These GTVs were then compared with those obtained via the formula and image-based manual segmentation methods with ITK software using the true tumour volume as the standard reference. The effects of tumour size and shape on GTVs measurements were also investigated. Our results showed that, when compared with the true tumour volume, segmentation for DWI(P = 0.060–0.671) resulted in better accuracy than that mMRI(P < 0.001) and the formula method(P < 0.001). Furthermore, semiautomatic segmentation for DWI resulted in higher reliability than manual segmentation(ICC = 0.9996–0.9998). Tumour size and shape had no effects on GTV measurement across all methods. Therefore, DWI-based semiautomatic segmentation, which is accurate and reproducible and also provides biological information, is the optimal GTV measurement method in the assessment of anti-tumour treatments.Accurate and repeatable measurement of the gross tumour volume(GTV) of subcutaneous xenografts is crucial in the evaluation of anti-tumour therapy. Formula and image-based manual segmentation methods are commonly used for GTV measurement but are hindered by low accuracy and reproducibility. 3D Slicer is open-source software that provides semiautomatic segmentation for GTV measurements. In our study, subcutaneous GTVs from nude mouse xenografts were measured by semiautomatic segmentation with 3D Slicer based on morphological magnetic resonance imaging(mMRI) or diffusion-weighted imaging(DWI)(b = 0,20,800 s/mm Typically, tumour volume is calculated via the manual segmentation method in MRI studies131920Therefore, the aim of this study was to evaluate different methods, including the formula method and the semiautomatic and manual segmentation methods for mMRI or DWI, with respect to their accuracy and reproducibility in GTV measurement in a subcutaneous tumour-xenograft nude mouse model with the true volume of the resected tumour as the reference standard.in vivo and ex vivo were successfully performed in 35 mice. No significant differences were observed between two repeated measurements taken by the same person using all the above-described methods (P = 0.119–0.853). Therefore, we calculated the mean volume of two measurements for further analysis with each method.The described volume measurements in vivo and ex vivo GTV measurement methods are shown in The mean and standard deviation (SD) for each GTV are summarized in 3 and was significantly larger than the true tumour volume (1.72 ± 1.35 cm3) (P < 0.001); the GTVs calculated from mMRI-based segmentation by ITK (1.77 ± 1.36 cm3) and 3D Slicer (1.77 ± 1.35 cm3) were also significantly larger than the true tumour volume . Furthermore, when taking tumour size and shape into account, GTVs of subgroups obtained via the formula method and mMRI-based manual and semiautomatic segmentation were all larger than the true tumour volume .As shown in 2) were 1.72 ± 1.34 cm3, 1.73 ± 1.33 cm3 and 1.73 ± 1.34 cm3, respectively, via the manual segmentation method, and all were 1.73 ± 1.35 cm3 with the semiautomatic segmentation method .As shown in 3 (ICC = 0.9993–0.9999) demonstrated better measurement reproducibility than the smaller volume group (ICC = 0.9908–0.9978); furthermore, the measurement reproducibility of the irregular tumour group (ICC = 0.9996–0.9999) was slightly better than that of the regular tumour group (ICC = 0.9994–0.9998) (2), the b value of 0 s/mm2 demonstrated the highest measurement reproducibility (ICC = 0.9998–0.9999) for both manual segmentation and semiautomatic segmentation (–0.9998) . Of the entation .GTV measurement is critical for all tumours as it is necessary for high accuracy therapy evaluationOur results showed that the tumour volumes measured by the modified ellipsoidal formula method were significantly greater than the true tumour volumes. We speculate that the overestimation of GTV may be due to the double layer of skin surrounding the tumour, which was also measured by external callipers and included for volume calculations. Moreover, given that this formula applies to tumours with a regular ellipsoid shape, when applied to cases with irregular shapes it may result in large variability and low reproducibility of GTV measurementsMorphological imaging  and functional imaging  have been used for the delineation of GTV measurements10131823Our study result suggested that, though we had optimized the mMRI sequence to aid in differentiation between the tumor and the surrounding bright subcutaneous fat tissue, mMRI-based manual segmentation by ITK and semiautomatic segmentation by 3D Slicer were significantly different from the true tumour volume, which indicated that mMRI-based segmentation was not ideal for GTV measurement. However, no significant differences were observed between DWI-based volume measurements and the true tumour volume when using either the manual or semiautomatic segmentation method. These findings suggest that the margins of tumorous tissue in DWI were obvious because of the high tumour cellularity, which was shown as restricted diffusion with higher signal intensity for DWI.When comparing the performance of these two segmentation methods in our study, no significant difference was observed between manual (ITK) and semiautomatic (3D Slicer) segmentation when they were applied to mMRI or DWIs, which is consistent with other studies222 resulted in the best measurement reproducibility. This might be explained by the higher signal to noise ratio (SNR) with the lower b value, resulting in increased image quality and facilitating tumour volume definition when compared with higher b valuesOur results showed that a b value of 0 s/mmIn addition, our results demonstrated better intra-observer agreement and GTV measurement reproducibility in larger tumours, which might be explained by the measurement error for a given measurement method being relatively smaller in larger tumours compared to smaller tumours. This hypothesis could also explain the interesting finding that irregularly shaped tumours demonstrated better intra-observer agreement and higher measurement reproducibility compared to regular tumours because irregular tumours are usually larger.et al.As presented by Wolf ex vivo specimen volume as the true tumour volume and revealed that DWI-based segmentation results in better accuracy of GTV measurements than both the mMRI-based segmentation and formula methods. Second, we compared the intraclass reproducibility of DWI-based semiautomatic segmentation (3D Slicer) with manual segmentation (ITK) and concluded that the semiautomatic segmentation method led to higher reliability. Therefore, DWI-based semiautomatic segmentation using 3D Slicer could be applied as a starting point for tumour volume measurements. Additionally, we observed that different b values showed excellent GTV measurement reproducibility in semiautomatic segmentation, especially when the b value was 0 s/mm2.Our study provides several contributions. First, we compared different non-invasive GTV measurement methods with 2, may allow a fairer comparison between mMRI and DWI segmentation. However, the initial design of the mMRI protocol was just to optimize the tumor to surrounding tissue contrast, which was achieved with the currently used mMRI sequence parameters. The study results demonstrated that the GTV measured based on this mMRI sequence is significantly larger than true tumour volume and DWI-based measurements. This finding is contradictory to popular belief that mMRI, with its less distortion and better spatial resolution to DWI, should provide a more accurate GTV2526Our study has a couple of limitations. First, the mMRI sequence we used in our study is a modified T2WI rather than the conventional T1WI or T2WI sequence. Because the image contrast acquired with the modified sequence has signal composition from both T1WI and T2WI due to the short TR and long TE, it offers clear tumor boundary delineation from the bright subcutaneous fat tissue as well as from the isointensity wrapping lean meat used for stabilizing the animal. Another choice for morphological MRI is fat-suppressed T2WI sequence, which has similar contrast to DWI of b value of 0 s/mmIn conclusion, DWI-based semiautomatic segmentation with 3D Slicer allows for more accurate and reproducible GTV measurements of the subcutaneous tumour-xenografted nude mouse model. We suggest that semiautomated segmentation with 3D Slicer for DWI should be used to evaluate the response to anti-tumour therapies in animal models.in vivo by external callipers and MRI segmentation.The Animal Ethical Committee of Guangdong General Hospital approved this animal study. The methods were performed in accordance with relevant guidelines and regulations. The nude mice (BALB/c-nu) were provided by Guangdong Medical Laboratory Animal Center. Hepatocellular carcinoma cells (MHCC-97) were obtained by legal jurisdiction and were implanted subcutaneously into the right armpit of male nude mice (n = 35). Three to seven weeks after implantation, subcutaneous tumours with different sizes and shapes were measured 2). All volume measurements were performed twice at an interval of 5 minutes by the same observer to generate intra-observer agreement.To determine the size of subcutaneous tumours, the greatest longitudinal diameter (A) and the greatest transverse diameter (B) were estimated with external callipers. Tumour volume was obtained from the modified ellipsoidal formula3, matrix = 100 × 100). The axial DW MRI was acquired with a single-shot SE-EPI (spin-echo echo planar imaging) sequence  with fat suppression achieved by SPIR .To avoid possible physiological changes, we did not use anaesthesiaAfter MR scanning was completed and the integrity of the data was confirmed by a radiologist (Z.L.), each mouse was sacrificed, the tumour was completely resected and the specimen volume was measured twice using the water displacement method by one observer; the average volume from two measurements was considered the true tumour volume2, 20 s/mm2) and one higher b value (800 s/mm2) for image segmentation.All MR images were downloaded from the MR scanner database onto a standalone workstation  and then successively run on two types of open volumetric analysis software by a trained radiologist with 5 years of experience in MRI and DWI interpretation. Considering the heavy workload required to deal with DWI with 12 b values, we only chose 3 representative sets of DWIs with two smaller b values (0 s/mmhttp://www.itksnap.org) to manually outline the visible tumour on each slice of the mMRI and 3 different DWI sets . After tracing, a 3D reconstruction of the tumour was generated, and the total tumour volume was automatically calculated. Ambiguities in outlining the tumours in the axial plane were cross-checked by outlining the tumours in the corresponding sagittal and coronal planesFor the evaluation of manual delineation, we used the freely available software ITK-SNAP , which is an extensible algorithm and free platform for semiautomatic segmentation2) and axial mMRI on the same slice are illustrated in the leftmost column. Moreover, 3D volumetric reconstructions of the subcutaneous tumour generated from 3D Slicer  and ITK  were compared. Images were assessed in a random order, and the observer was blinded to the results produced by other methods.To evaluate semiautomatic delineation, tumour segmentation was performed with 3D Slicer software . Normality was tested using the Kolmogorov-Smirnov method and then variance homogeneity was tested with the Levene test.in vivo MRI and external calliper; if there was no significant difference between the two measurements, the average volume from the two measurements for all methods was compared with the true tumour volume obtained with the water displacement method.A paired Student’s t-test was performed to evaluate the systematic bias of repeated volume measurements by 3 in this study). We also investigated the effects of tumour shape on GTV measurements by dividing tumours into 2 groupsTo assess the effects of tumour size on GTV measurement, animals were divided into 2 groups based on the median size of the true volume  was used to assess the reproducibility of tumour measurement methods with external callipers or MRI-based segmentations.http://www.medcalc.org). The tests were two-tailed, and a value of P < 0.05 was considered statistically significant. An ICC greater than 0.75 was regarded as being in good agreementStatistical analyses were performed with SPSS Statistics  and MedCalc software .


As with most cancers the prognosis in pharyngeal and oral cavity cancer largely depends on tumour stage. Physical examination, including endoscopy should be combined with technical radiologic imaging to record the precise extent of tumour. The TNM staging system of the head and neck region is, in fact, an anatomic staging system that describes the anatomic extent of the primary tumour as well as the involvement of regional lymph nodes and distant metastases. Modifications in the TNM staging system should consider not only the expert opinions and published reports in the literature but the technical advances in technology for improved assessment of tumour extent and the shifting paradigms in therapeutic strategies. “T” stage of the tumour is defined by its size, the depth of the invasion and the involvement of vital structures. In the 7th edition of TNM classification, for stage T4 tumors (larger than 4 cm), subcategories a and b were introduced to indicate the involvement of vital structures and their suitability for surgical resection (except for nasopharynx cancer). Nodal metastasis is the most important predictor of outcome for squamous cell cancer of the head and neck.Better and more reliable methods of pretreatment tumour assessment are therefore crucial to ensure that the clinical assessment of tumor approximates its actual pathologic extent.CT and MRI are both useful for assessing extensions of pharyngeal- and oral cavity cancer in advanced stage. MRI is superior in visualizing most primary tumour sites. Hungary is first in pharyngeal- and oral cavity cancer (Ph-OC-CA) mortality in Europe in either sex. The male Ph-OC-Ca mortality is fourth in all cancer mortality in Hungary.The majority of mucosal cancers in this country are squamous cell carcinomas (SCCA). Like in most cancers, the prognosis mainly depends on the stage of the tumour.Head and neck (HN) is a difficult region, both its anatomy and pathology is very complex, various connection points may exist between the sites that determines the extension of disease.Evaluation of Clinical Stage is based primarily on inspection, and palpation of the sites and on indirect and direct endoscopy. Neurologic evaluation of all cranial nerves is also required in advanced stage. Complete endoscopy, usually under general anesthesia, is performed after completion of other staging studies.Imaging plays a crucial role in defining the extension of cancer and in therapy planning, as well. The accuracy of image evaluation depends very much on the experience and competence of radiologists. They have to be familiar with the anatomy and pathology of this region and the clinical details of the patient as well, in order to determine the most accurate stage of tumour.There are new aspects in management of advanced Ph-OC-CA. One of the major endpoints of interest in management is to improve the quality of life, to preserve organ function without compromising survival. Chemotherapy and radiotherapy are considered as standards in treatment, but not all patients are suitable for organ preservation therapy. Patients with no response to standard therapy have to undergo salvage surgery. Criteria of inoperability have changed, consequently at present more extented resections and reconstructions are performed . Tthe 3DChanges in treatment strategy of advanced HN cancer, necessitate more accurate radiological evaluation, knowledge of more tumour characteristics and prognostic factors.It is crucial to ensure that the radiological diagnosis of the tumour status is concordant with the actual pathological status.) are important prognostic factors [Prognostic Factors affect patient’s survival and modify the therapeutic strategies. Tumour-related prognostic factors are: the primary tumour (T) size and its depth of invasion, the Grade of tumor, and the presence or absence of vascular invasion, − although the latter is particularly not included in the staging of HN tumours, but it should be noted when present ,4. The p factors . Mediast factors ,7. NasopIn addition to the importance of the TNM factors, the overall health of these patients clearly influences the outcome. In some ongoing studies authors attempt to use both tumour and non-tumour related factors for the better evaluation of prognosis ,8.Numerous factors affect patient’s survival, including the histologic diagnosis, cellular differentiation of the tumour (grade), location and size, local extension, and the status of regional lymph nodes as well as the presence of distant metastases . The impThe 7”th TNM Revision is valid from 01, January, 2010 onwards. The anatomic extent of the disease remained the decisive factor in establishing prognosis in Ph-OC-CA.The classification involves only four dominant clinical variables: tumour size, local extension of the tumour, nodal metastasis, and distant metastasis. Histologic grade, patient age and tumor site are important additional factors that should be recorded for future analysis and potential inclusion in the staging system.ESMO Guidelines/2010 approved by the ESMO Guidelines Working Group, accepted the new therapy-guided 7th TNM strategies [Clinical staging, based on the best possible imaging technique, estimates the extent of disease before the first treatment. In the last ESMO Guidelines/2010 the diagnostic modalities in clinical staging were determined: physical examination, CT, MRI, HN-endoscopy and chest X-ray. According to the new EHNS-ESMO-ESTRO Clinical Practice: Guidlines for diagnosis, treatment and follow-up of the squamous cell carcinoma of the head and neck: MRI is considered the preferable staging procedure for every tumour subsite of the HN - except laryngeal and hypopharyngeal cancer [In advanced stage thoracic CT is preferable to exclude lung metastasis or second lung primaries ,6,7.3 T MR scanners can provide higher resolution images for better tissue definition and can also benefit from MR-spectroscopic imaging (MRSI) applications. MRI is a true cancer imaging biomarker. It may provide more physiologic and functional qualitative and quantitative data using dynamic contrast enhanced MRI (DCE-MRI), diffusion weighted MRI (DW-MRI) and can further improve the assessment of target volumes and can provide an opportunity to nominate the biological target volume and the potential to determine treatment response. The diagnostic accuracy of DWI complements anatomical MR imaging for staging neck lymph nodes in head and neck cancer (HNCA) -14.The better estimation of target volumes with CT and MRI may permit treatment individualization . The supThese techniques may also be combined with PET/CT to further increase diagnostic sensitivity and specificity. The role of FDG-PET/CT in staging is under investigation, it has a lower specificity than sensitivity and is more useful for staging distant metastases and synchronous tumour than lymphnode metastasis ,17,18.The need for extensive imaging to identify metastatic disease depends on the consideration of tumour site, stage of disease and histology. In advanced Ph-OC-CA a careful multimodality imaging search is mandatory also for other primary tumours of the upper aerodigestive tract and because of the higher incidence of multiple independent primary tumours occuring simultaneously .US has been widely used in the assesment of cervical lymph node status, but it is not reliable for the deep nodes. US guided Fine-needle aspiration biopsy (USgFNAB) may confirm the tumour, its histopathologic nature, but it cannot rule out the presence of tumor .The oral cavity is divided into the following specific sites:Mucosal Lip (40% of OCCs), Buccal Mucosa, Lower Alveolar Ridge, Upper Alveolar Ridge, Retromolar Gingiva (Retromolar Trigone), Floor of the Mouth (15% of OCCs).Hard Palate (5% of OCCs), Anterior two-thirds of the tongue  The tongue is most commonly involved in the middle, and in the posterior third, mainly on the lateral, and lower surface. Human papilloma virus (HPV) DNA is prevalent in about 50% of oral cancer cases . In OCCAThe tongue is richly supplied with lymphatics, nearly half of patients have N metastases, 30%o of them are bilateral at the initial clinical presentation. Many of these nodes are clinically silent, detected only by imaging. Tumour thickness is also a prognostic factor that predicts subclinical nodal metastasis, local recurrence and patient survival .Clinical assessment of the extent of superficial mucosal involvement is more accurate than the radiographic assessment. MRI/CT are useful in evaluation of advanced tumours for the estimation of deep invasion Figure . MRI is T3 – TU more than 4 cm in greatest dimension•T4a – Moderately advanced local disease : tumour invades the cortical bone, mandible, inferior alveolar nerve, deep/extrinsic muscle of tongue , maxillary sinus, skin of face•T4b - Very advanced local disease: tumour invades the pterygoid plates, or skull base and/or encases internal carotid artery•Note: Superficial erosion alone of bone/tooth socket by gingival primary is not sufficient to classify T4. tumour [The primary tumour may be clinically occult and commonly present with neck nodal diseaseMost NPhCA arise in the lateral pharyngeal recess (fossa of Rosenmüller) and spread deeply, often obsruct the eustachian tube. The first two tumour stages are redefined in the 7th TNM: Tumour is T1 stage not only when confined to NPh, but extending to oropharynx and/or nasal cavity without parapharyngeal extension and T2 stage is only for parapharyngeal tumour extension. Primary NPhCA commonly spreads to the deep neck space and also intracranially Figures . MajoritNodes may be also clinically silent, and detectable by MRI/CT. MR provides better delineation of RP nodes from an adjacent primary tumour. CT is rarely used to look at bone invasion if MRI is available. In the vast majority of the cases the management of NPhCA is confined to radiotherapy.T3 – tumour invades bony structures of skull base and/or paranasal sinuses•T4 – tumour with intracranial extension and/or involvement of cranial nerves, hypopharynx, orbit, extension to the infratemporal fossa/masticator space•The OPh includes the following specific sites:The base of the tongue, the inferior (aterior) surface of the soft palate and the uvula, the anterior and posterior tonsillar pillars, the glossotonsillar sulci, the pharyngeal tonsils, and the lateral and posterior pharyngeal walls.The human papillomavirus (HPV) status of a tumour is a strong and independent prognostic factor for survival in patients with cancers of the oropharynx- and oral cavity CA. Studies demonstrated that high HPV prevalence has been consistently demonstrated in OCCA/OPhCA compared to a lower prevalence in other HN-SCCAs. HPV positive tumours were observed in younger, lighter alcohol-consuming patients with a better overall and disease specific survival .Also in OPhCA submucosal spread is common Figure . IntracrThe most common sites of lymphnode metastasis are the upper- (Level II) and mid-jugular- (Level III) and less commonly submental/submandibular (Level I) regions ,10,25.T3 – tumour >4 cm/extension to lingual surface of epiglottis•T4a – Moderately advanced local disease: tumour invades: larynx, extrinsic muscle of tongue, musculus pterygoideus medialis, hard palate, mandible•T4b - Very advanced local disease: tumour invades: musculus pterygoideus lateralis, pterygoid plates, NPh, skull base, prevertabral fascia, encases the carotid artery•Mucosal extension to lingual surface of epiglottis from primary tumours of the base of tongue and vallecula does not constitute invasion of larynx .Primary HPhCA may remain asymptomatic for a long period but at presentation the disease is often advanced commonly presenting with neck N disease 50-70%) ,10,25. T0% ,10,25Bilateral lymphatic drainage is common. HPhCA spreads to adjacent parapharyngeal, jugular, paratracheal nodes: Levels: II, III, IV, VI and VII.T3 – tumour more than 4 cm in greatest dimension, or with fixation of hemilarynx, or extension to esophagus•T4a – Moderately advanced local disease, tumour invades: thyroid-/cricoid cartilage, hyoid bone, thyroid gland, or central compartment soft tissue •T4b – Very advanced local disease, tumour invades retropharyngeal/prevertebral fascia, encases carotid artery, or involves mediastinal structures•The presence of neck adenopathies influences patient management, and largely determines the chance for locoregional control and the risk for distant metastasis. The risk of N metastasis is generally related to the depth of infiltration of the tumour.Nodal disease can be treated either surgically, by performing a neck dissection, or by chemo-radiotherapy. Occurrence of N metastasis decreases the overall survival to its half . TumoursNasopharyngeal cancer: commonly spreads to retropharyngeal, upper jugular (Level II) and spinal accessory (Level V) nodes, often bilaterally. NPhCA with retropharyngeal node involvement is N1 stage - independent of laterality and without cervical node involvement (it is new in the 7th TNM)•Oral cavity cancer: commonly spreads to submental, submandibular (Level I), internal jogular (Level II) nodes.•Oropharyngeal cancer: involves upper and mid-jugular nodes  and (less commonly) submental/submandibular nodes (Level I)•Hypopharyngeal cancer: commonly spreads to adjacent parapharyngeal, paratracheal (Level VI), and mid- and lower jugular nodes . Bilateral lymphatic drainage is common.•The level of involved nodes in the neck is prognostically significant, lower is worse, as is the size above 6 cm and presence of extranodal spread (ENS). Secondary to the ENS involvement of the carotid arteries, it has bad prognostic and therapeutic relevance ,27 Figu. The patThe cervical lymphnode classification for metastasis is uniform for all sites, except thyroid, nasopharynx, and skin. Node size, number and location are prognostic factors. Masses ≥ 3 cm are rarely single lymphnodes, but rather fusion of metastatic nodes.N1: single N ≤ 3 cm,•N2a: single N ipsilateral > 3 cm ≤ 6 cm,•N2b: multiple ipsilateral ≤ 6 cm,•N2c: bilateral or contralateral N ≤ 6 cm,•N3: > 6 cm.•(The lymphnode size should be measured in greatest dimension.)Midline N are considered ipsilateral N. The closer to the midline the tumour, the greater the risk of bilateral N metastasis is. Mediastinal N metastases are distant metastases, but superior mediastinal N are considered regional N (level VII) ,4.Cervical lymphadenopathy is one of the most important key points of Ph-OC-CA. The sensivity (Sv) and specificity (Sp) of palpation for neck N metastasis are in the range of 60%-70% . Clinicaradiological criteria of metastasis are based not only on increased N size (>1 cm), and round shape but rather on the presence of tumour colliquation, and tumour extension beyond the margin of the node. In the size criterion, the minimal axial diameter is more decisive than the other diameters [The iameters . The inhiameters ,29-31.US is superior to palpation and has been widely used in the assesment of cervical lymphnode status, but it is not reliable for deep nodes  because of its limited penetration into deeper layers. In addition, US is highly dependent on the experience of the operator. US is relatively cheap and capable of guiding tissue sampling. The USgFNAC has very high Sp, approaching 98-100% with a Sv of 73-80% , but thiA meta-analysis comparing CT with physical examination (PE) yielded the following results: Sv, 83% (CT) vs 74% (PE); Sp 83% (CT) vs 81% (PE); and Acc, 83% (CT) vs 77% (PE). Overall, PE identified 75% of patologic cervical adenopathies. This detection rate increased to 91% with addition of CT ,32.According to another analysis, the Acc of CT and MR in staging N involvement is almost similar (73-80%) . The advA tumour encircling the vessel over 270° on CT or MRI, or a tumour that is immobile from the vessel using sonopalpation, confirms the involvement of the vessel wall and is often non-resecable. With real time US can be helpful to detect carotid wall invasion ,34.MR-lymphography for N staging, using superparamagnetic iron oxid particles as contrast agents, may increase accuracy, Sv of 86% and Sp of 100% for metastatic nodes, but micrometastases may be missed also with this method [s method . (DisadvSentinel node biopsy is widely accepted as the standard practice in the management of breast cancer, cutaneous malignant melanoma and the procedure was also under investigation in HN-SCCA but with less accuracy than in the above mentioned tumours [ tumours -38.PET-CT can map functional and metabolic activity but less accurately can identify tumour in normal sized lymph nodes. Also the false negative necrotic nodes are potential pitfalls in the analysis of PET-CT. FDG-PET/CT has a lower specificity than sensitivity and more useful for detecting distant metastases and synchronous tumour than lymphnode metastasis [tastasis ,17,18.DW-MRI, indicates that a significantly higher sensivity may be attained [b0–1000 threshold of Sv 84%, Sp 94%, and Acc 91% for differentiation of malignant versus benign status of each lymphnode and Sv 94%, Sp 97%, and Acc 97% for differentiation at each neck level were achieved (Figure Early experience with attained ,11-14,39None of the currently available imaging methods, including FDG-PET/CT, are reliable to detect small tumour deposits within non-enlarged lymph nodes, or differentiate reactively enlarged lymph nodes from metastatic lymphadenopathy. Patients with stage N0 still undergo elective nodal resection for diagnostic staging and 20-25% of the patients have metastatic nodes in pathology .Accurate and reliable stratification of Ph-OC-CAs for the prediction of outcomes has been challenging, mainly because of the numerous anatomic sites and subsites from which tumours can arise and the diversity of histologic types of tumours in these locations.Accuracy of pretreatment staging has become more critical after the introduction of “organ preservation” protocols, since non-surgical therapy and the very extended, more invasive salvage surgery have become widely accepted treatment possibilities.“T” stage of the tumour is defined by its size, the depth of the invasion and the involvement of vital structures. Tumours that invade the prevertebral fascia, skull base, cranial nerves or encase the carotid or mediastinal great vessels are not resecable, are qualified as Stage T4b, according to the latest TNM classification.In most cases treatment outcome is strongly influenced by the presence or absence of cervical nodal metastasis. Nodal necrosis and extracapsular spread indicates metastatic disease, irrespectively of nodal size.Imaging plays an important role in clinical evaluation of head and neck lesions. A particular advantage of cross-sectional imaging is the ability to detect deep tumor extension or the presence or absence of metastases that cannot be judged by clinical examination. “Stage migration” occurs when patients are assigned to different clinical stages because of differences in the accuracy of the clinical examinations and imaging staging methods. Compared with conventional clinical examination, MRI and CT render a more precise assessment of tumour possible that may lead to the classification of the tumour into a higher clinical stage.CT/MR are also mandatory in selecting patients for a favourable group for radiotherapy by providing an estimate of tumour borders and volume.The radiologist’s task is to determine the site, extension and volume of the disease, to differentiate tumour from inflammation. Imaging can help oncologists, surgeons, radiotherapeutists better determine the location of tumours, confirm or exclude suspected diseases, avoid the complications, evaluate the clinical key points, and also detect the endoscopic ‘blind spots’ in clinically occult cases.The accuracy of image evaluation depends highly on the experience and competence of radiologists. The radiologist plays an indisputable role in the Ph-OC-CA multidisciplinary team and has to be strongly committed to the management of patients.The author declares that she has no competing interests.


ErbB2 is a member of the epidermal growth factor family of tyrosine kinases that is centrally involved in the pathogenesis of prostate cancer and several studies have reported that a high expression of this protein has prognostic value. In the present study, we have investigated whether tumour ErbB2 immunoreactivity (ErbB2-IR) has clinically useful prognostic value, i.e. that it provides additional prognostic information to that provided by routine clinical tests .ErbB2-IR was measured in a well-characterised tissue microarray of tumour and non-malignant samples obtained at diagnosis. Additionally, mRNA levels of ErbB2-IR in the prostate were determined in the rat following manipulation of circulating androgen levels. Tumour ErbB2-IR was significantly associated with the downstream signalling molecule phosphorylated-Akt and with the cell proliferation marker Ki-67. The significant association of tumour ErbB2-IR with the Gleason score at diagnosis was lost when controlled for the association of both parameters with Ki-67. In the rat prostate, mRNA for ErbB2 was inversely associated with circulating androgen levels. There was no association between ErbB2-IR and the androgen receptor (AR)-IR in the tumours, but an interaction between the two parameters was seen with respect to their association with the tumour stage. Tumour ErbB2-IR was confirmed to be a prognostic marker for disease-specific survival, but it did not provide significant additive information to the Gleason score or to Ki-67.It is concluded that tumour ErbB2-IR is of limited clinical value as a prognostic marker to aid treatment decisions, but could be of pathophysiological importance in prostate cancer. ErbB2 (Her-2/neu) is a member of the epidermal growth factor family of tyrosine kinases involved in a variety of cellular responses including apoptosis, migration, growth, adhesion and differentiation The importance of ErbB2 in the pathogenesis of prostate cancer (Pca) is less clear. Pca growth is regulated by androgen receptors (AR), and a key treatment of androgen-dependent Pca is a reduction of androgen levels either by surgical or medical castration. However, the effect of the treatment is temporary, and the cancers become androgen-resistant. In 1999, Craft et al. While the studies in cell lines and animal models point to a key role of ErbB2 in the pathogenesis of Pca, studies in humans are less clear. Different studies have reported very large variations in the levels of ErbB2 expression in prostate tumour tissue  approved of the study (no. 02-283) and waived the need for consent.Ethical permission (no. A110-12) for the animal experiments was obtained from the local animal ethical committee .The cohort used is from a consecutive series of 412 men who were diagnosed with prostate cancer following transurethral resection for lower urinary tract symtoms 2O2 in methanol for 20 min was undertaken. Antigen retrieval was performed with sections placed in a citrate buffer pH 6.0 and steamed in a microwave oven for 2 min. The solution was allowed to cool for 5 min, washed in distilled water and then TBS buffer. The protein-block  was performed for 15 min after which the sections were exposed to the primary monoclonal antibody (mouse c-erbB-2 Prediluted Cocktail Antibody (PM070AA), Biocare, CA, USA) for 2 h in RT. Then the secondary antibody (horse anti mouse (BA-2000), Vector Laboratories, Burlingame, CA, USA) was incubated at 30 min at RT followed by avidin-biotin complex tagging for 30 min at RT using the Elite ABC Kit (Vector Laboratories) and lastly DAB (DAKO) enhancement for 40 s at RT.The 4 µm paraffin-embedded tissue micro array sections were placed on slides, baked at 60°C, 1 h then deparaffinised and rehydrated. Peroxide block with 3% HTumour (n = 1822) and non-malignant (n = 1170) cores were scored for ErbB2 in prostate epithelial cells and tumour cells from digitally scanned images by one evaluator (JW) who did not at the time of the evaluation have access to the clinical data. The tumour samples were scored on basis of immunoreactive intensity  and distribution . Note that the distribution scores did not include stroma, since this did not express ErbB2-IR. Thus, a sample with only a small proportion of epithelial cells but with a large amount of stroma can still score a distribution of 100% and an intensity of 4. Then, for each core a composite value was determined (between 1–4). For example, a core with where 25% of the scorable sample had intensity 2 and 75% had intensity 3 would receive a composite score of (0.25×2+0.75×3) = 2.75. Median values were then determined for each case. To determine consistency, 301 tumour cores were scored and then rescored. Interclass correlation coefficient for consistency (mixed model) gave Cronbach's alpha of 0.90, 254 of 301 scores were within 0.5 score units of each other. The non-malignant cores were additionally scored for basal and luminal cells separately, when possible. Some cores (n = 482) had clearly identifiable basal and luminal cells and these have been returned as basal and luminal in the database. A diffuse basal layer (n = 436) was seen in some other cores and in the remaining cores (n = 252) basal cells could not be identified. These cores were not used here, so it should be remembered as a caveat that the scores for basal and luminal non-malignant ErbB2-IR represent a limited dataset. Ki67 index, pAkt-IR, androgen receptor (AR)-IR and the clinical characteristics for each patient were available in the database and have been reported in whole or in part previously Forty-two adult male Sprague-Dawley rats (284–430 g) were anesthetized with pentobarbitalnatrium (50 mg/kg) and castrated via the scrotum. Six intact animals served as controls. After 7 days, twenty-one of the animals received a subcutaneous injection of long acting testosterone  given as a single dose every second day as earlier described The experimental design of this study proceeded according to the guidelines for care and management of laboratory animals and was approved by the local animal ethical committee . Animals were housed under a controlled temperature in an artificially illuminated room (12-h light/12-h dark). Food and tap water were freely available.Total RNA from tissues was isolated according to the TRIzol method . RNA concentrations were quantified spectrophotometrically at 260 nm  and RNA integrity was verified by 28 S and 18 S rRNA integrity after agarose gel electrophoresis (data not shown).Five hundred ng total RNA was reversed transcribed using random hexamers  and Superscript II reverse transcriptase  in a 10 µl reaction according to the manufacturer's instructions. All cDNA reactions were run in duplicates.Quantification of ErbB2 mRNA was performed by real-time quantitative PCR using the ABI PRISM 7900HT Instrument . Reactions were run in a 20 µl volume using TaqMan gene expression assays Rn00566561_m1  with the TaqMan gene expression mastermix according to manufacturer's protocol. Each sample was analyzed for Rpl13a  and β-actin  expression to use as a normalizing reference controls. To confirm amplification specificity the PCR products were subjected to a melting curve analysis. The quantification data were analysed with SDS 2.4 Software (Applied Biosystems) and the relative values of ErbB2 mRNA in the samples are calculated from a standard curve obtained by amplification of five-fold serial dilution of reversed transcribed total RNA from a reference sample. An issue in this type of study is the appropriate housekeeping to use, since their levels can vary in cancer research studies The intraclass correlation coefficient, binary logistic and Cox proportional-hazards regression analyses were conducted using SPSS software (IBM). Ordinal regression analyses utilised software developed within the R project for statistical computing (version 2.15.2) A total of 357 (tumour) and 222  cases were scored for ErbB2-IR. Examples of different ErbB2-IR intensities from four tumour cores are shown in 2 test).The association of ErbB2-IR with clinical  and biochemical  measures within the same region are shown in In theory, a significant association of two parameters could be due to the fact that both parameters are associated with a third parameter. Thus, for example, if cases with a high rate of cell proliferation, as seen with the marker Ki67 index, more often have high Gleason scores and higher ErbB2-IR scores than cases with low rates of cell proliferation, then a correlation between ErbB2-IR and the Gleason scores would be induced. Consistent with this situation, the first-order correlations between ErbB2-IR and either the Gleason score or % of core that was tumour associated controlling for the tumour Ki67 index were not significant. However, the association between tumour ErbB2-IR and pAkt-IR remained significant . Thus, iper se in the tumour tissue  analyses, which plot for all possible cut-off values the true positive rate (sensitivity) vs. the false positive rate (1-specificity). For a ROC curve with an area under the curve [AUC] significantly greater than 0.5 , the optimal cut-off value  can be calculated  on its own and 45.6%  in combination with AR-IR + Ki67-IR (data not shown).In theory, it is possible that although the AUC for tumour ErbB2-IR is modest, it could contribute to a combination of markers with useful prognostic value. In order to investigate this possibility, two approaches have been taken, using the tumour ErbB2-IR together with three other tumour markers . The data have been normalised so that the maximum score in each case is 100%, and in the case of AR, the scores have been expressed as 100-normalised score, since a low, rather than a high, AR-IR is associated with a poor prognosis A univariate Cox proportional hazards regression analysis with disease-specific survival as end-point indicated that the relative risk for cases with a tumour ErbB2-IR score above the optimal cut-off, as defined by the Youden index, was approximately double that for those below the cut-off value (the Exp(B) value shown in In the present study, we have investigated the association of ErbB2-IR with disease severity at diagnosis and with disease outcome in a well-characterised tissue microarray In the tumour samples, ErbB2-IR was significantly associated with both the cell proliferation marker Ki67 and the immunoreactivity of pAkt, the phosphorylated form of the survival factor Akt. The association with the Ki67 is consistent with a large study using samples obtained at radical prostectomy, where the average Ki67 labelling index was higher for the 388 ErbB2-positive tumour samples than for the 1940 ErbB2-negative samples ; a positive association for the rate of cell proliferation as measured by the Ki-67 index; and a positive influence whereby a high AR-IR and a high ErbB2 are associated with a higher tumour stage.With respect to the androgen receptor itself, we did not see an association between AR-IR and ErbB2-IR, in agreement with the study of Ricciardelli et al. In the cases followed by expectancy after diagnosis, an ErbB2-IR above the optimal (Youden index) cut-off was associated with a poorer prognosis than for cases with an ErbB2-IR below this value. The prognostic value of ErbB2-IR in Pca has been the subject of considerable research, and in their meta-analysis, Neta et al. One important caveat should be made, namely that the prognostic value of ErbB2 may be dependent upon the time upon sampling and upon the subsequent treatment of the patients. In the present study, the samples were taken at diagnosis, and the prognostic determinations were made using the patients who were followed by expectancy, this being the standard treatment protocol at the time. Given the effects of androgen deprivation upon ErbB2 expression  and the present results do not rule out the possibility that patients with an over expression of a particular heterodimer subset are more at risk than other patients In conclusion, the three main findings of the present study are: 1) that the association of ErbB2-IR with the Gleason score seen at diagnosis is most likely due to the association of both parameters with the rate of tumour cell proliferation; 2) that although ErbB2 expression at the mRNA level is sensitive to the concentration of circulating androgens, there is no association between ErbB2-IR and AR-IR in prostate cancer. However, the two parameters interact with respect to their association with the tumour stage; and 3) that ErbB2 is not a clinically useful prognostic marker for predicting disease-specific survival as adjudged by its performance in the tissue microarray used here.Table S1(DOCX)Click here for additional data file.Table S2(DOCX)Click here for additional data file.Table S3(DOCX)Click here for additional data file.


Lejla Ferhatovic was supported by the Croatian Foundation for Science (HRZZ) grant no. 02.05./28. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.There are errors in the Funding section. The correct funding information is as follows: This study was funded in part by the VA Rehabilitation Research and Development grant 3690-03 (


Human lungs have the function of gas exchange in the body, performed efficiently by the unique anatomy of the alveoli. The alveolar epithelial lining fluid, reflecting a snapshot of molecular events happening there, can be extracted by bronchoscopic/nonbronchoscopic methods and used to study critical diseases. Although there are methods to study the pathophysiological conditions, there is still a need for newer and faster methods that can provide metabolic information about disease diagnosis, severity and progression.In this letter we present nuclear magnetic resonance-based metabolomics (a key component of system biology), which has potential for disease diagnosis and treatment monitoring .Acute respiratory distress syndrome (ARDS) is a disease with a high rate of mortality and morbidity worldwide, survival being only up to 40%. There is immense need for biomarkers associated with ARDS, and scientists have been working hard for the last four decades to discover these, without the anticipated success. Bronchoalveolar lavage fluid, mini-bronchoalveolar lavage (mBAL) fluid and serum have been the primary body fluids studied for this purpose. Recently, our group explored small molecular weight metabolites responsible for severity of ARDS, employing metabolomics in mBAL fluid and serum ,3. Both We used a nonbronchoscopic, catheter inside catheter technique to extract mBAL fluid . Most ofWith precautions, researchers will find application for this procedure in the study of diseases such as respiratory failure, interstitial lung disease, sarcoidosis and so forth. Besides the above-mentioned studies, this will be of extreme importance for clinicians as well as basic scientists trying to obtain more information about diseases where the balance of bronchoalveolar lavage fluid is affected.


The diagnosis of extrapulmonary tuberculosis (EPTB) is difficult. In recent years, T-cell interferon-γ release assays (IGRAs) are widely used in diagnosing tuberculosis. The aim of this meta-analysis is to evaluate the diagnostic accuracy of body fluid IGRAs in diagnosing EPTB. The PubMed, EMBASE, Web of Science, and Cochrane bibliographies were searched for English language articles. 22 studies met the inclusion criteria. The pooled sensitivity and specificity of body fluid IGRAs for diagnosing EPTB were 0.87 [95% confidence interval (CI): 0.83–0.92] and 0.85 (95% CI: 0.79–0.90), respectively. For the fluid T-SPOT.TB, the pooled sensitivity and specificity were 0.92 (95% CI: 0.88–0.95) and 0.85 (95% CI: 0.78–0.91), respectively. The diagnostic odds ratio (DOR) of the fluid T-SPOT.TB was 46.99 (95% CI: 13.69–161.28) for tuberculosis pleurisy, 26.46 (95% CI: 11.38–61.56) for tuberculosis peritonitis, and 97.86 (95% CI: 25.31–378.45) for tuberculosis meningitis. The application of T-SPOT. TB in the diagnosis of EPTB performed better in the body fluid than in the blood. The diagnostic values of the fluid T-SPOT.TB varied for different fluid categories. However, the utility of T-SPOT.TB was limited due to its suboptimal accuracy and higher cost compared with conventional tests. Tuberculosis (TB) is a serious global public health problem and a leading cause of morbidity and mortality throughout the world. Extrapulmonary tuberculosis (EPTB) includes meningitis, genitourinary infection, pericarditis, lymphadenitis, pleurisy, peritonitis, musculoskeletal infection, and cutaneous tuberculosis. In 2012, 6.1 million cases of TB were notified, and the prevalence of EPTB was approximately 13.1% (ranged 0.7%–38.0%)Rapid diagnosis and treatment is crucial for the effective control of TB in clinical practice in EPTB patients. Mycobacterial culture of the body fluid or biopsy specimens is considered the gold standard for the diagnosis of EPTB. However, the obtained fluid sample may be paucibacillary, the mycobacterial culture requires a long period of time, and the diagnostic yield of effusion is only 63%Mycobacterium tuberculosis (MTB)-specific antigens, early secretory antigenic target 6 (ESAT-6), and culture filtrate protein-10 (CFP-10). Two commercial tests are available: the T-SPOT.TB , which measures the number of IFN-γ-producing T cells by enzyme-linked immunospot (ELISPOT) assay, and the QuantiFERON-TB Gold In-Tube (QFT-GIT) test and its predecessor the QuantiFERON-TB Gold (QFT-G) test , which detect IFN-γ in culture supernatant by enzyme-linked immunosorbent assay (ELISA). One of the theoretical advantages of blood IGRAs over TST is their higher specificity, because IGRAs do not cross-react with the Bacillus of Calmette and Guérin (BCG) vaccine antigensM. tuberculosis antigen-specific T cells may accumulate at infection sites. Therefore, in EPTB, IGRAs of body fluid samples from infection sites may increase diagnostic specificities.Recently developed interferon-γ release assays (IGRAs) are sensitive, specific, and rapid immunodiagnostic tests for TB infection. They detect interferon-γ (IFN-γ) produced by lymphocytes in response to Recent studies mainly focused on blood IGRAs and reported suboptimal results in diagnosing EPTB89n = 1626; 111213141520212223242528293015161718192526271527A total of 1008 citations were found for patients with tuberculosis diagnosed by IGRAs . After i111213141516171819202122232425262728293031Confirmed cases were available in nine studies121320212425293016171825272728The numbers of patients were extracted from nine studies on tuberculous pleurisy1112131415232530112021222328Nine studies were performed in non-HIV patients11121315182428311617191420212223252627Indeterminate results were recorded in 11 studies11131417192021222528Only one study13151620232426The pooled sensitivities for IGRAs were 0.87 [95% confidence interval (CI): 0.83–0.92] in the body fluid and 0.81 (95% CI: 0.77–0.85) in the peripheral blood . The pooThe pooled sensitivities for T-SPOT.TB and QFT-G or QFT-GIT in the body fluid were 0.92 (95% CI: 0.88–0.95) and 0.78 (95% CI: 0.64–0.92), respectively. The pooled specificities for T-SPOT.TB and QFT-G or QFT-GIT in the body fluid were 0.85 (95% CI: 0.78–0.91) and 0.84 (95% CI: 0.75–0.94), respectively .The meta-analytic estimate of sensitivity, specificity, and AUC of T-SPOT.TB were 0.95, 0.88, and 0.97, respectively, for the body fluid, and 0.82, 0.70, and 0.88, respectively, for the blood. And sensitivity, specificity, and AUC of QFT-GIT were 0.78, 0.75, and 0.91, respectively, for the body fluid, and 0.79, 0.71, and 0.83, respectively, for the blood. Details are shown in In this subanalysis, the DOR of the body fluid T-SPOT.TB was 96.86 in patients with tuberculous peritonitis and 26.46 in patients with tuberculous meningitis . The senIn tuberculosis pleurisy, the sensitivity, specificity, PLR, NLR, and DOR were 0.94, 0.80, 4.83, 0.11, and 46.99 for the pleural fluid T-SPOT.TB; 0.92, 0.90, 9.03, 0.10, and 110.08 for the pleural fluid ADAThe sensitivity, specificity, PLR, and NLR were 0.94, 0.87, 6.93, and 0.07 for the peritoneal fluid T-SPOT.TB and 1.00, 0.97, 26.8, and 0.038 for the peritoneal fluid ADAIn tuberculous meningitis, the sensitivity, specificity, PLR, NLR, and DOR were 0.75, 0.91, 8.02, 0.29, and 26.46, respectively, for the cerebrospinal fluid (CSF) T-SPOT.TB and 0.79, 0.91, 6.85, 0.29, and 26.92, respectively, for the CSF ADAThe AUC of the fluid T-SPOT.TB was 0.97, 0.93, and 0.93 for pleurisy, peritonitis, and meningitis, respectively.In high-burden settings, fluid IGRAs had a sensitivity of 0.85 (95% CI: 0.77–0.93) and a specificity of 0.91 (95% CI: 0.84–0.98). In low-burden settings, the sensitivity of fluid IGRAs was 0.88 (95% CI: 0.81–0.94) and specificity was 0.81 (95% CI: 0.73–0.89) . For theIn non-HIV studies that used the fluid T-SPOT.TB, the sensitivity for developing EPTB was 0.95 (95% CI: 0.93–0.97), specificity was 0.91 (95% CI: 0.87–0.95), and the DOR was 163.53 (95% CI: 82.536–324.01).n = 1130, 6.2%) and that for the blood T-SPOT.TB was 19 . The pooled indeterminate rates were 0.06 (95% CI: 0.05–0.08) for the fluid T-SPOT.TB and 0.04 (95% CI: 0.02–0.05) for the blood T-SPOT.TB. For QFT-GIT, the indeterminate results in the fluid test was 47  and that in the blood test was 15 . The pooled indeterminate rates were 0.15 (95% CI: 0.10–0.19) for the fluid QFT-GIT and 0.09 (95% CI: 0.04–0.14) for the blood QFT-GIT.The indeterminate results for the fluid T-SPOT.TB was 81  but not for fluid IGRAs (P = 0.203) by the Egger test. No publication bias was found in both the fluid (P = 0.411) and the blood (P = 0.606) QFT-GIT studies.The funnel plots for publication bias showed some asymmetry . PublicaData on the diagnostic value of IGRAs in the body fluid are accumulating. In this meta-analysis, the T-SPOT.TB was found to be used for the diagnosis of EPTB in patients with pleurisy, pericarditis, peritonitis, and meningitis, while the QFT-GIT test was mainly applied in tuberculous pleurisy. Few meta-analyses have examined the performance of body fluid IGRAs in EPTB89M. tuberculosis antigen-specific T cells would accumulate at infection sites in active tuberculosis29This study reported pooled sensitivities and specificities of 0.92 and 0.85 for the fluid T-SPOT.TB, and 0.78 and 0.84 for the fluid QFT-GIT, respectively. In confirmed cases, both sensitivity and specificity of the fluid T-SPOT.TB (0.95 and 0.88) were higher than those of the fluid QFT-GIT (0.78 and 0.75), in agreement with another meta-analysis that evaluated extrasanguinous specimensThe diagnostic accuracy of the fluid T-SPOT.TB varied with the fluid category. The DOR of T-SPOT.TB with pleural fluid tended to be higher compared with CSF and lower compared with peritoneal fluid, but all the differences were not significant. The T-SPOT.TB sensitivities and specificities in patients with pleurisy and peritonitis were similar. However, the sensitivity was significantly lower in the CSF T-SPOT.TB than in the pleural fluid T-SPOT.TB (0.75 vs 0.94). One possible reason for the low sensitivity of the T-SPOT.TB assay in tuberculosis meningitis may be the low antigenic loading and severe disease manifestation early in the progression of tuberculosis meningitisHowever, the overall accuracy of the fluid T-SPOT.TB still showed no advantage over the body fluid ADA level analysis and pleural IFN-γ analysis. Nearly 20% of patients are misdiagnosed with tuberculosis pleurisy by T-SPOT.TB. For tuberculosis peritonitis, almost 13% non-TB patients would be incorrectly treated for tuberculosis. When diagnosed with fluid ADA, there would be about 10% and 3% of patients misdiagnosed with tuberculous pleurisy and tuberculous peritonitis, respectively. Additionally, in TB meningitis, 25% TB patients would be missed. Although the utility of the CSF ADA was also limited due to its low sensitivities, however, because the CSF ADA was convenient and inexpensive and had a specificity of 0.91 (95% CI: 0.89–0.93), it might assist in excluding tuberculous meningitis during differential diagnosis. Altogether, considering the lower cost and easier accessibility of the fluid ADA and the pleural fluid IFN-γ, IGRAs showed no obvious advantage in clinical application. However, because the sample size was much smaller in the peritonitis group, further studies are needed.Hypothetically, for blood IGRAs, the specificity should be lower in high-burden settings due to the high latent TB rate than in low-burden settings. However, in this study, no significant difference was found in both specificity and sensitivity of fluid and blood IGRAs between different TB-burden settings. Even more, the specificity of the fluid T-SPOT.TB appeared to be higher in high-burden settings than in low-burden settings. This finding suggests that the LTBI condition may have less influence on IGRAs, especially in fluid samples. The performance of the fluid T-SPOT.TB generates 6% false-negative and 8% false-positive results for EPTB diagnosis in high-burden settings and is not superior to the fluid ADA analysis.The HIV-associated immunocompromised state may weaken the ability of IGRAs to detect tuberculosis infection2526Identifying the cause of uninterpretable results is important. Most of the indeterminate results were due to a high nil control. The proportion of indeterminate results was higher in the QFT-GIT test than in the T-SPOT.TB assay. In some studies, the indeterminate results of QFT-GIT could be reduced through sample dilution17151415M. tuberculosis.This study had some limitations. First, publication bias may have been present due to the exclusion of conference abstracts, letters, and, particularly, non-English articles, as TB is more prevalent in non-English speaking countries. Second, the validity of the results is weakened by the inconsistencies across the studies. Heterogeneity was still present after performing subgroup analyses. Furthermore, because this meta-analysis was restricted to studies in adults, the utility of IGRAs in children was ignored, although they are the major sufferers for EPTB. The exclusion of indeterminate results in analyzing the diagnostic accuracy of IGRAs would cause inaccurate estimates in practical applications, and the confirmed cases were not true confirmation, because not all cases were diagnosed with the positive culture or nucleic acid amplification test (NAAT) of The overall performances of fluid and blood IGRAs for the diagnosis of tuberculosis were not as high as expected and varied by fluid category. The indeterminate result rates were high in fluid IGRAs. The fluid T-SPOT.TB was the best immunodiagnostic test for EPTB, and showed a better performance in high-burden settings, but was not remarkably superior to the fluid ADA test. With regard to its high cost, sophisticated technique, and difficulty in interpretation, the application of fluid IGRAs was limited in diagnosing EPTB.A systematic search of studies evaluating the diagnostic value of body fluid IGRAs in patients with EPTB was carried out. All English studies performed were searched on human subjects published until April 26, 2014, in electronic databases, including PubMed, EMBASE, Web of Science, and Cochrane-controlled central register of controlled trials. A lower date limit was not applied. The following search terms were used: “tuberculous,” “tuberculosis,” “fluid,” “effusion,” “interferon-γ,” “t-spot,” and “quantiferon.” The research strategy also contained text terms, such as “pleural,” “pericardial,” “peritoneal,” and “cerebral.” Citations in these articles were also searched.All the abstracts were read to select the appropriate studies on body fluid samples in extrapulmonary tuberculosis (EPTB) patients with full texts available online. Studies using noncommercial IGRAs or presenting nonoriginal data were excluded, as were conference abstracts, editorials, reviews, guidelines, animal studies, and studies conducted in children.Two investigators (L. YL and Z. XX) independently extracted data from the selected studies using a data extraction form designed before beginning the study, and the methodological qualities of the studies were assessed independently. Differences were resolved by consensus or a third investigator (S. HZ).This meta-analysis was conducted in accordance with the guidelines of the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statementM. tuberculosis culture was positive, a nucleic acid amplification test (NAAT) was positive, and/or histopathological examination revealed the presence of caseous necrosis with or without acid-fast bacilli, and/or granuloma formation. Patients were classified as probable EPTB, if MTB could not be identified from the aforementioned tests, and positive treatment responses to a full course of anti-TB therapy should be observed. Because no standard cutoff value for body fluid IGRAs are available, the results were analyzed with the best diagnostic accuracy, if provided, and the cutoff value recorded. Indeterminate results were excluded from further analysis. The results were grouped according to the tuberculosis burden reported by the World Health Organization (WHO)EPTB was defined when an I2 < 50% or P > 0.05 in Q test, a fixed-effect model (Mantel–Haenszel method) was used to evaluate the pooled sensitivity, specificity, PLR, NLR, and DOR. Otherwise, a random-effect model (DerSimonian–Laird method) was used. While comparing method A with method B, if the mean for method A was higher than the mean for method B without overlap of 95% CI, then A was better than B. A two-sided P value < 0.05 was considered statistically significant.Two statistical software programs were used for the analyses: Stata  and Meta-Disc for Windows . The following outcomes for each study were assessed and pooled when feasible: sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic likelihood ratio (DOR), and rates of indeterminate results. Heterogeneity across studies was detected by Chi-square-based Q test and Fisher’s exact tests, and publication bias was assessed by funnel plots and the Egger testHow to cite this article: Zhou, X.-X. et al. Body Fluid Interferon-γ Release Assay for Diagnosis of Extrapulmonary Tuberculosis in Adults: A Systematic Review and Meta-Analysis. Sci. Rep.5, 15284; doi: 10.1038/srep15284 (2015).


Copeptin, a surrogate marker for arginin vasopressin production, is evaluated as an osmo-dependent stress and inflammatory biomarker in different diseases. We investigated copeptin during the menstrual cycle and its relationship to sex hormones, markers of subclinical inflammation and estimates of body fluid.In 15 healthy women with regular menstrual cycles, blood was drawn on fifteen defined days of their menstrual cycle and was assayed for copeptin, progesterone, estradiol, luteinizing hormone, high-sensitive C-reactive protein, tumor necrosis factor-alpha and procalcitonin. Symptoms of fluid retention were assessed on each visit, and bio impedance analysis was measured thrice to estimate body fluid changes. Mixed linear model analysis was performed to assess the changes of copeptin across the menstrual cycle and the relationship of sex hormones, markers of subclinical inflammation and estimates of body fluid with copeptin.Copeptin levels did not significantly change during the menstrual cycle (p = 0.16). Throughout the menstrual cycle, changes in estradiol (p = 0.002) and in the physical premenstrual symptom score (p = 0.01) were positively related to copeptin, but changes in other sex hormones, in markers of subclinical inflammation or in bio impedance analysis-estimated body fluid were not .Although changes in estradiol and the physical premenstrual symptom score appear to be related to copeptin changes, copeptin does not significantly change during the menstrual cycle. Copeptin is increasingly evaluated as a volume- and osmo-dependent stress biomarker in different diseases. Arginin vasopressin (AVP), a hypothalamic hormone with a more subtle response to stress than cortisol During the menstrual cycle (MC), there are changes in hormones involved in fluid regulation and inflammatory markers Body fluid can be estimated by bioimpedance analysis (BIA) Physiological hormonal and fluid changes suggest that copeptin levels may vary throughout the MC. These changes could be clinically important confounding factors if copeptin is used as a point-of-care-tool in premenopausal women with acute or chronic illness. Therefore, we investigated the changes of copeptin during the MC and its relationship to sex hormones, markers of subclinical inflammation and estimates of body fluid, such as total body fluid measured by BIA and physical PMS symptoms.The study adheres to the declaration of Helsinki. It was approved by the local ethics committee in Basel, Switzerland (EKBB “Ethikkommission beider Basel”), and all participants signed and received a copy of a written informed consent form before taking part in the study.Participants were fifteen healthy women aged 18 to 36 years with a regular MC between 26 to 33 days and confirmed ovulation by progesterone level on day 21 of the MC. Exclusion criteria were intake of oral contraceptives within the past 6 months, any medication except occasional paracetamol, smoking, diabetes, history of premenstrual syndrome, minor illness within the previous month. Physical exercise was restricted to no more than 3 hours weekly.Women were studied during one complete MC. After an overnight fast of at least 10 hours, 30 ml blood was drawn between 0730 h and 0930 h on days 3, 5, 8–16, 18, 21, 24 and 27 of each participant's MC. Participants completed a standardized PMS questionnaire During EFP, MFP and MLP, patients were weighted and BIA was used to estimate total body fluid .PMS was calculated based on a validated 17-item daily symptom report The blood was immediately centrifuged, aliquoted, and stored at −70°C. Serum samples were assayed by batch analysis. For progesterone, estradiol, luteinizing hormone (LH), high-sensitive C-reactive protein (hs-CRP), tumor necrosis factor – alpha (TNF-a) and procalcitonin, standard assays were used as mentioned elsewhere Copeptin was measured by chemiluminescence sandwich immunoassay  with a lower detection limit of the assay of 0.4 pmol/L and a functional assay sensitivity of <1 pmol/L (<20% interassay CV).STATA  was used for data analysis. Mean values for copeptin, sex hormone levels and inflammatory markers and the physical symptom score were calculated for each subject in each of the seven MC phases, also for the descriptive analyses. Where necessary, the dependent variable was log-transformed to achieve an approximately normal distribution. For instance, this was the case for copeptin. Mixed linear model analysis with compound symmetry autocorrelation structure for repeated measurements was performed to study the changes of copeptin, estradiol, progesterone, LH and the physical PMS symptoms factor across the MC phases as well as the relationship of estradiol, progesterone, LH, hs-CRP, TNF-a, procalcitonin and physical PMS factor with copeptin (as the dependent variable) across the different MC phases. This same analysis was done for the relationship of copeptin with body fluid as estimated by BIA at the EFP, MFP and MLP. In a second step, analyses were adjusted for the different MC phases to detect potential associations of copeptin with other parameters unexplained by MC-phase. We also considered models with an AR-1 autocorrelation structure which showed almost identical results (data not shown). Differences in copeptin levels between women who reached a LLP and those who did not were calculated using Wilcoxon rank-sum test. In our setting of 15 women whose copeptin levels were assessed in seven different phases across the MC, we would have had 90% power to find a statistically significant effect of the MC if the variance of this effect across the 7 time intervals were 0.2 times the residual variance . With a found intraclass correlation coefficient (ICC) of 0.75 , this would imply that 75% of the total variance of log-copeptin is explained by the subject (between-subject variability), 5% by the average time effects and 20% by unexplained variation within subjects. P<0.05 was considered significant.Baseline characteristics are shown in th percentile) being 1.25, 0.33 and 0.5 in the 3 FP, 0 in the LH phase and 0.33, 1.1 and 8.1 in the 3 LP, respectively. Total body fluid (p = 0.72) and weight (p = 0.99) did not change between the EFP, MFP and the MLP.Physical PMS symptoms changed throughout the MC phases (p = 0.004) and were highest in the LFP. The median values overall of all MC phases were 0 (interquartile range 0–0.5), with values of the highest quartile , but not changes in progesterone or LH  and within the reported inter- and intraindividual variance in healthy women Subtle changes of AVP itself during the MC have only been found by those studies that measured at multiple time points, even with a low number of study participants ranging from 6 to 14 Our data on copeptin is therefore in accordance with the literature on AVP, which shows that hormones implicated in fluid regulation undergo subtle changes during the MC, appear to be influenced by estradiol, and are highest in the follicular phase We excluded subjects with premenstrual syndrome. Nevertheless, perceived changes of body fluid as assessed by the physical symptoms of the PMS score (fluid retention) were significantly related to copeptin. However, estimates of body fluid measured by BIA did not. This may on one hand be due to the small fluid changes throughout the MC in healthy women, and on the other hand due to not assessed confounding factors Although copeptin levels are elevated in inflammatory states The major limitation of this study is the small number of participants, which is in part compensated by serial hormone measurements. Possibly, in a larger sample, subtle MC-related changes might become apparent. However, such subtle changes within the inter- and intraindividual variance will probably not be of clinical importance.Second, only six women had measurements in the LLP due to the variability of MC length.Third, the data are only valid for morning measurements, as potential circadian changes of copeptin are not taken into account.We did not find any significant changes of copeptin levels during the MC in healthy regularly menstruating women, although we found a weak relationship between estradiol and copeptin. During the MC, subtle changes of body fluid assessed by physical symptoms of fluid retention were related to copeptin, but markers of subclinical inflammation were not.Table S1Estradiol. Estradiol values used for creating (XLSX)Click here for additional data file.Table S2Progesterone. Progesterone values used for creating (XLSX)Click here for additional data file.Table S3Luteinizing Hormone. Luteinizing hormone (LH) values used for creating (XLSX)Click here for additional data file.Table S4Copeptin. Copeptin values used for creating (XLSX)Click here for additional data file.


The present study investigated the cilia induced flow of MHD Jeffrey fluid through an inclined tube. This study is carried out under the assumptions of long wavelength and low Reynolds number approximations. Exact solutions for the velocity profile, pressure rise, pressure gradient, volume flow rate and stream function are obtained. Effects of pertinent physical parameters on the computational results are presented graphically. Dutch light microscopist Antoni van Leeuwenhoek discovered cilia in 1675. However, the first comprehensive account of cilia in English language may be credited to Sharpey (1835) who gave the detailed description of ciliary motion in a wide variety of reproductive and respiratory systems of mammals.During the last two decades much progress has been achieved in understanding of ciliary structures. These complex organelles have been examined by a number of experimental techniques. It is noticed that the difference between eukaryotic cilia and flagella is not rigorous. Cilia and flagella are organelles that are primarily used for the transportation of the cell. They propel the cell by flicking back and forth. Cilia motion propels the fluid in which it is moving by its cyclical movements which are asymmetric , moving with velocity c, to the fixed frame  are given byP is the pressure in fixed frame.Cilia are present in the physical model as we have considered the ciliated tube and are hinged near the base at the inner walls of the tube and the fluid motion is generated due to their swing. In existing literature many researchers  and are found to be in good agreement with the results of Siddiqui et al. (M, Jeffrey parameter λ1 and angle of inclination θ on pressure rise Δp, pressure gradient w and stream function In this paper we have presented a theoretical approach to study ciliary motion of Jeffrey fluid in an inclined tube under the effect of magnetic field. The fluid flow is induced by the metachronal wave formed at cilia tip. The tube symmetry is produced by considering the metachronal wave on the cilia tip adjacent to fluid layer. We have adopted the long wavelength and low Reynolds number approximations that simplifies the problem. Cilia motion in Newtonian and non-Newtonian fluids is a current topic of interest. Different studies exit in literature in which the cilia induced flow in different geometries and stresses are discussed (Siddiqui et al. bi et al. . The eff


Solitary fibrous tumours of the pleura (SFTP) are rare tumours. They are mostly benign. Only around 12% of them are malign ant. In the initial stage they are mostly asymptomatic and by growing they cause chest pain, irritating cough and dyspnoea on account of the pressure created on the surrounding structures. Rare giant tumours have compression symptoms on the mediastinal structures. The condition requires tiered diagnostic radiology. Preoperative biopsy is not successful in most cases. The therapy of choice is radical surgical tumour removal. Malignant or non-radically removed benign solitary fibrous tumours of the pleura additionally require neoadjuvant therapy.A 68-year old patient was hospitalized for giant solitary fibrous tumour of the pleura in the right pleural cavity. With its expansive growth the tumour caused the shift of the mediastinum by compressing the lower vena cava, right cardiac auricle as well as the intermediate and lower lobe bronchus. Due to cardiac inflow obstruction and right lung collapse, the patient’s life was endangered with signs of cardio-respiratory failure. After preoperative diagnostic radiology, the tumour was surgically removed. Postoperatively, the patient’s condition improved. No disease recurrence was diagnosed after a year.Giant solitary fibrous tumour of the pleura may cause serious and life-threatening conditions by causing compression of the pleural cavity with its expansive growth. Early diagnosis of the condition enables less aggressive as well as video-assisted thoracic surgery in patients with significantly better state of health. Large tumour surgeries in cardio-respiratory affected patients are highly risk-associated procedures. Solitary fibrous tumours of the pleura (SFTP) are rare mesenchymal tumours representing less than 5% of all tumours of the pleura.et al. to propose an origin of this tumour from ubiquitous dispersed dendritic interstitial cels.12Historically, SFTP are thought to derive from subpleural mesenchymal cells with fibroblasts or myofibroblast differentation.SFTP affect male and female patients equally; however, they may develop in all age periods (5 to 87 years) with the highest incidence between 60 and 70 years of age.16et al. set the basis for differentiating benign from malignant SFTP  was 91%, the patient had signs of heart failure with atrial fibrillation. Breathing was weakened and audible only apically on the right side. Pulmonary function test showed a significant decrease in values of the forced vital capacity , the forced expiratory volume in 1 second , and the FEV1/FVC ratio or Tiffeneau index . Gas analysis of arterial blood showed signs of chronic hypercapnic respiratory failure.Chest X-ray showed a large tumour mass in the right part of the thorax with mediastinal shift to the left . CT scanBronchoscopy showed a visibly compressed trachea from the right side, shift of the carina and the main right bronchus into the left and closed bronchus for the right lower lung lobe. Transbronchial tumour biopsy was negative; the material collected by means of transthoracic needle biopsy did not suffice for histological tumour confirmation.For purposes of further diagnosis and surgical treatment the patient was transferred to the Department of Thoracic Surgery. In the preoperative phase we performed an ultrasound (US) of the heart and angiography of the tumour. Heart US showed a compressed right atrium and lower vena cava as well as increased pressure in the right atrium and ventricle. Angiography displayed an extensive blood circulation of the tumour from the intercostal arteries 8, 9, 11, and 12 and inferior phrenic arteries from the right side .Because of the clinical status of the patient with the signs of respiratory failure, cardiac inflow obstruction and the possibility of massive bleeding, all together representing a high-risk surgery, a detailed plan was designed. A wide approach for safe and radical tumour removal was enabled with the right thoracosternotomy (hemiclamshell). By continuous ligation of blood vessels nourishing the tumour, the blood loss during surgery was only 1.5 l of blood, which was recycled by a cell-saver. Surgical preparation in the mediastinal area was difficult because of compressed structures and numerous postinflammatory adhesions. A fully removed tumour was sent for pathohistological examination .Macroscopic examination of the resected specimen showed firm lobulated and bosselated white-grey tumour measuring 25 cm x 16 cm x 13 cm. The surface of the tumour was covered with thin, shiny, smooth capsule. The cut surface was rubbery, vaguely nodular, grey-white, focally glassy and haemorrhagic. On the edges tiny calcifications were present. Macroscopically no necrotic areas were identified.Microscopically the bland appearing tumour cells were arranged in a “patternless pattern” (storiform and fascicular pattern), the hypercellular regions were mixed with hypocellular areas with hyalinised stroma. In some areas stromal myxoid change and degeneration of collagen was present, too. Stroma was highly vascularized with angiofibromatous and haemangiopericytic vascular pattern. The tumour cells were spindle and oval with scant cytoplasm and nuclei with dense chromatin. Focally spindle cells showed wavy nuclei, resembling schwanian cells and also there were some areas with pleomorphic and giant cells population. The nuclei of the pleomorphic cells were larger, hyperchromatic, and different in shape. Very rare mitotic figures (<2/10 high-power fields [HPF]) were present and there was no necrosis .Immunochistochemically tumour cells were reactive for CD34, CD99 and bcl2 and typically no immunoreactivity was observed with S-100, WT-1, Desmin, CEA, CK AE1/AE3, CK5/6 and calretinin .According to the morphology and cellular immunophenotype the diagnosis of benign giant pleural SFT was signed out.The patient was placed for seven days into a room with perioperative intensive care and extubated after two days. Longer intubation was required to ventilate a long time collapsed right intermediate and lower lung lobe. She left the hospital on day 22 after surgery. At the follow-up after a year, no recurrence of the disease was present.SFTP are a rare pathology of the pleural cavity, which most of the time develop from submesothelial fibroblasts of the visceral pleura and usually in the lower parts of the chest. Prior to the introduction of immunohistochemical examinations and electronic microscopy, they were classified into a large group of mesotheliomas as a localized form of this dangerous, asbestos-related pathology.via one or two thoracotomies at two different levelsvia right thoracosternotomy (hemiclamshell) provides an optimal view of the pleural cavity and mediastinal structures.Due to their non-characteristic clinical picture, SFTP are usually diagnosed in the later stages of the development, when causing pressure on the surrounding structures on account of their size. Smaller, accidentally discovered SFTP are relatively easy to remove surgically. A much more significant issue are radical surgical procedures of giant SFTP in patients affected by the pressure of the tumour on the mediastinal structures and lungs. Only a few cases of giant SFTP that cover almost the entire pleural space are described in literature. SFTP that we removed belongs to the largest so far described cases in global literature. Certain authors report of having performed the surgery Preoperative diagnostics needs to be systematic to enable the surgeon a precise estimation of the scope of the surgical procedure, tumour operability, blood flow of the tumour and the relation to neighbouring structures.A CT scan provides valuable data on the exact location of SFTP, its relation to surrounding structures, tumour homogeneity or potential bleeding areas or necrosis, chest wall destruction and the presence of pleural effusion.34Preoperative histological confirmation of such tumour changes in the chest remains a big problem. The diagnosis of SFTP is rarely reached before surgical excision and pathological examination of the mass.et al. (Because in most cases the biological potential of SFTp is not preoperatively histologically confirmed, neoadjuvant therapy is not appropriate. After removing the tumour surgically we opt for adjuvant therapy in malignant or non-radically removed benign SFTP in accordance with the guidelines provided by De Perrot et al. .16 BecauIt is possible that the tumour will recur, which mainly depends on the histological characteristics of SFTP and radical nature of the surgical procedure. The possibility of benign pedunculated tumours recurring is around 2%, for benign sessile tumours around 8%, malignant pedunculated tumour around 14%, and for malignant sessile tumours around 63%.SFTP are rare pleural neoplasms, stemming from submesothelial fibroblast cells and are in more than 80% benign. Initially, they are asymptomatic and by growing they create pressure on the surrounding structures of the chest and cause chest pain, coughing, dyspnoea, and by pressuring on the mediastinum they can cause life-threatening signs of mediastinal shift. Tiered diagnostic radiology is very important and provides valuable data in the most appropriate manner of treatment. Preoperative biopsy is usually not successful and the final diagnosis is obtained in most cases only after the surgical removal of the tumour. Radical surgical resection is the method of choice when treating benign and operable SFTP and need to be upgraded in malignant or non-radically removed benign tumours with adjuvant therapy. Extensive surgical resections can be avoided with timely diagnosis of smaller tumours, which can be radically removed with VATS. Regular check-up are required due to possible disease recurrence.


Better understanding of alveolar mechanics is very important in order to avoid lung injuries for patients undergoing mechanical ventilation for treatment of respiratory problems. The objective of this study was to investigate the alveolar mechanics for two different alveolar sac models, one based on actual geometry and the other an idealized spherical geometry using coupled fluid-solid computational analysis. Both the models were analyzed through coupled fluid-solid analysis to estimate the parameters such as pressures/velocities and displacements/stresses under mechanical ventilation conditions. The results obtained from the fluid analysis indicate that both the alveolar geometries give similar results for pressures and velocities. However, the results obtained from coupled fluid-solid analysis indicate that the actual alveolar geometry results in smaller displacements in comparison to a spherical alveolar model. This trend is also true for stress/strain between the two models. The results presented indicate that alveolar geometry greatly affects the pressure/velocities as well as displacements and stresses/strains. The alveolar region of the lungs plays an important role in breathing through the process of gas exchange. It occurs between the alveolar membrane and the underlying capillaries. During mechanical ventilation, the distribution of forced air within lung parenchyma results in the overdistension of the alveolar wall leading to a cascade of other conditions. These conditions include volutrauma/barotrauma (extreme stress/strain), atelectrauma  and biotrauma. If the aforementioned conditions are increased multi-system organ failure (MSOF) can occur ,2.2 [The human alveolus is extremely small with only a thin membrane separating the air from the pulmonary capillaries. The sheer number of alveoli makes up for their small size, giving a total gas exchange surface area of 143 m2 ,6. Damag2 ,7. This Computational models have been used in the past to better understand the internal stresses of the lungs. They have also been used to understand the changes that occur when a patient is on a ventilator. Numerous models have also examined the nature of the collagen and elastin fibers in their role of supporting the alveoli –11. Veryet al. [et al. [Several studies focused on the effects of mechanical ventilation on the diseased and healthy lungs at the tissue and cellular levels. Li et al.  studied  [et al.  investig [et al.  investigIn order to better understand single alveolar sac airway mechanics, a three-dimensional model of the actual alveolar sac model was developed in this study and investigated the stress/strain environment using a coupled fluid-solid analysis. In addition, an idealized spherical model is also developed and the results obtained are compared between the two alveolar sac models.Two alveolar sac models, one with actual geometry obtained from a scanning electron micrograph (SEM) of a typical alveolar sac from a rabbit lung from Bachofen and Schürch . A seconThe computational model involves both fluid and solid domains of the alveolar sac. The solid domain is the alveolar sac itself, while the fluid domain is the air contained within the sac. The alveolar sac was considered as rigid (no deformation) in fluid analysis through computational fluid dynamics (CFD) from which the airway were obtained. However, from coupled fluid-solid analysis through fluid-structure interaction, the strains on alveolar sac were obtained by considering the alveolar sac tissue as physiologically compliant (able to deform). The transient interactions between airflow and sac tissue during mechanical ventilation were investigated by solving two coupled sets of governing equations with associated boundary conditions. The governing equations for airflow and airways are briefly described below.The governing equations for transient airflow are the Navier-Stokes equations on a moving mesh with the assumption of incompressible flow. These equations govern the principles of mass and momentum conservation and are described below.Conservation of mass: Conservation of momentum: jx̃ represents the moving mesh location, i.e. the local computational control-volume size, gρ is the fluid density, p is the fluid pressure, μ is the fluid viscosity, and u is the fluid velocity [In these equations velocity ,2.The governing equations for the movement of the alveolar sac walls during inhalation and exhalation are the time-dependent structural equations described below using Einstein’s repeated index convention.Equation of Motion: Constitutive Relations: σ is the stress in each direction, F is the body force, ρ is the density, u is the displacement, C is the elasticity tensor, and ε is the strain in each direction [In the equations above irection ,2.i.e. able to move. The fluid model equations were solved first to obtain fluid pressures, which were then applied to the solid model. Displacements were solved for in the solid model equations, which were then applied to the fluid model. The fluid model equations are resolved using the structural displacements at the boundaries. The process iterates until a converged solution is found for each time step. The equations for each domain are described above.The alveolar sac models generated from Solid Works software were imported into ANSYS Workbench, where FSI was conducted using ANSYS Mechanical Version 12.1) and ANSYS CFX (Version 12.1). ANSYS Mechanical is a general finite element (FE) software program for structural modeling, and ANSYS CFX is a general purpose computational fluid dynamics (CFD) software program for modeling fluid flows. The individual models were coupled using a fluid-structure interaction (FSI) algorithm [.1 and ANi.e. zero displacement. A no slip boundary condition was applied at the fluid-solid interface.The fluid domain of the alveolar sac model was comprised of 1,364,551 tetrahedral elements with 238,688 nodes, and the solid domain had 135,129 tetrahedral elements with 222,762 nodes see . The flu3, Young’s Modulus of 5 kPa, and a Poisson’s ratio of 0.4 [For the alveolar sac model, the wall was assumed to be made of a homogeneous and linearly elastic material ,2. The wo of 0.4 . The air3 as shown in v is the airflow velocity (m/s), t is time (s), τ is the time constant, and iA is the cross-sectional area of the inlet. Both the inhalation and exhalation are scaled to obtain the velocity in the alveolus assuming that the flow divides equally for 24 bifurcations. The waveform is based off of the waveform used by Pidaparti et al. [The airflow rate during mechanical ventilation is assumed to be a constant 60 L/min for inhalation at the tracheal level. Inhalation occurs for 0.7 seconds to correspond to a tidal lung volume of 700 cmi et al. ,2. This For presenting analysis results, two times were selected as representable for all times, since the actual analysis was run for a total simulation time of 4.01 seconds, with time steps of 0.1 seconds, giving over 400 time steps.The results of pressure distributions for both the models were presented in The results of velocity distributions for both the models were presented in The results from fluid analysis between the two fluid models are very similar, with no large differences in pressure or velocity, particularly in magnitude. Due to the greatly different geometries, the pressure and velocity waveforms have different appearances, but ignoring the changes in shape, the overall waveforms are similar.The results of displacement distributions for both the models were presented in The results of von-Mises stress distributions for both the models were presented in The alveolar model experienced smaller strains but much greater stresses than the spherical model. This is partially explained by the different geometries, but the fact that they are different by a few orders of magnitude is highly unusual. For the displacements, the results are about as expected, excluding the large magnitude variations. The largest displacements occur at different locations due to geometry variations. The sphere distributed the stress fairly evenly all around the sides, but the alveolus model did not due to the varied geometry. The various contours in the body created numerous areas of stress concentration.Based on the coupled fluid-solid analysis results, the displacements and stresses are vastly different between the alveolar sac model and the spherical model. The difference in geometry and possibly the difference in entrance lengths to the two alveolus models caused small displacements and high stresses to occur in the alveolus model compared to the spherical model.Two different alveolar sac models were developed, one based on actual geometry and the other an idealized spherical geometry. Both the models were analyzed through coupled fluid-solid analysis to estimate the alveolar mechanics parameters such as pressures/velocities and displacements/stresses. From the fluid analysis, results obtained indicate that both the alveolar geometries give similar results for pressures and velocities. However, the results obtained from coupled fluid-solid analysis indicate that the actual alveolar geometry results in smaller displacements in comparison to a spherical alveolar model. This trend is also true for stress/strain between the two models. The results presented indicate that alveolar geometry greatly affects the pressure/velocities as well as displacements and stresses/strains. More research is needed to further investigate how these models affect the actual strains set-up within the alveolar tissue, which is being pursued as a future work.