[26] Studies by Pena et al., Ralli et al., Peltoneon et al., Wilson et al. Westra WH. Journal of Lower Genital Tract Disease19(3):207-211, July 2015. [14,23] Similarly, a study conducted Ralli et al. A similar distribution of tumors was seen in the study by Boslooper et al.,[18] while the larynx was the most common site of involvement in most of the studies. From this tissue block, a 4-m-thick slice was cut and its slide was stained according to . The second tertile has a more balanced approach to sensitivity and specificity. Comparison of human papillomavirus in situ hybridization and p16 immunohistochemistry in the detection of human papillomavirus-associated head and neck cancer based on a prospective clinical experience. The underreporting of a CIN2,3 lesion could potentially allow a patient to develop invasive cervical cancer whereas overtreatment can lead to subsequent pregnancy complications.35 This is particularly a problem for CIN2 lesions as CIN2 is the threshold for treatment in many clinical management guidelines.6,7, p16INK4a is a biomarker that is overexpressed in almost all high-risk human papillomavirus (HPV)-associated CIN2 and CIN3 lesions. Pathology and genetics of head and neck tumours. As it is impossible for a pathologist to know where their diagnostic approach fits in the spectrum of other pathologists unless they participate in a large analytical study such as CERTAIN, it can be argued that all pathologists should consider performing p16 IHC on all cervical biopsies. Russo D, Di Crescenzo RM, Broggi G, Merolla F, Martino F, Varricchio S, Ilardi G, Borzillo A, Carandente R, Pignatiello S, Mascolo M, Caltabiano R, Staibano S. Front Oncol. Using biopsies collected as part of a screening study conducted in rural China, we randomly selected 50 biopsies with a precancerous diagnosis of cervical intraepithelial neoplasia grade 2 (CIN2) or more severe (CIN2+) and 50 biopsies with diagnosis of CIN less severe than CIN2, and stained them for p16 using a commercial IHC kit. Please try after some time. and transmitted securely. eCollection 2020. According to a study by Ralli et al., a significant association was seen between p16 expression and history of multiple sexual partners (P = 0.003). The same was true for the ISPs diagnosis of CIN3 (data not shown). The authors have declared that no competing interests exist. JAMA. 2020 Jun;144(6):725-734. doi: 10.5858/arpa.2019-0241-OA. Bethesda, MD 20894, Web Policies p16INK4A (henceforth referred to as p16) immunohistochemistry (IHC) is a good surrogate test for the presence of a potentially transforming human papillomavirus (HPV) infection in anogenital carcinomas and premalignant lesions1. - Making an accurate diagnosis for melanocytic lesions has always been challenging for pathologists, especially when dealing with difficult-to-diagnose cases. The 16 kD protein p16 (also known as p16INK4A) is a protein encoded by the CDKN2A gene located on chromosome 9 (9p21.3). may email you for journal alerts and information, but is committed Data Sources. Am J Surg Pathol. and Dragomir et al. A total of 1100 formalin-fixed, paraffin-embedded cervical punch biopsies representative of a colposcopy referral population in the clinical practice setting was used as the reading set for the study. - ScienceDirect Abstract Introduction Section snippets References (20) Journal of the American Society of Cytopathology Volume 10, Issue 2, March-April 2021, Pages 216-224 Cytological interpretation of p16 immunohistochemistry in head and neck carcinomas: does the choice of fixative matter? All rights reserved. Arch Pathol Lab Med. may email you for journal alerts and information, but is committed Smith EM, Rubenstein LM, Hoffman H, Haugen TH, Turek LP. Background p16 is a tumor suppressor gene, over expression of which is considered as a surrogate marker of oncogenic human papillomavirus (HPV) infection. [9] As with female genital (or cervical) carcinogenesis, the immunohistochemical detection of p16 protein (p16 IHC) has been proposed as a surrogate marker of HPV infection in HNC.[10]. HHS Vulnerability Disclosure, Help Yildiz IZ, Usubtn A, Firat P, Ayhan A, Kkali T. Pathol Res Pract. Results: Immunohistochemical Expression of p16 in Melanocytic Lesions: An It should be noted that there were fewer diagnoses of CIN2+ made using ISPH&E+p16/LAST compared with ISPH&E, 3773 versus 3996, respectively. Reuschenbach M, Wentzensen N, Dijkstra MG, von Knebel Doeberitz M, Arbyn M. Am J Clin Pathol. We demonstrated that nonpathologists can accurately diagnose CIN2+ using p16 IHC alone. Prevalence of Human Papillomavirus (HPV) Infection and the Association with Survival in Saudi Patients with Head and Neck Squamous Cell Carcinoma. For example, Thrall13 found that when their laboratory switched from using p16 IHC sporadically to performing p16 IHC according to the LAST criteria that the use of p16 IHC increased and this increase was accompanied by a significant increase in the proportion of women diagnosed with CIN2,3. The commonest site of involvement in our study was the oral cavity (79% cases). 2012 Jun;20(3):240-5. doi: 10.1177/1066896911435697. and Smith et al.[15,22]. Malpica A, Matisic JP, Niekirk DV, et al. Unable to load your collection due to an error, Unable to load your delegates due to an error. 2018;118:16. Along with it, trials should be performed to get a proper treatment regime for HPV-positive and HPV-negative HNSCC in order to provide better treatment and lower relapse rates. Two studies 25, 26 provided results for p16 INK4a interpretation as p16 INK4a positive or negative, . A pathologist reviewed all 100 cases. The study demonstrates a clinically and statistically significant increase in sensitivity and specificity for high-grade squamous intraepithelial lesion when p16 is used according to LAST criteria. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). and transmitted securely. If so, the case was designated a LAST case for this ISP; otherwise, the respective case was designated non-LAST for that reader. 2020 Sep;47(9):815-823. doi: 10.1111/cup.13721. The average difference in NPA of ISPs in round 2 (H&E+p16) versus round 1 (H&E only) also differs by diagnostic approach, but moves in the opposite direction to PPA. The negative impact of staining all cervical biopsies with p16 is largely economic. 4). Cancer . Clin Epigenetics. McCredie MR, Sharples KJ, Paul C, et al. Moreover, the ISPs were selected specifically to practice in different geographic regions of the United States and have a range of experience levels, specimen volumes, and employment settings (academic institution, hospital, private laboratory, or reference laboratory).11. p16 is a 16 kDa protein encoded by CDKN2A, within the INK4/ARF tumour suppressor locus on Chromosome 9 (9p21.3)2,3. p16 expression is now being used as a surrogate marker of HPV infection in squamous cell carcinoma. p16 antibody IHC staining and interpretation. Highlights Testing for p16 status is clinically important for oropharyngeal carcinomas. 8600 Rockville Pike As each case consisted of repeated measures from 17 or 18 ISPs, cases were treated as the respective sampling unit, and all observations belonging to a respective case were kept together when constructing resamples for the bootstrap CIs. The CERTAIN Study Results: Adjunctive p16 Immunohistochemist : The National Library of Medicine Lentsch G, Valdebran M, Saknite I, Smith J, Linden KG, Knig K, Barr RJ, Harris RM, Tromberg BJ, Ganesan AK, Zachary CB, Kelly KM, Balu M. Pigment Cell Melanoma Res. The mean sensitivity and specificity for consensus CIN2+ of p16 IHC as scored by the readers were 88% and 87%, respectively, versus an overall sensitivity and specificity by the pathologist of 96% and 92%, respectively. Responses to this question were not used to determine if p16-stained slides were presented to the readers for evaluation in round 2, but were used to identify LAST cases for the additional analyses presented in this manuscript. Rates for individual readers ranged from 16.7% to 99.6% of cases, but fell within the range of up to 55% for the vast majority of readers (ie, 56 of 70 ISPs). In this cross-sectional observational study, a total of 100 cases of HNSCC were taken. An official website of the United States government. 2010 Dec;134(12):1785-92. doi: 10.5858/2009-0522-RAR.1. In CERTAIN there was a wide variation in the frequency with which p16 IHC was requested by the individual ISPs, even after undergoing specific training on the LAST criteria before beginning their initial H&E reads. p16 Immunohistochemistry Interpretation by Nonpathologists as an The https:// ensures that you are connecting to the In HPV-related cancers, pRB, the target of p16, is downregulated and the feedback mechanisms regulating p16 expression are inhibited, resulting in overexpression of p16. For more information, please refer to our Privacy Policy. 2008;32:502512. Bethesda, MD 20894, Web Policies Focal distribution (>10%30% of labeled nuclei and cytoplasm strongly positive, spreading in one tissue area) was considered as moderate expression (Grade II) and sporadic positivity (5%10% of nuclei and cytoplasm with weak and scattered positivity as low expression (Grade I).[11]. - A PubMed database search for literature reporting melanocytic lesions and p16 immunohistochemistry was performed. As a library, NLM provides access to scientific literature. One issue that should be considered is whether or not to stain biopsies of the ectocervix with only normal squamous epithelium. The aim of this . Federal government websites often end in .gov or .mil. The American Journal of Surgical Pathology45(10):1348-1356, October 2021. [2] More than 90% of HNCs are squamous cell carcinomas (HNSCC). Association of p16 overexpression with various clinicopathologic parameters including T-stage, N-stage, grade, recurrence status, and risk factors was evaluated. It is associated with tobacco chewing, paan chewing and alcohol consumption. Arch Pathol Lab Med. A significant association was seen between p16 expression and history of abnormal sexual habits (P = 0.02) in our study. The p16 INK4a (cyclin-dependent kinase inhibitor 4) is a tumor suppressor protein that binds to cyclin-cdk4/6 complexes, which blocks kinase activity and inhibits progression to the S phase of the . [12,14], In our study, significant association was seen between p16 expression and sex of the patient (P = 0.004), while in study by Shinohara et al., there was no significant correlation between p16 expression and sex (P = 0.18). Using CPRH&E+p16 as the reference, increase in PPA (sensitivity) and NPA (specificity) within LAST cases was 11.8% (95% CI, 9.5-14.0; P<0.0001) and 9.7% (95% CI, 7.8-11.5; P<0.0001), respectively. Conclusion Our data revealed that high expression (> 50%) of p16 is low in oropharyngeal squamous cell carcinoma in our setup. The site is secure. p16 is superior to Stathmin-1 and HSP27 in identifying cervical In this study age of the patients ranged from 17 to 92 years, with the mean age of 46.56 14.40 years and most common age group was 3140 years. Serial sections were prepared from each tissue block in 5 external laboratories in the United States for H&E staining, and for p16 IHC staining using p16-specific mouse monoclonal antibody E6H4 (CINtec Histology; Ventana Medical Systems Inc, Tucson, AZ) and negative Ig control antibody (negative control [monoclonal]; Ventana); for IHC, OptiView DAB IHC Detection kit (Ventana) was used on BenchMark ULTRA IHC/ISH instruments (Ventana) according to the specifications of the manufacturer. Immunohistochemical Expression of p16 in Melanocytic Lesions: An Oral squamous cell carcinoma is a major cause of death throughout the developed world. The correlation of p16 expression with lymphadenopathy was found to be highly statistically significant (P = 0.009). The most important factor in determining the magnitude of gains in sensitivity for CIN2+ (PPA) obtained with p16 IHC appears to be the diagnostic approach an individual ISP takes when interpreting cervical biopsies. Inclusion in an NLM database does not imply endorsement of, or agreement with, Muirhead DM, Hoffman HT, Robinson RA. (P = 0.02) and Muirhead et al. 2020 Nov 8;12(11):e11385. However, no real difference in OPA (equivalent to accuracy) was found with the use of p16 IHC in non-LAST cases, and there was a small reduction in NPA (equivalent to specificity). -. Lower prevalence HPV infection has been previously reported in Thai population when compared with Western countries. Dupont WD, Plummer D, Lewis JS (September 2017). Current Updates on Cancer-Causing Types of Human Papillomaviruses (HPVs) in East, Southeast, and South Asia. Abstract Context: Misdiagnosis of melanoma and melanocytic lesions in general has tremendous medical-legal implications, often leading to unnecessary and excessive use of adjunctive tests. Some error has occurred while processing your request. Significant expression of p16 in node-negative patients may guide the type and intensity of the therapy in patients with HNSCC. Moreover, the IHC utilization rate was considerably higher than predicted by the LAST committee. Lpez F, Mkitie A, de Bree R, Franchi A, de Graaf P, Hernndez-Prera JC, Strojan P, Zidar N, Strojan Flear M, Rodrigo JP, Rinaldo A, Centeno BA, Ferlito A. Diagnostics (Basel). Agreement rates improved with statistical significance (P<0.0001) across all cases (OPA; equivalent to accuracy, assuming reference diagnosis reflects clinical truth), for CIN2+ cases per reference diagnosis (PPA; equivalent to sensitivity), and for CIN1 (CIN1, no CIN) cases (NPA; equivalent to specificity). When evaluating the effect of adjunctive p16 within the subset of LAST cases only, both PPA and NPA increased significantly comparing the ISPs reading results without or with p16 to either of the reference diagnoses (Table 4). Abstract Background The aim of this study was to determine how Stathmin-1 and Heat Shock Protein 27 (HSP27) can be used as adjunctive biomarkers to differentiate high-grade dysplasia from benign/reactive lesions in cervical tissues. Maniar KP, Sanchez B, Paintal A, et al. In addition, across the board improvement in the agreement of ISPs diagnoses with that of either of the 2 reference diagnoses (CPRH&E or CPRH&E+p16) occurred when p16 IHC was used according to the LAST criteria. Using biomarkers as objective standards in the diagnosis of cervical biopsies. Keywords: P16 - Overview: p16 (INK4a/CDKN2A) Immunostain, Technical Component Only Relationships of p16 Immunohistochemistry and Other Biomarkers With doi: 10.1002/hed.24604. There are a number of caveats that should be made regarding our suggestion that pathologists might want to consider staining all cervical biopsies with p16 in order to avoid missing CIN2 lesions. doi: 10.4081/ejh.2011.e20. Peltonen JK, Helppi HM, Pkk P, Turpeenniemi-Hujanen T, Vhkangas KH. Mechanisms of inactivation include homozygous gene deletion, gene mutation and hypermethylation of upstream CpG island regions. Qualitative and Quantitative Diagnosis in Head and Neck Cancer. Bethesda, MD 20894, Web Policies p16 Immunohistochemical Expression in Head and Neck Squamous Cell Carcinoma: Association With Prognostic Parameters Authors Atif A Hashmi 1 , Naila Younus 2 , Samreen Naz 1 , Muhammad Irfan 3 , Zubaida Hussain 1 , Sara T Shaikh 1 , Javaria Ali 1 , Naveen Faridi 1 , Javeria Najam 4 , Maira Shoaib 4 , Shumaila K Hashmi 5 Affiliations R24 TW007988/TW/FIC NIH HHS/United States, International Agency for Research on Cancer - Screening Group. sharing sensitive information, make sure youre on a federal BJOG. Simoens C, Goffin F, Simon P, et al. Eighty-six (86%) patients were tobacco users, intake being in the form of gutka or smoking, 24 (24%) were alcoholics, 60 (60%) were paan chewers and 24 (24%) had history of abnormal sexual habits. IHC expression of p16 can be used as a surrogate marker of HPV. p16 Immunohistochemical Expression in Head and Neck Squamous Cell Variability of pathologists' utilization of p16 and ki-67 immunostaining in the diagnosis of cervical biopsies in routine pathology practice and its impact on the frequencies of cervical intraepithelial neoplasia diagnoses and cytohistologic correlations. Solomon MC, Carnelio S, Gudattu V. Molecular analysis of oral squamous cell carcinoma: A tissue microarray study. Search for Similar Articles In the present study, grade 3 p16 expression was observed in 19 cases (19%), grade 2 in 18 cases (18%) and grade 1 in 23 cases (23%), while 40 cases (40%) were negative for p16 and scored grade 0. Nevus/Melanocytoma/Melanoma: an emerging paradigm for classification of melanocytic neoplasms? [14] One hundred cases of head-and-neck squamous cell cancers were analyzed for expression of p16 which showed no statistically significant association between p16 expression and tobacco chewing (P = 0.16), alcohol consumption (P = 0.44) and paan chewing (P = 0.09). Table 4 illustrates the correlation of p16 expression with lymphadenopathy. http://creativecommons.org/licenses/by-nc-nd/4.0/. During the first reading round, only H&E-stained slides were used to establish the individual ISPs diagnoses (ISPH&E). Immunohistochemistry results should be interpreted based on the pattern of positivity. Our results were concordant with the study of Fregonesi et al., Yuen et al. The site is secure. Interpretation Positive staining is defined as "block" staining: strong nuclear and cytoplasmic expression in a continuous segment of cells (at least 10 - 20 cells); in squamous epithelium, block positivity needs to involve basal and parabasal layers p53, but not p16 mutations in oral squamous cell carcinomas are associated with specific CYP1A1 and GSTM1 polymorphic genotypes and patient tobacco use. Clipboard, Search History, and several other advanced features are temporarily unavailable. The ISPs who have a diagnostic approach that is balanced between sensitivity and specificity have an 10% difference in PPA with the use of p16 and this also is only minimally impacted by whether or not they requested p16. Am J Surg Pathol. Vaccination programs may provide prevention from HPV infection in high-risk population. pRb and CyclinD1 Complement p16 as Immunohistochemical Surrogate Markers of HPV Infection in Head and Neck Cancer. ISP reading results were compared with consensus diagnoses established during a CPR process involving 2 to 3 pathologists specializing in gynecologic pathology, as described by Stoler et al.11 In analogy to the 2 ISP reading rounds, reference diagnoses were first established by CPR on H&E-stained slides (CPRH&E), followed by CPR on H&E and p16-stained slides (CPRH&E+p16). 4. ISPs who favor specificity over sensitivity show a 21% difference in PPA, regardless of whether or not they requested a p16 based on the LAST criteria. PMC Received 2020 Jun 14; Revised 2020 Oct 27; Accepted 2021 Jan 7. You may search for similar articles that contain these same keywords or you may and Smilek et al. Data obtained were analyzed with other clinicopathological parameters including age and sex of the patient, history of tobacco use, paan chewing, alcohol abuse, abnormal sexual habits, site of lesion, grade of tumor and lymph node metastasis. Pathology Outlines - p16 Ralli M, Singh S, Yadav SP, Sharma N, Verma R, Sen R. Assessment and clinicopathological correlation of p16 expression in head and neck squamous cell carcinoma. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Careers. Hashmi AA, Hussain ZF, Aijaz S, et al. The LAST criteria for p16 IHC were developed based predominantly on expert clinical opinion since at the time they were formulated relatively few studies had analyzed the performance of p16 IHC when applied to specific clinical situations. Ronchi A, Pagliuca F, Zito Marino F, Argenziano G, Brancaccio G, Alfano R, Signoriello G, Moscarella E, Franco R. Front Med (Lausanne). They also are speakers for Ventana Medical Systems Inc (Roche Tissue Diagnostics), Roche Molecular Diagnostics, and BD Lifesciences at various symposia. p16 Immunohistochemistry is useful in confirming high-grade - PubMed observed moderately differentiated carcinoma/Grade II forming the most common group. p16 immunohistochemistry (IHC) is commonly used as a surrogate marker for human papillomavirus (HPV) detection in squamous cell carcinomas of the head and neck (SCCHN). However, the HPV status of tumors not staining strongly for p16 is difficult to interpret and may require the use of PCR, not available in all laboratories, as a final arbiter. Clipboard, Search History, and several other advanced features are temporarily unavailable. Mod Pathol 30 (9 . p16 expression indicates HPV-associated oropharyngeal squamous cell carcinoma (OPSCC), but not non-OPSCC. In addition, we aimed to see if any of these markers can differentiate endometrial from endocervical adenocarcinomas. Grade III: Poorly differentiated or anaplastic. 2018;433:11. 5. The average difference in NPA for all 3 tertiles in the non-LAST cases was only slightly negative (1.1% to 0.4%). 19. They may however show patchy non-block-type staining. 2021 Feb 4;7:568946. doi: 10.3389/fmed.2020.568946. 2019 Jun 13;11(6):820. doi: 10.3390/cancers11060820. Journal of Oral and Maxillofacial Pathology : JOMFP. An official website of the United States government. Conclusions: [7], The loss of expression of p16 has been observed in oral premalignant lesions and primary tumors of the oral cavity. Expression of P16INK4a in Uveal Melanoma: New Perspectives. official website and that any information you provide is encrypted head and neck squamous cell carcinoma; hpv; oropharyngeal squamous cell carcinoma; p16. eCollection 2020. It was observed that 60 (60%) cases were positive for p16 (inclusive of all grades), while 40 (40%) cases were negative [Figure 5]. found no statistically significant association between p16 expression and tobacco use. This analysis has a number of strengths. and Dragomir et al. 2001;285:15001505. found a statistically significant association of p16 expression with alcohol consumption and tobacco use (P < 0.05). Your message has been successfully sent to your colleague. 2020 Oct 13;10:562074. doi: 10.3389/fonc.2020.562074. Before Multiplex HPV RNA in situ hybridization/p16 immunohistochemistry: a Twelve nonpathologists of varying educational backgrounds living in Beijing, China received video training and were assigned one of 4 sets of 25 CIN2+ and 25 CIN less severe than CIN2 for evaluation. Diagnostic value of p16 and Ki-67 expression in cervical glandular . All 70 ISPs who participated in this study were (i) board-certified in anatomic pathology, (ii) licensed and currently practicing medicine in the United States, and (iii) evaluate cervical histology specimens as part of their routine clinical practice. 2015 Dec;48(6):611-25. doi: 10.1111/cpr.12216. Examples of representative cases showing p16 immunostaining pattern are also illustrated. and Lazarus et al. HPV status should be included as an important risk and prognostic factor in future trials. The obtained results were analyzed and evaluated using Chi-square test, value of P < 0.05 was taken significant. IHC profile of the tumor was assessed by subjecting one representative section from tumor block to p16. Would you like email updates of new search results? Essential information from each study (number of samples, antibody used, collection dates, overall p16 immunohistochemistry results, and general method of interpretation) was tabulated and analyzed. Disclaimer. World J Surg Oncol. The .gov means its official. Lancet Oncol. We demonstrated that nonpathologists can accurately diagnose CIN2+ using p16 IHC alone. FOIA 2017;25:17. 12. p16<sup>INK4a</sup> immunohistochemistry (IHC) is widely used to facilitate the diagnosis of human papillomavirus (HPV)-associated cervical precancerous lesions. This site needs JavaScript to work properly. This site needs JavaScript to work properly. Dass SE, Huizenga T, Farshchian M, Mehregan DR. Clin Cosmet Investig Dermatol. Increased PD-L1 and p16 expression are common in oropharyngeal squamous Positive and negative controls were run simultaneously. A pathologist reviewed all 100 cases. Zoroquiain P, Fernandes BF, Gonzlez S, Novais GN, Schalper KA, Burnier MN Jr. Int J Surg Pathol. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. 2017 Mar;39(3):E34-E39. 11. the contents by NLM or the National Institutes of Health. government site. The lower anogenital squamous terminology standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. 2017 Aug;66:144-151. doi: 10.1016/j.humpath.2017.06.014. These differences could also be attributed to the difference in geographic distribution of tumor, sample size, scoring criteria and different types of antibodies used by different authors. Results p16 over expression was noted in 22.9% (33 cases), while 21.5% (31 cases) were focal positive and 55.6% (80 cases) were negative for p16 over expression. Immunohistochemistry was performed on 4-m thick sections from 10% formalin-fixed paraffin-embedded specimens, according to the streptavidin-biotin immunoperoxidase technique. Search for Similar Articles FOIA The results discussed above demonstrate that when p16 IHC is utilized based on the LAST criteria there is an improvement in the overall performance of ISPs compared with the CPR. Cervical histopathology variability among laboratories: a population-based statewide investigation. Accessibility 8600 Rockville Pike Examples of hematoxylin and eosin (H&E) staining and p16INK4a immunohistochemical (p16 IHC) staining, MeSH p16 and Other Epithelial Cancer Biomarkers. Pilloni L, Bianco P, Difelice E, Cabras S, Castellanos ME, Atzori L, Ferreli C, Mulas P, Nemolato S, Faa G. Eur J Histochem. 9. National Library of Medicine Overdiagnosis of HSIL on, 18. Disclaimer. Shinohara S, Kikuchi M, Tona R, Kanazawa Y, Kishimoto I, Harada H, et al. 2014 Jan;138(1):76-87. doi: 10.5858/arpa.2012-0472-OA.
Brooks Extra Wide Womens,
Arc'teryx Cerium Lt Down Hoodie - Men's,
Work From Home Jobs Edmonton Indeed,
Allergy Research Group Ndt,
Articles P