Publications by authors named "Payam Mehrian"

34 Publications

Clinical Significance of Quantitative FDG PET/CT Parameters in Non-Small Cell Lung Cancer Patients.

Tanaffos 2020 Jul;19(3):186-194

Tracheal Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: An initial evaluation of non-small cell lung cancer (NSCLC) patients with 18F- fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scan can modify treatment planning. We investigated the clinical significance of FDG PET/CT quantitative parameters (QPs) in NSCLC patients.

Materials And Methods: We included 125 NSCLC patients for initial staging FDG PET/CT scan. The primary tumor (T), regional lymph node metastases (N), and distant metastases (M) were evaluated on FDG PET/CT images. QPs, including standard uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were calculated separately for each T, N, and M lesion and also for the whole body. Statistical analysis through SPSS version 22 was used to evaluate the clinical significance of PET/CT QPs concerning primary tumor pathology characteristics, initial tumor stage, and patient's prognosis.

Results: We followed the patients for 19.28 (±11.42) months. Considering primary tumor pathology, there was a significant difference in FDG PET/CT QPs, including primary tumor SUVmax (p=0.00), metastases SUVmax (p=0.014), whole-body MTV (p=0.045), and whole-body TLG (p=0.002). There was also a significant difference in QPs, including primary tumor SUVmax (p=0.00) and regional lymph node metastases SUVmax (p=0.048) when accounting for tumor initial stage. There was a significant prognostic value for the whole-body TLG (p=0.01) and a cut-off point of 568 was reached to differentiate better versus worse survival outcome.

Conclusion: We demonstrated a statistically significant difference in FDG PET/CT QPs when accounting for primary NSCLC pathology characteristics and initial stage, as well as patient's prognosis, and recommend incorporating QP values into clinical PET/CT reports.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008410PMC
July 2020

Serum cytokine levels of COVID-19 patients after 7 days of treatment with Favipiravir or Kaletra.

Int Immunopharmacol 2021 Apr 22;93:107407. Epub 2021 Jan 22.

National Heart and Lung Institute, Imperial College London and the NIHR Imperial Biomedical Research Centre, London, UK; Priority Research Centre for Asthma and Respiratory Disease, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, Australia.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has infected 86,4 M patients and resulted in 1,86 M deaths worldwide. Severe COVID-19 patients have elevated blood levels of interleukin-6 (IL-6), IL-1β, tumor necrosis factor (TNF)α, IL-8 and interferon (IFN)γ.

Objective: To investigate the effect of antiviral treatment serum cytokines in severe COVID-19 patients.

Methods: Blood was obtained from 29 patients (aged 32-79 yr) with laboratory-confirmed COVID-19 upon admission and 7 days after antiviral (Favipiravir or Lopinavir/Ritonavir) treatment. Patients also received standard supportive treatment in this retrospective observational study. Chest computed tomography (CT) scans were evaluated to investigate lung manifestations of COVID-19. Serum was also obtained and cytokines levels were evaluated. 19 age- and gender-matched healthy controls were studied.

Results: Anti-viral therapy significantly reduced CT scan scores and the elevated serum levels of C-reactive protein (CRP) and lactate dehydrogenase (LDH). In contrast, serum levels of IL-6, IL-8 and IFNγ were elevated at baseline in COVID-19 subjects compared to healthy subjects with IL-6 (p = 0.006) and IL-8 (p = 0.011) levels being further elevated after antiviral therapy. IL-1β (p = 0.01) and TNFα (p = 0.069) levels were also enhanced after treatment but baseline levels were similar to those of healthy controls. These changes occurred irrespective of whether patients were admitted to the intensive care unit.

Conclusion: Antiviral treatments did not suppress the inflammatory phase of COVID-19 after 7 days treatment although CT, CRP and LDH suggest a decline in lung inflammation. There was limited evidence for a viral-mediated cytokine storm in these COVID-19 subjects.
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http://dx.doi.org/10.1016/j.intimp.2021.107407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826095PMC
April 2021

Pulmonary embolism and COVID-19 pneumonia: the role of non-enhanced chest computed tomography.

Rev Cardiovasc Med 2020 12;21(4):493-495

School of Medicine, Tehran University of Medical Sciences, 14155-6559, Tehran, Iran.

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http://dx.doi.org/10.31083/j.rcm.2020.04.246DOI Listing
December 2020

Diffuse Subcutaneous Metabolic Activity in Post Bone Marrow Transplant Hodgkin Lymphoma.

Clin Nucl Med 2021 Apr;46(4):e226-e227

From the Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Abstract: We present a 14-year-old adolescent boy with Hodgkin lymphoma. He had prior completed chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) regimen followed by bone marrow transplantation 6 months ago. Currently, he has neither specific clinical complaint nor receiving any specific medication. Follow-up FDG PET/CT scan demonstrated diffuse increased metabolic activity in the entire body subcutaneous tissue. This finding is rarely reported in the literature and may represent an underlying active inflammatory process, most likely attributed to the received treatments. This could impair the diagnostic quality of the scan, affecting the image interpretation, and should be recognized when present.
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http://dx.doi.org/10.1097/RLU.0000000000003413DOI Listing
April 2021

Diagnosis of allergic bronchopulmonary aspergillosis in patients with persistent allergic asthma using three different diagnostic algorithms.

Mycoses 2021 Mar 8;64(3):272-281. Epub 2020 Dec 8.

Department of Medical Mycology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

Background: Allergic bronchopulmonary aspergillosis (ABPA) has been reported in various degrees among patients with persistent allergic asthma (PAA). Currently, there is no gold standard approach for diagnosis of ABPA.

Objectives: In the current study, we aimed the evaluation of three different mainly used algorithms as Rosenberg & Patterson (A), ISHAM Working Group (B) and Greenberger (C) for diagnosis of ABPA in 200 patients with underlying PAA.

Methods: All patients were evaluated using Aspergillus skin prick test (SPTAf), Aspergillus-specific IgE (sIgEAf) and IgG (sIgGAf), total IgE (tIgE), pulmonary function tests, radiological findings and peripheral blood eosinophil count. The prevalence rate of ABPA in PAA patients was estimated by three diagnostic criteria. We used Latent Class Analysis for the evaluation of different diagnostic parameters in different applied ABPA diagnostic algorithms.

Results: Aspergillus sensitisation was observed in 30 (15.0%) patients. According to algorithms A, B and C, nine (4.5%), six (3.0%) and 11 (5.5%) of patients were diagnosed with ABPA, respectively. The sensitivity and specificity of criteria B and C were (55.6% and 99.5%) and (100.0% and 98.9%) respectively. sIgEAf and sIgGAf showed the high significant sensitivity. The performance of algorithm A, in terms of sensitivity and specificity, was somewhat better than algorithm B.

Conclusion: Our study demonstrated that the sensitivity of different diagnostic algorithms could change the prevalence rate of ABPA. We also found that all of three criteria resulted an adequate specificity for ABPA diagnosis. A consensus patterns combining elements of all three criteria may warrant a better diagnostic algorithm.
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http://dx.doi.org/10.1111/myc.13217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902363PMC
March 2021

Hypersensitivity Pneumonitis High-resolution Computed Tomography Findings, and Their Correlation with the Etiology and the Disease Duration.

Prague Med Rep 2020 ;121(3):133-141

Chronic Respiratory Diseases Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Hypersensitivity pneumonitis (HP) is an immune-mediated diffuse parenchymal lung disease induced by inhaled antigens. High-resolution computed tomography (HRCT) is widely used in the diagnosis and follow-up of patients and determining the progression and prognosis of the disease. In this retrospective study, 45 consecutive patients with the final diagnosis of HP, seen at a large tertiary care center during a period of 4 years, were included and their HRCT findings were evaluated. The most common HRCT findings were ground glass opacity and reticulation. Some HRCT patterns were detected more severely in bird fanciers in comparison with other etiologies. There is no "gold standard" for the diagnosis of HP. HRCT findings play an important role in hypersensitivity pneumonitis diagnosis and CT scan also help to define the severity of hypersensitivity pneumonitis injuries. In our study, reticulation and ground glass opacity were the most common findings in HRCT of patients with HP. We also find that patients with avian contacts had a significantly higher rate of fibrosis.
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http://dx.doi.org/10.14712/23362936.2020.12DOI Listing
December 2020

Computerised tomography scan in multi-drug-resistant versus extensively drug-resistant tuberculosis.

Pol J Radiol 2020 23;85:e39-e44. Epub 2020 Jan 23.

Mycobacteriology Research Centre (MRC), National Research Institute of Tuberculosis and Lung Disease (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Purpose: Multi-drug-resistant tuberculosis (MDR-TB) is simultaneously resistant to isoniazid and rifampin. Of course, this germ may also be resistant to other anti-tuberculosis drugs. Patients with extensively drug-resistant tuberculosis (XDR-TB) are also resistant to all types of fluoroquinolone and at least one of the three injectable medications: amikacin, clarithromycin, or kanamycin, in addition to isoniazid and rifampin. Therefore, the main objective of the current study was to evaluate and compare the computed tomography (CT) scan findings of MDR-TB and XDR-TB patients.

Material And Methods: In this comparative descriptive cross-sectional study 45 consecutive TB patients who referred to Masih Daneshvari Hospital, Tehran, Iran from 2013 to 2019 were enrolled. TB was diagnosed based on sputum smear and sensitive molecular and microbial tests. Patients were divided into two groups (MDR-TB and XDR-TB) based on two types of drug resistance. CT scan findings were compared for cavitary, parenchymal, and non-parenchymal disorders. The early diagnostic values of these factors were also calculated.

Results: Findings related to cavitary lesions including the pattern, number, size of the largest cavity, maximum thickness of the cavity, lung involvement, number of lobes involved, and the air-fluid levels in the two patient groups were similar ( > 0.05). Parenchymal findings of the lung also included fewer and more nodules of 10 mm in the MDR-TB and XDR-TB groups, respectively. Tree-in-bud, ground-glass-opacity, bronchiectasis, cicatricial emphysema, and lobar atelectasis were similar in the two patient groups ( > 0.05). Findings outside the parenchymal lung, including mediastinal lymphadenopathy and pericardial effusion, showed no statistically significant difference between the MDR-TB and XDR-TB groups ( > 0.05). Parenchymal calcification was more common in the XDR group than in the MDR group (64.7% and 28.6%, respectively) with a significant difference ( = 0.01).

Conclusions: CT scan findings in patients with XDR-TB are similar to those of patients with MDR-TB for cavitary, parenchymal, and non-parenchymal lung characteristics. However, patients with XDR-TB tend to have more parenchymal calcification and left-sided plural effusion. CT characteristics overlap between XDR-TB and those with MDR-TB. It can be concluded that CT scan features are not sensitive to the diagnosis.
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http://dx.doi.org/10.5114/pjr.2020.93123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064012PMC
January 2020

Computer Tomography (CT) Characteristics of Pulmonary Cystic Echinococcosis.

Med Arch 2019 Oct;73(5):338-343

Department of Radiology, Imam Ali Hospital, Zahedan University of Medical Sciences, Zahedan, Iran.

Introduction: Cystic echinococcosis (CE) is a common zoonosis worldwide. The two most frequent location of CE are liver and lung. Confirmatory diagnosis of CE is routinely performed sung imaging methods such as computer aided tomography and nuclear magnetic resonance in humans.

Aim: to investigate CT scan imaging of patients with pulmonary CE in Masih Daneshvari Hospital from 2011 to 2017.

Matarial And Methods: This descriptive-analytic study was carried out on patients with pulmonary CE referring to Masih Daneshvari Hospital. By using the convenience sampling, 195 cases were selected from eligible patients. The data collection tool was a researcher-made questionnaire that included demographic, clinical and laboratory information. Data were analyzed using SPSS software version 20.

Results: In this study, 84.1% and 15.9% of patients were diagnosed using surgical method and CT scan, respectively. Our findings indicated CE was most commonly located in liver (28.2%) and spleen was considered as the lowest location (3.1%). Furthermore, cough was the most common clinical symptom of patients. The lower right lobe opacity was found to be higher, while and Lingula was the least frequent.

Conclusion: According to the findings of this study, surgery is the most important diagnostic and cough method as the most common clinical symptom of the disease. Since the CE with atypical symptoms is relatively common, physicians should always consider the lung CE in differential diagnosis of localized radiological images.
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http://dx.doi.org/10.5455/medarh.2019.73.338-343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885213PMC
October 2019

Primary Ewing sarcoma of the kidney.

BMJ Case Rep 2019 Jan 28;12(1). Epub 2019 Jan 28.

Pathology, Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, The Islamic Republic of Iran.

Primary Ewing sarcoma (ES) or primitive neuroectodermal tumour (PNET) is a rare tumour in adults and primary renal involvement is extremely rare. Patients with renal ES or PNET respond to and would benefit from conventional ES treatment according to ES study protocols. Here, we report a case of a young woman, presenting with right flank pain and haematuria. After ultrasound and CT evaluation, a right middle pole renal mass was detected. The patient underwent radical right nephrectomy, and a grade 4 ES with peritoneal involvement was documented. Subsequently, the patient underwent adjuvant chemotherapy for 5 months. Follow-up 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scan demonstrated bilateral cervical, hilar, mediastinal and retroperitoneal FDG-avid adenopathies associated with mild right-sided pleural effusion with no metabolic activity, signifying the role of PET/CT scan in tumour restaging.
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http://dx.doi.org/10.1136/bcr-2018-227198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350699PMC
January 2019

Rectal adenocarcinoma presenting with thigh muscle metastasis as the only metastatic site.

BMJ Case Rep 2019 Jan 22;12(1). Epub 2019 Jan 22.

PET/CT, Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, The Islamic Republic of Iran.

Rectal carcinoma with metastasis to skeletal muscle is a rare finding. According to literature review, 17 cases of skeletal muscle metastasis from colorectal carcinoma have been documented where only six cases were rectal carcinomas.We discuss a case of a middle-aged man with a known history of high-grade mucinous adenocarcinoma of the rectum, status post abdominoperineal resection followed by adjuvant radiotherapy and chemotherapy. During the planned chemotherapy course, a right proximal thigh subcutaneous mass was incidentally found which on subsequent biopsy proved to be metastatic from rectal primary site. On subsequent 18F-FDG (Fluorodeoxyglucose) positron emission tomography (PET)/CT scan after completion of chemotherapy for the purpose of treatment response evaluation, only FDG-avid lesion was residual right proximal thigh metastatic mass without involvement of other common sites, such as liver and lung. In this case, the 18F-FDG-PET/CT scan was able to exclude additional metastatic sites and also evaluate the patient's treatment response.
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http://dx.doi.org/10.1136/bcr-2018-226802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347927PMC
January 2019

The association between computed tomography scan findings of pulmonary infection caused by atypical mycobacteria and bacillus count in sputum samples.

Int J Mycobacteriol 2018 Oct-Dec;7(4):355-357

Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Disease, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: The use of imaging techniques is important for prompt diagnosis and treatment of atypical mycobacterial infections; it also reduces the burden of these infections. The purpose of the present study was to determine the association between computed tomography (CT) scan findings of pulmonary infection caused by atypical mycobacteria and bacillus count in sputum samples.

Methods: This cross-sectional, observational, comparative study included 50 consecutive patients with pulmonary infection caused by atypical mycobacteria, who were hospitalized in Masih-Daneshvari Hospital of Tehran, Iran during 2012-2017. The association between CT scan findings of pulmonary infection caused by atypical mycobacteria and bacillus count in sputum samples was determined in these patients.

Results: The results demonstrated that the presence of nodules smaller than 5 mm in diameter, consolidation, bronchiectasis, and pleural thickening were related to bacillus count in sputum samples (P < 0.05).

Conclusion: Some CT scan findings, such as nodule diameter smaller than 5 mm, consolidation, bronchiectasis, and pleural thickening, may be indicators of atypical mycobacterial infection. Increased number of involved lobes with bronchiectasis can promote early diagnosis in patients with higher smear and culture grading.
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http://dx.doi.org/10.4103/ijmy.ijmy_139_18DOI Listing
June 2019

An adult autosomal recessive chronic granulomatous disease patient with pulmonary Aspergillus terreus infection.

BMC Infect Dis 2018 Nov 8;18(1):552. Epub 2018 Nov 8.

Clinical Tuberculosis and Epidemiology Research Centre, National Research Institute for Tuberculosis and Lung Disease (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: Genetic mutations that reduce intracellular superoxide production by granulocytes causes chronic granulomatous disease (CGD). These patients suffer from frequent and severe bacterial and fungal infections throughout their early life. Diagnosis is usually made in the first 2 years of life but is sometimes only diagnosed when the patient is an adult although they may have suffered from symptoms since childhood.

Case Presentation: A 26-year-old man was referred with weight loss, fever, hepatosplenomegaly and coughing. He had previously been diagnosed with lymphadenopathy in the neck at age 8 and prescribed anti-tuberculosis treatment. A chest radiograph revealed extensive right-sided consolidation along with smaller foci of consolidation in the left lung. On admission to hospital he had respiratory problems with fever. Laboratory investigations including dihydrorhodamine-123 (DHR) tests and mutational analysis indicated CGD. Stimulation of his isolated peripheral blood neutrophils (PMN) with phorbol 12-myristate 13-acetate (PMA) produced low, subnormal levels of reactive oxygen species (ROS). Aspergillus terreus was isolated from bronchoalveolar lavage (BAL) fluid and sequenced.

Conclusions: We describe, for the first time, the presence of pulmonary A. terreus infection in an adult autosomal CGD patient on long-term corticosteroid treatment. The combination of the molecular characterization of the inherited CGD and the sequencing of fungal DNA has allowed the identification of the disease-causing agent and the optimal treatment to be given as a consequence.
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http://dx.doi.org/10.1186/s12879-018-3451-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225587PMC
November 2018

Distribution and Characteristics of Intrathoracic Lymphadenopathy in TB/HIV Co-Infection.

Infect Disord Drug Targets 2019 ;19(4):414-420

Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: Intrathoracic Lymphadenopathy (ITLN) in Human Immunodeficiency Virus (HIV) infected patients may have various etiologies and prognoses. Etiologies of ITLN can be distinguished based on the distribution of enlarged lymph nodes. Sometimes tuberculosis (TB) is the first sign of underlying HIV infection.

Objectives: We sought to determine ITLN distribution and associated pulmonary findings in TB/HIV co-infection using Computed Tomography (CT) scan.

Methods: In this retrospective, observational, cross-sectional study, chest CT scans of 52 patients with TB/HIV co-infection were assessed for enlarged intrathoracic lymph nodes (>10 mm in short axis diameter), lymphadenopathy (LAP) distribution, calcification, conglomeration, the presence of hypodense center and associated pulmonary abnormalities. LAP distribution was compared in TB/HIV co-infection with isolated TB infection.

Results: Mediastinal and/or hilar LAP were seen in 53.8% of TB/HIV co-infection patients. In all cases, LAP was multistational. The most frequent stations were right lower paratracheal and subcarinal stations. Lymph node conglomeration, hypodense center and calcification were noted in 25%, 21.4% and 3.5% of patients, respectively. LAP distribution was the same as that in patients with isolated TB infection except for the right hilar, right upper paratracheal and prevascular stations. All patients with mediastinal and/or hilar adenopathy had associated pulmonary abnormalities.

Conclusion: All patients with TB/HIV co-infection and mediastinal and/or hilar adenopathy had associated pulmonary abnormalities. Superior mediastinal lymph nodes were less commonly affected in TB/HIV co-infection than isolated TB.
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http://dx.doi.org/10.2174/1871526518666181016111142DOI Listing
May 2020

Correlation of quantified metabolic activity in nonsmall cell lung cancer with tumor size and tumor pathological characteristics.

Medicine (Baltimore) 2018 Aug;97(32):e11628

Pediatric Respiratory Diseases Research Center Chronic Respiratory Diseases Research Center Lung Transplantation Research Center (LTRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

The aim of this study was to evaluate the relationship between maximum standardized uptake value (SUVmax) with tumor size and tumor pathological characteristics as well as suggesting equations between SUVmax and tumor size in patients with nonsmall cell lung cancer (NSCLC) to help differentiate between pathology types.We retrospectively analyzed the fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) findings of 98 patients with NSCLC. Statistical differences were considered significant when P < .05. Correlation between SUVmax and other variables was determined by Pearson and Spearman correlation. Both linear and nonlinear regression analysis were used to determine equations between SUVmax and tumor size to help differentiate between pathology types.The mean SUVmax in patients with squamous cell carcinoma was significantly higher than that of adenocarcinoma (21.35 ± 1.73 vs 13.75 ± 0.89, P = .000). The results of regression analysis indicated that among all equations determined with relative accuracy, the "cubic equation" has the highest accuracy when considering the relationship between SUVmax and tumor size in patients with adenocarcinoma. In patients with squamous cell carcinoma, the most accurate equation was obtained using the "quadratic equation."There was a significant correlation between SUVmax and tumor differentiation and tumor size in patients with adenocarcinoma. SUVmax of patients with squamous cell carcinoma also had a significant correlation with tumor size. Overall SUVmax of patients with NSCLC could be predicted by tumor size value. In patients with squamous cell carcinoma compared with those with adenocarcinoma, SUVmax with less accuracy can be determined by tumor size. Linear regression analysis line slope can be used as an index for distinguishing adenocarcinoma from squamous cell carcinoma.
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http://dx.doi.org/10.1097/MD.0000000000011628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133455PMC
August 2018

Recurrent inflammatory myofibroblastic tumour of the lung: FDG PET/CT scan findings.

BMJ Case Rep 2018 Jul 13;2018. Epub 2018 Jul 13.

Department of Pathology, Tracheal Diseases Research Center (TDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital. Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Inflammatory myofibroblastic tumour (IMT) is a rare neoplasm, occurring most often in children and young adults. IMTs have intermediate biological behaviour with the chance of local invasion, recurrence and even distant metastasis. Wide range of clinical presentations makes the precise diagnosis of IMT more challenging. The best method for definitive diagnosis is tissue biopsy and newer imaging modalities including fleurodeoxyglucose (FDG) positron emission tomography (PET)/CT are useful tools in detection of disease recurrence or distant metastasis. Complete surgical resection is the best-known treatment for this tumour. Here we are presenting an IMT case in a 12-year-old girl in which her recurrent pulmonary IMT was diagnosed based on FDG PET/CT findings and referred for further salvage treatment. Overall imaging modalities are not specific, but PET/CT scan can be useful tool for evaluation of IMT regarding initial staging and restaging to assess treatment response and recurrence.
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http://dx.doi.org/10.1136/bcr-2018-224373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047701PMC
July 2018

Mantle cell lymphoma presenting as bilateral adrenal huge masses.

BMJ Case Rep 2018 Apr 17;2018. Epub 2018 Apr 17.

Telemedicine Research Center (TRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), University of Medical Sciences, Tehran, Iran.

We present a middle-aged woman complaining of weakness, lethargy and weight loss for 6 months. Positron emission tomography (PET)/CT scan revealed huge bilateral adrenal masses with intense 18F-fluorodeoxyglucose avidity. Biopsy and immunohistochemical staining were compatible with mantle cell lymphoma (MCL). The patient received six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) followed by four cycles of intrathechal methotrexate chemotherapy. Bone marrow aspiration biopsy was performed for initial staging and also before bone marrow transplantation. Follow-up PET/CT scan after completion of chemotherapy and before bone marrow transplantation demonstrated complete metabolic response with no evidence of abnormal metabolic activity in either adrenal gland or bone marrow. MCL has an aggressive nature and is usually considered incurable; however, there have been a few reports indicating favourable treatment response when MCL is rarely arising from the adrenal glands. Dramatic response of a primary adrenal MCL to R-CHOP is documented in this case.
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http://dx.doi.org/10.1136/bcr-2017-223247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5905789PMC
April 2018

Susceptibility to mycobacterial disease due to mutations in IL-12Rβ1 in three Iranian patients.

Immunogenetics 2018 06 18;70(6):373-379. Epub 2017 Dec 18.

Mycobacteriology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

In the last decade, autosomal recessive interleukin-12 receptor β1 (IL-12Rβ1) deficiency, the most common cause of Mendelian susceptibility to mycobacterial disease (MSMD), has been diagnosed in a few children and adults with severe tuberculosis in Iran. Here, we report three cases referred to the Immunology, Asthma and Allergy ward at the National Research Institute of Tuberculosis and Lung Diseases (NRITLD) at Masih Daneshvari Hospital from 2012 to 2017 with Mycobacterium tuberculosis and non-tuberculous mycobacteria infections due to defects in IL-12Rβ1 but with different clinical manifestations. All three were homozygous for either an IL-12Rβ1 missense or nonsense mutation that caused the IL-12Rβ1 protein not to be expressed on the cell membrane and completely abolished the cellular response to recombinant IL-12. Our findings suggest that the presence of IL-12Rβ1 deficiency should be determined in children with mycobacterial infections at least in countries with a high prevalence of parental consanguinity and in areas endemic for TB like Iran.
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http://dx.doi.org/10.1007/s00251-017-1041-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943370PMC
June 2018

Hypermetabolic Thyroid Incidentaloma on Positron Emission Tomography: Review of Laboratory, Radiologic, and Pathologic Characteristics.

J Thyroid Res 2017 20;2017:7176934. Epub 2017 Aug 20.

Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Introduction: Incidental hypermetabolic thyroid lesions on Positron Emission Tomography have significant clinical value and may harbor malignancy. In this study we evaluated laboratory, radiologic, and pathologic characteristics of incidental hypermetabolic thyroid lesions.

Materials And Methods: We evaluated 18 patients prospectively with various malignancies and hypermetabolic thyroid incidentaloma. The thyroid function tests, ultrasound assessment, and guided FNA biopsy were performed on all cases.

Results: We included 9 male and 9 female patients with mean age of 51 years. Most common malignancy was colon cancer. Metabolic activity quantification using maximum standard uptake value demonstrated range between 1.4 and 65.4 with mean value of 9.4. We found highest metabolic activity in patients with lung adenocarcinoma, B-cell lymphoma, and colon adenocarcinoma. On ultrasound exam most thyroid lesions were of solid, hypoechoic, noncalcified nature with either normal or peripheral increased vascularity. FNA biopsy report was benign in 15 cases and malignant or highly suggestive for malignancy in 3 other cases. Two of the three malignant cases demonstrated metabolic activity higher than average SUV max.

Conclusion: Most thyroid hypermetabolic incidentalomas are benign lesions, while higher values of SUV max are in favor of malignancy. This mandates further evaluation of incidentally found thyroid hypermetabolic lesions on routine PET/CT scans.
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http://dx.doi.org/10.1155/2017/7176934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585596PMC
August 2017

Role of FDG PET/CT Scan in Head and Neck Cancer Patients.

Arch Iran Med 2017 07;20(7):452-458

Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Introduction: PET/CT scan has an emerging role in head and neck oncology with a few well-established indications, including: detection of unknown primary tumor site, tumor staging, radiotherapy planning, treatment response assessment and detection of recurrent disease. The purpose of this study is reporting PET/CT findings in head and neck cancer patients to emphasize its role in head and neck oncology.

Materials And Methods: In a retrospective study, we reviewed our PET/CT database and found 94 patients with primary head and neck cancer. This is a descriptive report of PET/CT scan findings in head and neck cancer patients referred to Masih Daneshvari hospital, Tehran, Iran between 2013 and 2016.

Results: The most common primary tumor sites were oral cavity (27%) and nasopharynx (22%). The most common indication for referral was tumor restaging (76%) including treatment response evaluation and differentiation between recurrence and post-treatment fibrosis. In 60% of patients with negative primary tumor site, PET/CT was able to detect evidence of regional or distant metastasis. PET/CT was able to localize the primary tumor site in 66% of patients with unknown primary tumor site. We also had 19 patients with primary head and neck cancer referred for initial staging, demonstrating evidence of metastasis in 66% of all cases.

Conclusion: Most patients are referred for restaging and demonstrate evidence of regional or distant metastasis with significant value for further treatment planning. Providing insurance coverage and familiarizing referring physicians about correct indications of this relatively new diagnostic modality will be to the best interest of head and neck cancer patients in the long run.
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July 2017

Synovial Sarcoma of the Esophagus: A Case Report and Review of Literature.

Middle East J Dig Dis 2017 Apr;9(2):111-113

Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Synovial sarcoma is an uncommon soft tissue tumor occurring mainly in the periarticular region of the extremities in young adults. It happens less frequently in the head and neck, mediastinum, lungs, heart, and digestive tract. A 28-year-old man two months after total esophagectomy with final diagnosis of esophageal synovial sarcoma was referred to our Positron Emission Tomography (PET-CT) department for the evaluation of treatment response and further treatment planning. To our knowledge this case is the 11th case of esophageal synovial sarcoma, being reported in the literature. We presented the 11th case of esophageal synovial sarcoma. Synovial sarcomas are very rare tumor entities, particularly in the gastrointestinal tract and are likely to be mistaken with other more common tumors such as gastrointestinal stromal tumors.
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http://dx.doi.org/10.15171/mejdd.2017.60DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471102PMC
April 2017

A new ataxia-telangiectasia mutation in an 11-year-old female.

Immunogenetics 2017 07 9;69(7):415-419. Epub 2017 May 9.

Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, NRITLD, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Ataxia-telangiectasia (A-T), a rare inherited disorder, usually affects the nervous and immune systems, and occasionally other organs. A-T is associated mainly with mutations in the ataxia telangiectasia mutated (ATM) gene, which encodes a protein kinase that has a major role in the cellular response to DNA damage. We report here a novel ATM mutation (c.3244_3245insG; p.His1082fs) in an 11-year old female. This subject presented with typical features, with the addition of chest manifestations including mediastinal lymphadenopathy and diffuse bilateral micronodular infiltration of the lungs, along with a high EBV titer. The subject died as a result of rapid B-cell lymphoma progression before chemotherapy could be initiated. This case highlights the need for the rapid diagnosis of A-T mutations and the detection of associated life-threatening outcomes such as cancers.
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http://dx.doi.org/10.1007/s00251-017-0983-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486830PMC
July 2017

Computed Tomography Findings of Pulmonary Infection.

Can Respir J 2017 3;2017:6913564. Epub 2017 Jan 3.

Mycobacteriology Research Center, National Research Institute of Tuberculosis and Lung Disease (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Biotechnology, School of Advanced Technology in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Nontuberculous mycobacterial (NTM) pulmonary infections can be quite similar to tuberculosis, both clinically and radiologically. However, the treatment protocol is not similar. is a rare cause of NTM pulmonary infection. Herein, we aimed to evaluate and compare the computed tomography (CT) scan findings of infection in lungs. For this reason, thirty-four patients ( = 34) with lung infection were retrospectively evaluated. Diagnosis was confirmed by American Thoracic Society (ATS) guidelines and CT scans were reviewed in both lung and mediastinal windows. The average age of patients was 63 ± 14.54 years and 52.9% were male. The majority of patients had cough (91.2%) and sputum production (76.5%). Clinically, 41.2% of patients had previous history of TB (14/34), 38.2% had cardiac diseases (13/34), and 35.3% had diabetes mellitus (12/34). The most common CT findings in our study were nodular lesions (100%) and bronchiectasis (85.29%). Regarding the severity, grade I bronchiectasis was the most prevalent. Other prominent findings were tree-in-bud sign (88.2%), consolidation (52.94%), and lobar fibrosis and volume loss (67.6%). There was no significant zonal distribution of findings. In conclusion, nodular lesions and bronchiectasis are the most frequent features in CT scan of pulmonary infection.
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http://dx.doi.org/10.1155/2017/6913564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5239841PMC
September 2017

Relation between smear positivity and imaging findings in children with pulmonary tuberculosis.

Int J Mycobacteriol 2016 Dec 19;5 Suppl 1:S163. Epub 2016 Sep 19.

Department of Pediatric Respiratory Medicine, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Objective/background: We investigated the relationship between high-resolution computed tomography (HRCT) imaging manifestation of tuberculosis (TB) in childhood and the results of sputum smear. The aim of this study was to identify an alternative indicator of infectivity to prevent disease transmission through special isolation methods in children who have a clinical condition that suggests TB.

Methods: This retrospective comparative study was performed on 95 children under the age of 15years with a diagnosis of TB based on World Health Organization criteria and laboratory data (smear and culture positive for Mycobacterium tuberculosis). Investigations were performed on children admitted to the National Research Institute of Tuberculosis and Lung Disease for detection of TB between 2008 and 2012. Samples were collected from direct smear or gastric lavage method. We also performed HRCT on all of the children. The children were divided into two groups based on the results of their smear test. A multivariate analytical model was used for comparison of HRCT abnormalities in these two groups.

Results: Consolidation, tree-in-bud pattern, upper lobe nodular infiltration, and cavitation were the most prevalent findings in the positive smear group. Lymphadenopathy, consolidation, collapse, and nodular infiltration in the upper lobe were dominant in the negative smear group.

Conclusion: We found an association between cavity, tree-in-bud, and upper lobe nodular infiltration, and smear positivity in children with TB. Furthermore, we also found an association between lymphadenopathy and collapse in the negative smear group. Moreover, the positive smear group had radiologic manifestation of postprimary TB, whereas the negative smear group had primary TB manifestation.
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http://dx.doi.org/10.1016/j.ijmyco.2016.08.007DOI Listing
December 2016

Determining the lymphadenopathy characteristics of the mediastinum in lung CT scan of children with tuberculosis.

Int J Mycobacteriol 2016 09 15;5(3):306-312. Epub 2016 Jul 15.

Mycobacteriology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Objective/background: Most tuberculosis cases in children are primary infection, with difficult and imprecise diagnosis mainly based on the existence of mediastinal lymphadenopathy. Here, we investigated the characteristics of mediastinal lymphadenopathy in lung computed tomography (CT) scans of children with tuberculosis.

Methods: This cross-sectional study was performed on 75 children with tuberculosis referred to Masih Daneshvari Hospital in Tehran, Iran, from 2009 to 2013. Their medical records were investigated, and CT-scan characteristics were extracted by a radiologist.

Results: Mean±standard deviation age of cases was 11.2±4.6years. CT-scan results indicated 94.7% of cases had lymphadenopathy, with lower paratracheal, upper paratracheal, hilar, and subcarinal forms observed in 81.7%, 69.1%, 53.5%, and 47.9% of cases as the most involved stations in lymph nodes, respectively. In 74.6% of patients with mediastinal lymphadenopathy, perilymph node fat inflammation (matting) was observed, with 52.11% exhibiting conglomeration. Bronchial pressure was observed in 4.23% of children with tuberculosis, and bilateral-, right-, and left-parenchymal involvement was observed in 42.7%, 25.3%, and 8% of these cases, respectively. Left- and right-pleural effusion and calcification was reported in 6.7%, 12%, and 5.6% of patients, respectively. Additionally, nearly 80% of patients exhibited mediastinal lymphadenopathy and lung-parenchyma involvement simultaneously. Lung-parenchyma involvement was significantly correlated with subcarinal (p<.001), hilar (p<.001), subaortic (p=.030), lower paratracheal (p=.037), and axillary (p=.006) stations.

Conclusion: Situation of mediastinal lymphadenopathy and its synchronicity with lung-parenchyma involvement can help in differential diagnosis of pulmonary tuberculosis from other lung diseases.
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http://dx.doi.org/10.1016/j.ijmyco.2016.06.015DOI Listing
September 2016

Intraocular Silicone Oil Masquerading as Terson Syndrome.

Case Rep Ophthalmol Med 2016 22;2016:4942109. Epub 2016 Sep 22.

Eye Research Center, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran; Noor Ophthalmic Research Center, Noor Eye Hospital, Tehran, Iran.

. Terson syndrome is described as intraocular hemorrhage in association with any type of intracranial hemorrhage and is associated with higher mortality rate and vision loss. Intraocular hemorrhage in Terson syndrome may be diagnosed using computed tomography but there are false positive results. Silicone oil which is widely used for internal tamponade of complicated retinal detachments has high attenuation on computed tomography and hyperintensity on T1-weighted magnetic resonance imaging that can mimic intraocular hemorrhage. This report shows that silicone oil is another origin of false positive results in interpreting CT findings for detecting Terson syndrome. . A 71-year-old diabetic woman presented with loss of consciousness. Brain computed tomography revealed right cerebellar hemorrhage and ventricular hemorrhage and hyperdensity in vitreous cavity of the left eye that was initially interpreted as vitreous hemorrhage. Terson syndrome was the initial diagnosis but ophthalmoscopic examination and brain MRI showed that the left eye had silicone oil tamponade. . Without knowing the history of previous vitreoretinal surgery, CT scan findings of intraocular silicone oil may be interpreted as vitreous hemorrhage. In patients with concomitant intracranial hemorrhage, it can masquerade as Terson syndrome.
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http://dx.doi.org/10.1155/2016/4942109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055946PMC
September 2016

Computed tomography features of pulmonary nocardiosis in immunocompromised and immunocompetent patients.

Pol J Radiol 2015 7;80:13-7. Epub 2015 Jan 7.

Department of Radiology, Zanjan University of Medical Sciences, Zanjan, Iran.

Background: Nocardiosis primarily occurs in the setting of immunocompromising conditions. However, it may also occur in immunocompetent patients. We described computed tomography features of pulmonary nocardiosis and compared immunocompetent and immunocompromised patients.

Material/methods: CT images of 25 patients (Mean age of 39.5 years; 76% male) with pulmonary nocardiosis proved by bronchoalveolar lavage or biopsy were reviewed by two experienced pulmonary radiologists and detailed findings were reported on. Fourteen patients (56%) were immunocompetent, while 44% had an underlying immunocompromising condition, including chronic granulomatous disease (CGD) (n=4), diabetes mellitus (DM) (n=2), malignancy (n=2), HIV (n=1), concomitant CGD and DM (n=1), and steroid therapy for nephrotic syndrome (n=1).

Results: Most patients had bilateral involvement with no zonal predominance. Multiple pulmonary nodules (96%) were the most common CT findings, followed by consolidation (76%) and cavity (52%). Other findings included bronchiectasis (48%), pleural thickening (40%), ground glass opacity (32%), mass-like consolidation (20%), intrathoracic lymphadenopathy (16%), pleural effusion (12%), reticular infiltration (4%), and pericardial effusion (4%). There was no statistically significant difference in the CT findings of immunocompromised and immunocompetent groups.

Conclusions: Pulmonary nocardiosis presents mainly as multiple pulmonary nodules, consolidations, and cavity in both immunocompromised and immunocompetent patients. However, these features are more suggestive of nocardiosis in the setting of an underling immunocompromised condition.
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http://dx.doi.org/10.12659/PJR.892042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4288394PMC
January 2015

The spectrum of presentations of cryptogenic organizing pneumonia in high resolution computed tomography.

Pol J Radiol 2014 5;79:456-60. Epub 2014 Dec 5.

Chronic Respiratory Disaeses Research Center, National Research Institute of Tuberculosis and Lung Disease, Masih-e-Daneshvari Hospital, Shahid Beheshti Medical University, Tehran, Iran ; Department of Radiology, Masih-e-Daneshvari Hospital, Shahid Beheshti Medical University, Tehran, Iran.

Background: Various radiologic patterns of cryptogenic organizing pneumonia (COP) in X-rays have been reported for more than 20 years, and later, in computed tomography scans. The aim of the present study was to describe the spectrum of radiologic findings on high resolution computed tomography (HRCT) scans in patients with COP.

Material/methods: HRCT scans of 31 sequential patients (mean age: 54.3±11 years; 55% male) with biopsy-proven COP in a tertiary lung center between 2009 and 2012 were reviewed by two experienced pulmonary radiologists with almost perfect interobserver agreement (kappa=0.83). Chest HRCTs from the lung apex to the base were performed using a 16-slice multi-detector CT scanner.

Results: The most common HRCT presentation of COP was ground-glass opacity (GGO) in 83.9% of cases, followed by consolidation in 71%. Both findings were mostly asymmetric bilateral and multifocal. Other common findings were the reverse halo (48.4%), parenchymal bands (54.8%) and subpleural bands (32.3%). Pulmonary nodules were found in about one-third of patients and were frequently smaller than 5 mm in diameter. Both GGOs and consolidations were revealed more often in the lower lobes.

Conclusions: The main presentations of COP on HRCT include bilateral GGOs and consolidations in the lower lobes together with the reverse halo sign.
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http://dx.doi.org/10.12659/PJR.891011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259518PMC
December 2014

Evaluation of the relationship between smear positivity and high-resolution CT findings in children with pulmonary tuberculosis.

Pol J Radiol 2014 26;79:120-5. Epub 2014 May 26.

Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: The aim of this study is to find a relationship between the radiological manifestations of childhood tuberculosis on a high-resolution computed tomography (HRCT) and the results of sputum smear. This study aims to propose an alternative indicator of infectivity in terms of prevention of disease transmission through selective isolation policy in children whose clinical condition is highly suggestive of tuberculosis.

Material/methods: This retrospective comparative study was performed on 95 children under 15 years of age diagnosed with tuberculosis based on both WHO criteria and positive sputum culture for mycobacterium Tuberculosis. The children were admitted for TB screening in the pediatric department of national research institute of tuberculosis and lung disease (NRITLD) between 2008-2012. Direct smear collected from sputum or gastric lavage, as well as HRCT were performed in all children prior to administration of medical therapy. Children were divided into 2 groups based on positive and negative smear results. HRCT abnormalities, as well as their anatomical distribution were compared between these 2 groups using multivariate analytic model.

Results: The most prevalent abnormalities in the positive smear group were consolidation, tree-in-bud pattern, upper lobe nodular infiltration and cavitation. The negative smear group featured lymphadenopathy, consolidation, collapse and nodular infiltration in the upper lobe. Cavity, tree- in-bud pattern and upper lobe nodular infiltration were highly associated with smear positivity in children. Conversely, lymphadenopathy and collapse had significant association with a negative smear.

Conclusions: This study revealed that cavity, tree-in-bud and upper lobe nodular infiltration has significant association with smear positivity in childhood tuberculosis. On the other hand, lymphadenopathy and collapse were closely associated with smear negativity in this age group. It was also demonstrated that children with a positive smear most likely presented with radiological features of post primary tuberculosis, while the negative smear group most often manifested with primary tuberculosis.
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http://dx.doi.org/10.12659/PJR.889749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038638PMC
June 2014

Nonspecific Interstitial pneumonia (NSIP)/ Overlap or Distinct Entity: A case report from the National Research Institute of Tuberculosis and Lung Disease (NRITLD).

Caspian J Intern Med 2014 ;5(2):118-22

Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: In many cases of ILD (interstitial lung disease), overlap diagnosis is considered. Here, a few cases with diagnosis of a variety of ILDs, where eventual open lung biopsy has been performed are selected. Reference will be made to reliable sources to show that NSIP can still be a variant of UIP (Usual interstitial pneumonia) with better treatment response and prognosis.

Case Presentation: In case 1, there is a difference between the HRCT(High Resolution Computed Tomography) result (NSIP pattern without fibrosis) and pathologic result (which includes fibrosing NSIP more closely related to UIP).Case 2 shows obvious discord between HRCT result (UIP pattern) and pathologic result (NSIP pattern). In case 3, there is again a discrepancy between HRCT report (very mild architectural distortion suggestive for ILD like NSIP) and pathology report (destructed lung tissue with interstitial fibrosis suggestive of HP (Hypersesitivity Pneumonitis) and not NSIP.

Conclusion: In this paper, we demonstrate that although NSIP can be a distinct diagnosis in most cases, but in rare cases the distinction between the other kinds of ILD especially UIP and NSIP in spite of full workup including tissue assessment can be very difficult.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992240PMC
April 2014