Outcomes of WHO-conforming, longer, all-oral multidrug-resistant TB regimens and analysis implications.

BACKGROUND: Evidence of the effectiveness of the WHO-recommended design of longer individualized regimens for multidrug- or rifampicin-resistant TB (MDR/RR-TB) is limited.OBJECTIVES: To report end-of-treatment outcomes for MDR/RR-TB patients from a 2015-2018 multi-country cohort that received a regimen consistent with current 2022 WHO updated recommendations and describe the complexities of comparing regimens.METHODS: We analyzed a subset of participants from the endTB Observational Study who initiated a longer MDR/RR-TB regimen that was consistent with subsequent 2022 WHO guidance on regimen design for longer treatments. We excluded individuals who received an injectable agent or who received fewer than four likely effective drugs.RESULTS: Of the 759 participants analyzed, 607 (80.0%, 95% CI 77.0-82.7) experienced successful end-of-treatment outcomes. The frequency of success was high across groups, whether stratified on number of Group A drugs or fluoroquinolone resistance, and ranged from 72.1% to 90.0%. Regimens were highly variable regarding composition and the duration of individual drugs.CONCLUSIONS: Longer, all-oral, individualized regimens that were consistent with 2022 WHO guidance on regimen design had high frequencies of treatment success. Heterogeneous regimen compositions and drug durations precluded meaningful comparisons. Future research should examine which combinations of drugs maximize safety/tolerability and effectiveness.

Immunomodulation in leukemia: cellular aspects of anti-leukemic properties.

Immunomodulation is a mechanism that stimulates or inhibits immune responses under the influence of secretory mediators. This study will review the role of cytokines and chemotherapy in the modulation of immune responses in leukemia. We searched the PubMed database and Google scholar search engine of English-language papers (1995-2018) using the "Immunomodulation", "Leukemia", "Tregs", "Natural killer cells", "Mesenchymal stem cells", "Macrophages" and "chemotherapy" as keywords. In leukemias, T regulatory cells (Tregs), natural killer cells (NK), macrophages (MQs) and mesenchymal stem cells (MSCs) alter their functional and secretion patterns. Some of the changes in NK cells and classic MQ (M1) potentiate the immune responses against leukemia, but some Tregs changes will compromise the immune system. The effect of a cell on immunomodulation is in contrast to another cell, in which the cells are engaged in a competition so that a cell that having a higher effect on immunomodulation will be the contest winner. The outcome of immunomodulation in response to leukemia is determined by the ratio of stimulatory activity of NK cells and M1 to the inhibitory effect of Tregs, while the dual role of MSCs through immunomodulators and cytokines can be effective in weakening/enhancing the immune response.

The role and clinical implications of the endosteal niche and osteoblasts in regulating leukemia

Osteoblasts are one among the critical components of the endosteal bone marrow (BM) niche. In addition to hematopoietic stem cell fate, their role in leukemogenesis as well as metastasis of a variety of cancers has been demonstrated in various studies. In this regard, endosteal niche can have a dual role as an initiator and protective role against leukemia. Knowledge of growth factors, chemokines and cytokines secreted by osteoblasts as well as their interaction with signaling pathways inform our understanding of the development, prognosis, recurrence and treatment of malignant BM diseases. Clinical progress in targeting the endosteal niche is also discussed (AU)

No disponible

MicroRNAs as prognostic biomarker and relapse indicator in leukemia

Despite significant progress in the treatment of different types of leukemia, relapse remains a challenging clinical problem that is observed in a number of patients who are often resistant to chemotherapy and exhibit multi-drug resistance. Identification of new functional biomarkers, including microRNAs, is essential to determine prognosis and relapse at the time of diagnosis. The aim of this study was to detect the specific microRNAs involved in predicting relapse or progression in acute and chronic leukemias, as well as their relationship with overall survival (OS) and relapse-free survival (RFS). The relevant literature was identified through a PubMed and Scholar search (2008-2016) of English-language papers using the terms Leukemia, microRNAs, survival and relapse. Different leukemia types and subtypes show specific microRNA expression profile and different changes, which can be useful in the differentiation between leukemias and evaluation of relapse at the time of diagnosis. Altered microRNA expression profiles can turn these molecules into oncogenes or tumor suppressors, which affect the expression of relapse-related genes. Therefore, monitoring of specific microRNA expression profiles from diagnosis and during follow-up of patients can contribute to the assessment of outcome and determination of relapse and prognosis of leukemic patients (AU)

No disponible

Estimation of diagnosis and prognosis in ET by assessment of CALR and JAK2V617F mutations and laboratory findings: a meta-analysis

Background. Essential thrombocythemia (ET) is a benign disease with slow progress in which thrombosis is a cause of mortality. JAK2V617F and calreticulin (CALR) are the most frequent mutations in this disease. In this systematic review and meta-analysis, we compared the prevalence of JAK2V617F and CALR mutations in ET and examined the incidence of thrombosis and other hematologic indices. Methods. After choosing MeSH keywords, including essential thrombocythemia, JAK2V617F, calreticulin, prognosis, and diagnosis, as well as searching Medline/PubMed and Scopus, 12 papers were selected. Data were pooled, and summary prevalence and OR were estimated using either a random-effects model or a fixed-effects model. Results. The frequency of JAK2V617F and CALR shows heterogeneity in Caucasian population [JAK2V617I2% = 84.3, P < 0.001, 95% CI 0.56 (0.51-0.61)], [CALR I2% = 96.1, P < 0.001, 95% CI 0.23 (0.15-0.31)]. The prevalence of JAK2V617F and CALR was 0.57 (95% CI 0.53-0.61), I2% = 79.3 and 0.22 (95% CI 0.16-0.27), I2% = 94, respectively. JAK2V617F positive ET was associated with increasing odds of thrombosis [OR 2.35 (95% CI 1.83-3.02), P < 0.001]. The incidence of splenomegaly was not statistically different between these two mutations. Hemoglobin, platelet, and WBC count did not affect the risk of thrombosis. Conclusions. Detection of CALR mutation is helpful for molecular diagnosis of ET patients as well as JAK2V617F. Due to reduction of thrombosis in CALR-positive patients, it can be stated that such patients have less thrombotic disorders and better prognosis relative to patients bearing JAK2V617F mutation. Therefore, detection of mutation in CALR and JAK2V617F may contribute to diagnosis and prognosis of ET patients (AU)

No disponible

MicroRNAs as prognostic biomarker and relapse indicator in leukemia.

Despite significant progress in the treatment of different types of leukemia, relapse remains a challenging clinical problem that is observed in a number of patients who are often resistant to chemotherapy and exhibit multi-drug resistance. Identification of new functional biomarkers, including microRNAs, is essential to determine prognosis and relapse at the time of diagnosis. The aim of this study was to detect the specific microRNAs involved in predicting relapse or progression in acute and chronic leukemias, as well as their relationship with overall survival (OS) and relapse-free survival (RFS). The relevant literature was identified through a PubMed and Scholar search (2008-2016) of English-language papers using the terms Leukemia, microRNAs, survival and relapse. Different leukemia types and subtypes show specific microRNA expression profile and different changes, which can be useful in the differentiation between leukemias and evaluation of relapse at the time of diagnosis. Altered microRNA expression profiles can turn these molecules into oncogenes or tumor suppressors, which affect the expression of relapse-related genes. Therefore, monitoring of specific microRNA expression profiles from diagnosis and during follow-up of patients can contribute to the assessment of outcome and determination of relapse and prognosis of leukemic patients.

The role and clinical implications of the endosteal niche and osteoblasts in regulating leukemia.

Osteoblasts are one among the critical components of the endosteal bone marrow (BM) niche. In addition to hematopoietic stem cell fate, their role in leukemogenesis as well as metastasis of a variety of cancers has been demonstrated in various studies. In this regard, endosteal niche can have a dual role as an initiator and protective role against leukemia. Knowledge of growth factors, chemokines and cytokines secreted by osteoblasts as well as their interaction with signaling pathways inform our understanding of the development, prognosis, recurrence and treatment of malignant BM diseases. Clinical progress in targeting the endosteal niche is also discussed.

Estimation of diagnosis and prognosis in ET by assessment of CALR and JAK2V617F mutations and laboratory findings: a meta-analysis.

BACKGROUND: Essential thrombocythemia (ET) is a benign disease with slow progress in which thrombosis is a cause of mortality. JAK2V617F and calreticulin (CALR) are the most frequent mutations in this disease. In this systematic review and meta-analysis, we compared the prevalence of JAK2V617F and CALR mutations in ET and examined the incidence of thrombosis and other hematologic indices. METHODS: After choosing MeSH keywords, including essential thrombocythemia, JAK2V617F, calreticulin, prognosis, and diagnosis, as well as searching Medline/PubMed and Scopus, 12 papers were selected. Data were pooled, and summary prevalence and OR were estimated using either a random-effects model or a fixed-effects model. RESULTS: The frequency of JAK2V617F and CALR shows heterogeneity in Caucasian population [JAK2V617 I 2% = 84.3, P < 0.001, 95% CI 0.56 (0.51-0.61)], [CALR I 2% = 96.1, P < 0.001, 95% CI 0.23 (0.15-0.31)]. The prevalence of JAK2V617F and CALR was 0.57 (95% CI 0.53-0.61), I 2% = 79.3 and 0.22 (95% CI 0.16-0.27), I 2% = 94, respectively. JAK2V617F positive ET was associated with increasing odds of thrombosis [OR 2.35 (95% CI 1.83-3.02), P < 0.001]. The incidence of splenomegaly was not statistically different between these two mutations. Hemoglobin, platelet, and WBC count did not affect the risk of thrombosis. CONCLUSIONS: Detection of CALR mutation is helpful for molecular diagnosis of ET patients as well as JAK2V617F. Due to reduction of thrombosis in CALR-positive patients, it can be stated that such patients have less thrombotic disorders and better prognosis relative to patients bearing JAK2V617F mutation. Therefore, detection of mutation in CALR and JAK2V617F may contribute to diagnosis and prognosis of ET patients.

Signaling and molecular basis of bone marrow niche angiogenesis in leukemia

Angiogenesis, the process of blood vessel formation, is necessary for tissue survival in normal and pathologic conditions. Increased angiogenesis in BM niche is correlated with leukemia progression and resistance to treatment. Angiogenesis can interfere with disease progression and several angiogenic (such as vascular growth factors) as well as anti-angiogenic factors (i.e. angiostatin) can affect angiogenesis. Furthermore, miRs can affect the angiogenic process by inhibiting angiogenesis or increasing the expression of growth factors. Given the importance of angiogenesis in BM for maintenance of leukemic clones, recognition of angiogenic and anti-angiogenic factors and miRs as well as drug resistance mechanisms of leukemic blasts can improve the therapeutic strategies. We highlight the changes in angiogenic balance within the BM niche in different leukemia types. Moreover, we explored the pathways leading to drug resistance in relation to angiogenesis and attempted to assign interesting candidates for future research (AU)

No disponible

Central nervous system niche involvement in the leukemia

Central nervous system (CNS) impairment is commonly involved in leukemia, as it can be observed upon onset or relapse of the disease. It is associated with poor prognosis and is a challenging clinical problem. The objective of this paper was to provide a characterization of the CNS niche in leukemia, to elucidate the culprits of CNS involvement, including diagnostic micro RNAs (miRs) and early leukemia prognosis. CNS niche is a proper location for homing of leukemic stem cells, thus representing a candidate target in the treatment of leukemia. Recent advances in the study of leukemia hallmarks have enlightened miRs as novel biomarkers for diagnosis and detection of CNS involvement in leukemia, thus providing the opportunity to develop novel therapeutic approaches. Given the importance of prognosis and early diagnosis of CNS involvement in leukemias as well as the severe side effects of current treatments, diagnostic and therapeutic approaches should focus on identification and inhibition of the factors contributing to CNS involvement, including CXCR3, P-selectin glycoprotein ligand-1 and MCP1. MiRs such as miR-221 and miR-222 are emerging as potential tools for an innovative non-invasive therapy of CNS in leukemia affected patients (AU)

No disponible

Twist as a new prognostic marker in hematological malignancies

Twist proteins are members of basic helix-loop-helix family and are major regulators of embryogenesis. In adult humans, Twist proteins are mainly expressed in precursor cells, including myogenic, osteoblastic, chondroblastic and myelomonocytic lineages, maintaining their undifferentiated state. In addition, they play important roles in lymphocyte function and maturation. Recently, several studies have reported regulatory roles for Twist in the function and development of hematopoietic cells as well as in survival and development of numerous hematological malignancies. It is activated by numerous signal transduction pathways, including Akt, nuclear factor κB, Wnt, signal transducer and activator of transcription 3, mitogen-activated protein kinase and Ras signaling. Activated Twist has an anti-apoptotic role and protects cancer cells from apoptotic cell death. In addition, overexpression of Twist promotes the process of epithelial-mesenchymal transition, which has an essential role in cancer metastasis. Hereby, we review the aberrant expression of Twist in hematopoietic malignancies such as leukemias, lymphomas and myelodysplastic syndrome, which is related with poor prognosis and drug resistance in these disorders. Inactivation of Twist by small RNAs technology or chemotherapeutic inhibitors targeting Twist and upstream or downstream molecules of Twist signaling pathways may be helpful in management of disease to improve treatment strategies in malignancies (AU)

No disponible

Signaling and molecular basis of bone marrow niche angiogenesis in leukemia.

Angiogenesis, the process of blood vessel formation, is necessary for tissue survival in normal and pathologic conditions. Increased angiogenesis in BM niche is correlated with leukemia progression and resistance to treatment. Angiogenesis can interfere with disease progression and several angiogenic (such as vascular growth factors) as well as anti-angiogenic factors (i.e. angiostatin) can affect angiogenesis. Furthermore, miRs can affect the angiogenic process by inhibiting angiogenesis or increasing the expression of growth factors. Given the importance of angiogenesis in BM for maintenance of leukemic clones, recognition of angiogenic and anti-angiogenic factors and miRs as well as drug resistance mechanisms of leukemic blasts can improve the therapeutic strategies. We highlight the changes in angiogenic balance within the BM niche in different leukemia types. Moreover, we explored the pathways leading to drug resistance in relation to angiogenesis and attempted to assign interesting candidates for future research.

Central nervous system niche involvement in the leukemia.

Central nervous system (CNS) impairment is commonly involved in leukemia, as it can be observed upon onset or relapse of the disease. It is associated with poor prognosis and is a challenging clinical problem. The objective of this paper was to provide a characterization of the CNS niche in leukemia, to elucidate the culprits of CNS involvement, including diagnostic micro RNAs (miRs) and early leukemia prognosis. CNS niche is a proper location for homing of leukemic stem cells, thus representing a candidate target in the treatment of leukemia. Recent advances in the study of leukemia hallmarks have enlightened miRs as novel biomarkers for diagnosis and detection of CNS involvement in leukemia, thus providing the opportunity to develop novel therapeutic approaches. Given the importance of prognosis and early diagnosis of CNS involvement in leukemias as well as the severe side effects of current treatments, diagnostic and therapeutic approaches should focus on identification and inhibition of the factors contributing to CNS involvement, including CXCR3, P-selectin glycoprotein ligand-1 and MCP1. MiRs such as miR-221 and miR-222 are emerging as potential tools for an innovative non-invasive therapy of CNS in leukemia affected patients.

Twist as a new prognostic marker in hematological malignancies.

Twist proteins are members of basic helix-loop-helix family and are major regulators of embryogenesis. In adult humans, Twist proteins are mainly expressed in precursor cells, including myogenic, osteoblastic, chondroblastic and myelomonocytic lineages, maintaining their undifferentiated state. In addition, they play important roles in lymphocyte function and maturation. Recently, several studies have reported regulatory roles for Twist in the function and development of hematopoietic cells as well as in survival and development of numerous hematological malignancies. It is activated by numerous signal transduction pathways, including Akt, nuclear factor κB, Wnt, signal transducer and activator of transcription 3, mitogen-activated protein kinase and Ras signaling. Activated Twist has an anti-apoptotic role and protects cancer cells from apoptotic cell death. In addition, overexpression of Twist promotes the process of epithelial-mesenchymal transition, which has an essential role in cancer metastasis. Hereby, we review the aberrant expression of Twist in hematopoietic malignancies such as leukemias, lymphomas and myelodysplastic syndrome, which is related with poor prognosis and drug resistance in these disorders. Inactivation of Twist by small RNAs technology or chemotherapeutic inhibitors targeting Twist and upstream or downstream molecules of Twist signaling pathways may be helpful in management of disease to improve treatment strategies in malignancies.

Skin manifestation of methylmalonic acidemia: case report and review of the literature.

Skin manifestations, including scalded skin, desquamation, and chronic periorificial dermatitis, are rare clinical signs in patients with methylmalonic acidemia. This condition may be due to enzyme deficiency or multi-nutrient deficiency because of nutritional restriction. Bullous skin lesion is very rare in these patients and consequently, this type of skin lesion can be the presenting sign of methylmalonic acidemia.

Prevalence of otomycosis in Khouzestan Province, south-west Iran.

BACKGROUND: This study aimed to investigate the prevalence of otomycosis and aetiological agents in Khouzestan province, south-west Iran. METHODS: This cross-sectional study examined and cultured 881 swabs from suspected external otitis cases, collected from throughout Khouzestan province. Fungal agents were identified by slide culture and complementary tests when necessary. RESULTS: The mean patient age was 37 years. The 20-39 year age group had the highest prevalence of otomycosis: 293 cases, comprising 162 (55.3 per cent) women and 131 (44.7 per cent) men. The seasonal distribution of cases was: summer, 44.7 per cent; autumn, 28.7 per cent; winter, 14.7 per cent; and spring, 11.9 per cent. The fungal agents isolated were Aspergillus niger (67.2 per cent), Aspergillus flavus (13 per cent), Candida albicans (11.6 per cent), Aspergillus fumigatus (6.2 per cent) and penicillium species (2 per cent). CONCLUSION: Fungal otomycosis is still one of the most important external ear diseases. In this study in south-west Iran, Aspergillus niger was the predominant aetiological agent. However, clinicians should be cautious of candidal otomycosis, which has a lower rate of incidence but is more prevalent among 20-39 year olds.

Immunologic factors in patients with chronic polypoid sinusitis.

BACKGROUND: Nasal polyposis is the benign protrusion of soft tissue into the nasal cavity, with multifactorial origin. This study is designed to examine the suggested role of IgE and CD4 and CD8 lymphocytes in the pathogenesis of nasalpolyposis. METHODOLOGY: Blood samples were taken from 32 patients with chronic polypoid sinusitis and 32 controls. CD4 and CD8 total lymphocyte count were determined by flow cytometry and the level of serum IgE was measured by ELISA. Nasal discharge samples were also collected for determining IgE level in both patients and controls during surgery. RESULTS: In 68.8% of patients a history of allergy was present. The level of nasal discharge IgE was significantly higher (p < 0.001) in patients compared to controls, but the difference between serum IgE levels was not significant (p > 0.05). CD8 concentration and blood lymphocytes were significantly higher (p < 0.001) in the patients group, while CD4 concentration was significantly lower (p < .OO01) in them. Finally, CD4/CD8 ratio was significantly lower(p < 0. 001) in the patients group. CONCLUSION: This study suggests that a change in the amount of CD4 and CD8 lymphocytes and an increased level of local IgE contribute to nasal polyposis, but the results should be confirmed in more extensive studies including cytokine analyses. Such increasing insights in the pathophysiology of nasal polyposis open perspectives for new pharmacological treatment options, with immunologic factors as potential targets.

Anatomical variations of neurovascular structures adjacent sphenoid sinus by using CT scan.

The aim of this research was to study of the relationship between anatomical variations of neurovascular structures adjacent sphenoid sinus with sex and position of appearance by using CT scan. In this retrospective study paranasal sinuses CT scan has been taken from 399 patients (210 male, 189 female) that referred to Imam Khomeini and Apadana Hospitals, Ahwaz, Iran. Furthermore, protrusion and dehiscence of Internal Carotid Artery (ICA), Maxillary Nerve (MN), Vidian Nerve (VN) and Optic Nerve (ON) into the sphenoid sinuses cavity have been investigated by using CT scan results. In 210 male patients the protrusion of interested variables were noticed as: ICA in 102 (48.5%) cases, ON in 80 (38%) cases, MN in 74 (35.5%) cases, and VN in 60 (28.5%) cases, respectively. Also in 189 female patients group the protrusion of ICA, ON, MN, VN were noticed in 65 (34.3%), 66 (34.9%), 62 (32.8%) and 43 (22.7%) cases, respectively. The statistical analysis show significant difference (p = 0.001) of protrusion of ICA between male and female groups. In 210 male patients the dehiscence of ICA, ON, MN, VN were noticed in 82 (39%), 60 (28.5%), 60 (28.5%) and 66 (31.4%) cases, respectively. Also in 189 female patients the dehiscence of interested variables were noticed as: ICA in 85 (44.9%), ON in 87 (46%), MN in 69 (36.5%), VN in 71 (37.5%) cases, respectively. The statistical analysis show significant difference (p = 0.03) of dehiscence of on variable in male and female groups. In order to increase the risk of intra-operative complications detailed preoperative investigation of neurovascular structures in sphenoid sinuses by use of CT scan images should be done properly.

Immunologic factors in patients with chronic polypoid sinusitis.

BACKGROUND: Nasal polyposis is the benign protrusion of soft tissue into the nasal cavity, with multifactorial origin. This study is designed to examine the suggested role of IgE and CD4 and CD8 lymphocytes in the pathogenesis of nasal polyposis. METHOD: Blood samples were taken from 32 patients with chronic polypoid sinusitis and 32 controls. CD4 and CD8 total lymphocyte count were determined by flow cytometry and the level of serum IgE was measured by ELISA. Nasal discharge samples were also collected for determining IgElevel in both patients and controls during surgery. RESULTS: In 68.8% of patients a history of allergy was present. The level of nasal discharge IgE was significantly higher (p < 0.001) in patients compared to controls, but the difference between serum IgE levels was not significant (p > 0.05). CD8 concentration and blood lymphocytes were significantly higher (p < 0.001) in the patients group, while CD4 concentration was significantly lower (p < 0.001) in them. Finally, CD/CD8 ratio was significantly lower (p < 0.001) in the patients group. CONCLUSION: This study suggests that a change in the amount of CD4 and CD8 lymphocytes and an increased level of local IgE contribute to nasal polyposis, but the results should be confirmed in more extensive studies including cytokine analyses. Such increasing insights in the pathophysiology of nasal polyposis open perspectives for new pharmacological treatment options, with immunologic factors as potential targets.