infused at a rate of 4 mL/h per kg BM, initiated 60 minutes before CM administration and continued throughout the observation period of 100 minutes. Urine volume was measured gravimetrically, urine viscosity was measured by a microviscometer, and GFR was determined by creatinine clearance. RESULTS: As compared with saline infusions, NaHCO3 infusions did not significantly alter the effects that iodixanol and iopromide exerted on urine flow rate, urine viscosity, and GFR. In the iopromide protocols, CM-induced increase in urine flow was about 50% greater than in the respective iodixanol protocols. Conversely, in the iodixanol protocols, urine viscosity was up to 10-fold greater than in the respective iopromide protocol. In the iodixanol protocols, GFR decreased transiently (10-30 min post-CM) by up to 50%, whereas GFR did not decrease in the iopromide protocols. CONCLUSION: Infusing either saline or NaHCO3 seems to make little difference with regard to urine flow, urine viscosity, and GFR. However, the CM used has a significant effect on these measures. Iopromide enhances urine flow by a greater magnitude than iodixanol, whereas the latter increases urine viscosity to a larger degree than iopromide and transiently decreases GFR.

Differential effects of ethanol on IFN-gamma- and TNF-alpha-producing splenic T lymphocytes in a murine model of gram-negative pneumonia.

The incidence of bacterial pneumonia is increased in alcoholic patients. Alcohol consumption has been shown to impair cytokine production. Tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) are critical for host defense against Klebsiella pneumoniae (K. pneumoniae). In order to examine the influence of alcohol on the immune response to infection, we investigated the frequency of TNF-alpha and IFN-gamma produced by splenic T-lymphocytes in a murine model of gram-negative pneumonia initiated after 8 days of alcohol treatment. Thirty-two Balb/c mice were pretreated with ethanol (3 mg/g body weight) or saline intraperitoneally over 8 days. On day 7 half of each group was administered K. pneumoniae. Mice were sacrificed 24 hours later to excise lungs and liver for histological assessment and spleens for cell isolation. IFN-gamma- and TNF-alpha-producing CD4(+) and CD8(+) lymphocytes were determined by FACS analysis. In mice with Klebsiella infection, the percentages of IFN-gamma-producing CD4(+) (P < 0.01) and CD8(+) (P < 0.01) were significantly decreased, the percentages of TNF-alpha-producing CD4(+) (P = 0.01) and CD8(+) (P < 0.01) T cells were significantly elevated after alcohol treatment compared with mice with saline treatment. The histological assessment showed an aggravation of K. pneumoniae-induced pneumonia in alcohol-treated mice. Alcohol differentially affects IFN-gamma and TNF-alpha production in Klebsiella-infected mice. Both effects obviously led to a weakened immune response as seen by increased histological damage. This suggests a role of T cells in the increased susceptibility of the alcoholic host to nosocomial infection due to inadequate cytokine response.