Comparative Effectiveness of Second-line Antihyperglycemic Agents for Cardiovascular Outcomes: A Large-scale, Multinational, Federated Analysis of the LEGEND-T2DM Study.

Background: SGLT2 inhibitors (SGLT2is) and GLP-1 receptor agonists (GLP1-RAs) reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head trials. Methods: Across the LEGEND-T2DM network, we included ten federated international data sources, spanning 1992-2021. We identified 1,492,855 patients with T2DM and established cardiovascular disease (CVD) on metformin monotherapy who initiated one of four second-line agents (SGLT2is, GLP1-RAs, dipeptidyl peptidase 4 inhibitor [DPP4is], sulfonylureas [SUs]). We used large-scale propensity score models to conduct an active comparator, target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, we fit on-treatment Cox proportional hazard models for 3-point MACE (myocardial infarction, stroke, death) and 4-point MACE (3-point MACE + heart failure hospitalization) risk, and combined hazard ratio (HR) estimates in a random-effects meta-analysis. Findings: Across cohorts, 16·4%, 8·3%, 27·7%, and 47·6% of individuals with T2DM initiated SGLT2is, GLP1-RAs, DPP4is, and SUs, respectively. Over 5·2 million patient-years of follow-up and 489 million patient-days of time at-risk, there were 25,982 3-point MACE and 41,447 4-point MACE events. SGLT2is and GLP1-RAs were associated with a lower risk for 3-point MACE compared with DPP4is (HR 0·89 [95% CI, 0·79-1·00] and 0·83 [0·70-0·98]), and SUs (HR 0·76 [0·65-0·89] and 0·71 [0·59-0·86]). DPP4is were associated with a lower 3-point MACE risk versus SUs (HR 0·87 [0·79-0·95]). The pattern was consistent for 4-point MACE for the comparisons above. There were no significant differences between SGLT2is and GLP1-RAs for 3-point or 4-point MACE (HR 1·06 [0·96-1·17] and 1·05 [0·97-1·13]). Interpretation: In patients with T2DM and established CVD, we found comparable cardiovascular risk reduction with SGLT2is and GLP1-RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of GLP1-RAs and SGLT2is should be prioritized as second-line agents in those with established CVD. Funding: National Institutes of Health, United States Department of Veterans Affairs.

Data-driven automated classification algorithms for acute health conditions: applying PheNorm to COVID-19 disease.

OBJECTIVES: Automated phenotyping algorithms can reduce development time and operator dependence compared to manually developed algorithms. One such approach, PheNorm, has performed well for identifying chronic health conditions, but its performance for acute conditions is largely unknown. Herein, we implement and evaluate PheNorm applied to symptomatic COVID-19 disease to investigate its potential feasibility for rapid phenotyping of acute health conditions. MATERIALS AND METHODS: PheNorm is a general-purpose automated approach to creating computable phenotype algorithms based on natural language processing, machine learning, and (low cost) silver-standard training labels. We applied PheNorm to cohorts of potential COVID-19 patients from 2 institutions and used gold-standard manual chart review data to investigate the impact on performance of alternative feature engineering options and implementing externally trained models without local retraining. RESULTS: Models at each institution achieved AUC, sensitivity, and positive predictive value of 0.853, 0.879, 0.851 and 0.804, 0.976, and 0.885, respectively, at quantiles of model-predicted risk that maximize F1. We report performance metrics for all combinations of silver labels, feature engineering options, and models trained internally versus externally. DISCUSSION: Phenotyping algorithms developed using PheNorm performed well at both institutions. Performance varied with different silver-standard labels and feature engineering options. Models developed locally at one site also worked well when implemented externally at the other site. CONCLUSION: PheNorm models successfully identified an acute health condition, symptomatic COVID-19. The simplicity of the PheNorm approach allows it to be applied at multiple study sites with substantially reduced overhead compared to traditional approaches.

Multinational patterns of second line antihyperglycaemic drug initiation across cardiovascular risk groups: federated pharmacoepidemiological evaluation in LEGEND-T2DM.

Objective: To assess the uptake of second line antihyperglycaemic drugs among patients with type 2 diabetes mellitus who are receiving metformin. Design: Federated pharmacoepidemiological evaluation in LEGEND-T2DM. Setting: 10 US and seven non-US electronic health record and administrative claims databases in the Observational Health Data Sciences and Informatics network in eight countries from 2011 to the end of 2021. Participants: 4.8 million patients (≥18 years) across US and non-US based databases with type 2 diabetes mellitus who had received metformin monotherapy and had initiated second line treatments. Exposure: The exposure used to evaluate each database was calendar year trends, with the years in the study that were specific to each cohort. Main outcomes measures: The outcome was the incidence of second line antihyperglycaemic drug use (ie, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, dipeptidyl peptidase-4 inhibitors, and sulfonylureas) among individuals who were already receiving treatment with metformin. The relative drug class level uptake across cardiovascular risk groups was also evaluated. Results: 4.6 million patients were identified in US databases, 61 382 from Spain, 32 442 from Germany, 25 173 from the UK, 13 270 from France, 5580 from Scotland, 4614 from Hong Kong, and 2322 from Australia. During 2011-21, the combined proportional initiation of the cardioprotective antihyperglycaemic drugs (glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors) increased across all data sources, with the combined initiation of these drugs as second line drugs in 2021 ranging from 35.2% to 68.2% in the US databases, 15.4% in France, 34.7% in Spain, 50.1% in Germany, and 54.8% in Scotland. From 2016 to 2021, in some US and non-US databases, uptake of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors increased more significantly among populations with no cardiovascular disease compared with patients with established cardiovascular disease. No data source provided evidence of a greater increase in the uptake of these two drug classes in populations with cardiovascular disease compared with no cardiovascular disease. Conclusions: Despite the increase in overall uptake of cardioprotective antihyperglycaemic drugs as second line treatments for type 2 diabetes mellitus, their uptake was lower in patients with cardiovascular disease than in people with no cardiovascular disease over the past decade. A strategy is needed to ensure that medication use is concordant with guideline recommendations to improve outcomes of patients with type 2 diabetes mellitus.

Annular Erythema of Infancy With Reactive Helper T Lymphocytes.

Annular erythemas of infancy (AEIs) are rare benign skin eruptions characterized by persistent, annular, urticarial, nonpruritic patches and plaques that develop in patients younger than 1 year. Histologically, a skin biopsy typically demonstrates a perivascular infiltrate in the dermis composed of small lymphocytes, neutrophils, and increased scattered eosinophils. We report a case of an AEI in an 11-month-old girl with uncommon histologic features. Recognition of these benign cells is important to avoid misdiagnosing them as atypical or neoplastic. We also provide a review of the differential diagnosis for AEIs.

Morphea (Localized Scleroderma) Presenting With Recurrent Skin and Soft Tissue Infections: A Diagnostic Dilemma.

Morphea or localized scleroderma is reported to be triggered through diverse stimuli. We present a case of morphea that presented as a non-healing wound with superimposed methicillin-sensitive Staphylococcus aureus (MSSA) infection. In our case, morphea was thought to have been potentially triggered by a post-surgical infection. We discuss the potential infectious triggers and common infections that may confound the diagnosis.

Is the Climb Worth the View? The Savings/Alert Ratio for Reducing Vitamin D Testing.

BACKGROUND: Despite guideline recommendations, vitamin D testing has increased substantially. Clinical decision support (CDS) presents an opportunity to reduce inappropriate laboratory testing. OBJECTIVES AND METHODS: To reduce inappropriate testing of vitamin D at the Vanderbilt University Medical Center, a CDS assigned providers to receive or not receive an electronic alert each time a 25-hydroxyvitamin D assay was ordered for an adult patient unless the order was associated with a diagnosis in the patient's chart for which vitamin D testing is recommended. The CDS ran for 80 days, collecting data on number of tests, provider information, and basic patient demographics. RESULTS: During the 80 days, providers placed 12,368 orders for 25-hydroxyvitamin D. The intervention group ordered a vitamin D assay and received the alert for potentially inappropriate testing 2,181 times and completed the 25-hydroxyvitamin D order in 89.9% of encounters, while the control group ordered a vitamin D assay (without receiving an alert) 2,032 times and completed the order in 98.1% of encounters, for an absolute reduction of testing of 8% (p < 0.001). CONCLUSION: This CDS reduced vitamin D ordering by utilizing a soft-stop approach. At a charge of $179.00 per test and a cost to the laboratory of $4.20 per test, each display of the alert led to an average reduction of $14.70 in charges and of $0.34 in spending by the laboratory (the savings/alert ratio). By describing the effectiveness of an electronic alert in terms of the savings/alert ratio, the impact of this intervention can be better appreciated and compared with other interventions.

Acute kidney injury risk-based screening in pediatric inpatients: a pragmatic randomized trial.

BACKGROUND: Pediatric acute kidney injury (AKI) is common and associated with increased morbidity, mortality, and length of stay. We performed a pragmatic randomized trial testing the hypothesis that AKI risk alerts increase AKI screening. METHODS: All intensive care and ward admissions of children aged 28 days through 21 years without chronic kidney disease from 12/6/2016 to 11/1/2017 were included. The intervention alert displayed if calculated AKI risk was > 50% and no serum creatinine (SCr) was ordered within 24 h. The primary outcome was SCr testing within 48 h of AKI risk > 50%. RESULTS: Among intensive care admissions, 973/1909 (51%) were randomized to the intervention. Among those at risk, more SCr tests were ordered for the intervention group than for controls (418/606, 69% vs. 361/597, 60%, p = 0.002). AKI incidence and severity were the same in intervention and control groups. Among ward admissions, 5492/10997 (50%) were randomized to the intervention, and there were no differences between groups in SCr testing, AKI incidence, or severity of AKI. CONCLUSIONS: Alerts based on real-time prediction of AKI risk increased screening rates in intensive care but not pediatric ward settings. Pragmatic clinical trials provide the opportunity to assess clinical decision support and potentially eliminate ineffective alerts.

Atypical cellular neurothekeoma: A potential diagnostic pitfall for benign and malignant spindle cell lesions in skin.

Cellular neurothekeomas (CNTs) are rare, benign cutaneous tumors that arise primarily on the head and neck, with a slight female predominance. CNTs with atypical features have been described, including those with an infiltrative growth pattern. Although CNTs with atypical features are benign, recognition of this entity can pose diagnostic challenges. Here, we report a case of CNT with an unusual clinical presentation on the left second digit, and with atypical histological features including an infiltrative growth pattern, which could have been mistaken for features of malignancy.

An unusual clinical presentation of myxoid dermatofibrosarcoma protuberans with a prominent vasculature: A potential pitfall in the diagnosis of myxoid soft tissue tumors.

Dermatofibrosarcoma protuberans (DFSP) is a rare soft tissue tumor that arises primarily on the trunk and extremities but seldom on the scalp. Several variants of DFSP have been described, including myxoid DFSP. Although typical DFSP may have focally myxoid areas, myxoid DFSP, in which most of the stroma is myxoid, is rare and can pose diagnostic challenges. Here, we report a case of myxoid DFSP with an unusual clinical presentation that could have been mistaken for a lipoma. Additionally, the myxoid DFSP displayed prominent vasculature in a myxoid stroma, which could have been mistaken for a myxoid liposarcoma.

Electronic health record-based predictive models for acute kidney injury screening in pediatric inpatients.

BackgroundAcute kidney injury (AKI) is common in pediatric inpatients and is associated with increased morbidity, mortality, and length of stay. Its early identification can reduce severity.MethodsTo create and validate an electronic health record (EHR)-based AKI screening tool, we generated temporally distinct development and validation cohorts using retrospective data from our tertiary care children's hospital, including children aged 28 days through 21 years with sufficient serum creatinine measurements to determine AKI status. AKI was defined as 1.5-fold or 0.3 mg/dl increase in serum creatinine. Age, medication exposures, platelet count, red blood cell distribution width, serum phosphorus, serum transaminases, hypotension (ICU only), and pH (ICU only) were included in AKI risk prediction models.ResultsFor ICU patients, 791/1,332 (59%) of the development cohort and 470/866 (54%) of the validation cohort had AKI. In external validation, the ICU prediction model had a c-statistic=0.74 (95% confidence interval 0.71-0.77). For non-ICU patients, 722/2,337 (31%) of the development cohort and 469/1,474 (32%) of the validation cohort had AKI, and the prediction model had a c-statistic=0.69 (95% confidence interval 0.66-0.72).ConclusionsAKI screening can be performed using EHR data. The AKI screening tool can be incorporated into EHR systems to identify high-risk patients without serum creatinine data, enabling targeted laboratory testing, early AKI identification, and modification of care.

Metastatic atypical fibroxanthoma: a series of 11 cases including with minimal and no subcutaneous involvement.

Atypical fibroxanthoma (AFX) is a dermal mesenchymal neoplasm arising in sun-damaged skin, primarily of the head and neck region of older men. Conservative excision cures most. However, varying degrees of subcutaneous involvement can lead to a more aggressive course and rare metastases. Thus, AFX involving the subcutis are termed pleomorphic dermal sarcomas or other monikers by some to recognize the more threatening natural history. We reviewed cases of "metastatic AFX" from our institution and from the files of a consultative dermatopathology practice. Nine of 152 patients with AFX were identified at a single institution (2000-2011). Two additional patients were identified from the files of a consultative practice. Clinical, radiological, and pathological features were reviewed and cases with histologically verified metastases identified. Median age was 67 (range, 45-91) years, all male, and involving the head and neck region. Two cases had no documented involvement of the subcutis, and 2 cases had only superficial subcutis involvement. Median time to metastases was 13 (range, 8-49) months. Three patients developed solitary regional lymph node metastases while 8 had widespread metastases. Five patients developed local recurrence within 8 months, and all 5 developed widespread metastasis. With median follow-up of 26 (range, 10-145) months, 6 died of disease (median, 19 months; range, 10-35 months), 4 were alive and well, and 1 was alive with disease. AFX has very rare metastatic potential, even those without or with minimal subcutis involvement, and can lead to mortality. Most metastasis and local recurrence occurred within 1 year of presentation. Solitary regional metastases were associated with better outcomes than those with multiple distant metastases. Patients with repeated local recurrences portended more aggressive disease including development of distant metastases.

Impact of the 2009 (7th edition) AJCC melanoma staging system in the classification of thin cutaneous melanomas.

CONTEXT: The 7th (2009) edition of the AJCC melanoma staging system incorporates tumor (Breslow) thickness, MR, and ulceration in stratifying T1 primary melanomas. Compared to the prior 6th (2001) edition, MR has replaced CL for thin melanomas. OBJECTIVE: We sought to identify and report differences of the classification of thin melanomas as well as outcome of SLNB in patients according to the 6th and 7th editions at our institution. RESULTS: 106 patients were identified with thin melanomas verified by wide excision. 31 of 106 thin melanomas were reclassified according to the 7th edition of the AJCC. Of those 31, 15 CL II/III patients (6th edition T1a) were reclassified as T1b based on the presence of mitoses while 16 CL IV patients (6th edition T1b) were categorized as T1a based on the absence of mitoses. 26/31 reclassified patients underwent SLNB, and all were negative. Patients with thin melanoma and a +SLNB (N = 3) were all classified as T1b according to both staging systems. CONCLUSIONS: In our experience, 29% of thin melanomas were reclassified according to the 7th edition with similar proportions of patients re-distributed as T1a (14%) and T1b (15%). Cases with +SLN corresponded with T1b lesions in both 6th and 7th editions.

Ambiguous melanocytic tumors in a tertiary referral center: the contribution of fluorescence in situ hybridization (FISH) to conventional histopathologic and immunophenotypic analyses.

The diagnosis of benign versus malignant melanocytic proliferations remains an important challenge. The current diagnostic algorithm typically involves an assessment of histopathologic and immunohistochemical parameters by light microscopy. Recently, fluorescence in situ hybridization (FISH) was reported as a useful ancillary diagnostic tool in melanocytic lesions, but the utility of FISH in melanocytic tumors that are difficult to diagnose with standard morphologic analysis remains controversial. To address this issue, we collected 34 ambiguous melanocytic tumors for FISH testing (NeoGenomics). Before FISH testing, cases were designated as "favor benign" (n=24) or "favor malignant" (n=10) by a consensus group (up to 7 dermatopathologists) on the basis of clinical, histopathologic, and immunophenotypic parameters. FISH was positive in 3/24 "favor benign" lesions and in 5/10 "favor malignant" lesions. The histopathologic, immunophenotypic, and FISH parameters informing our diagnostic impression were correlated with the final consensus diagnosis and clinical follow-up; in all cases, the initial diagnosis remained unchanged. In this series, the sensitivity of FISH for the histopathologic diagnosis of melanoma was 50%, the specificity was 87.5%, the positive predictive value was 62.5%, and the negative predictive value was 80.7%. Follow-up information was available for 25 patients (17 benign and 8 malignant diagnoses). Among benign lesions, the mean follow-up was 16.8 months (range, 8 to 25 mo); no metastases have been reported to date. Among the malignant lesions, the mean follow-up was 14.6 months (range, 7 to 23 mo); a single lymph node metastasis was identified in a 4-year-old girl with a histopathologic diagnosis of melanoma, which was negative on FISH. In our experience, in the setting of a lesion with predominantly benign findings, a negative FISH test-given its high specificity-is a reassuring finding that supports a benign diagnosis. In contrast, a positive FISH test should be carefully interrogated in the context of the complete histopathologic findings.

Immunodetection of phosphohistone H3 as a surrogate of mitotic figure count and clinical outcome in cutaneous melanoma.

In the American Joint Committee on Cancer (AJCC)-TNM (2009) staging system, the key prognostic factor in cutaneous melanoma is the depth of dermal invasion (Breslow thickness) with further refinement according to the presence of epidermal ulceration or dermal mitoses. Immunodetection of phosphohistone H3 has been shown to facilitate the identification of mitotic figures in various neoplasms. We selected 120 cases of primary cutaneous melanoma with completely annotated histopathologic parameters and clinical outcomes and performed double immunohistochemical staining for MLANA (Mart-1/Melan-A) and phosphohistone H3. One hundred and thirteen cases were amenable to antiphosphohistone H3 staining from 66 men and 47 women, with mean age of 64 years (9-93), including 61 superficial spreading type, 24 nodular, 6 lentigo maligna, 8 acral lentiginous, and 14 unclassified. The mean Breslow thickness was 2.53 mm (0.20-25), ulceration was present in 25/113 (22%) and the mean mitotic count was 3.2/mm(2) (<1-29/mm(2)). In 27/113 (24%) of the cases, antiphosphohistone H3 failed to highlight mitotic figures anywhere in the tissue (normal or tumor cell), whereas in 86/113 (76%) antiphosphohistone H3 detected at least one mitotic figure. Among the latter, antiphosphohistone H3 did not detect mitotic figures in dermal tumor cells in 37/86 cases (43%), whereas anti-PHH3 identified at least one melanocytic mitotic figure in the other 49/86 cases (57%; range: 1-66/mm(2)). The relationship between phosphohistone H3 and manual mitotic count was statistically significant (Pearson correlation=0.59, P<0.0001). Logistic regression analyses demonstrated an association between the development of subsequent metastatic disease and the following variables: mitotic figures (odds ratio (OR)=5.7; P=0.0001); phosphohistone H3-positive mitotic figures (OR=3.0; P=0.008); Breslow thickness (OR=4.0 per mm; P=0.0002); ulceration (OR=3.94; P=0.008). The application of phosphohistone H3 immunohistochemistry to the description of primary cutaneous melanoma is useful in identifying mitotic figures, improves upon the specificity of this designation when used together with MLANA, and correlates with an increased risk for metastasis in univariate analyses.

Multidisciplinary management of primary adenoid cystic carcinoma of the eyelid with perineural invasion.

Primary cutaneous adenoid cystic carcinoma of the eyelid is an extremely rare entity with the propensity to recur locally, spread to regional lymph nodes, and invade perineural spaces. Of the 8 cases previously reported in the literature, only 2 were noted to be associated with perineural invasion, and neither of these was treated with radiation therapy. The authors report the case of a 35-year-old woman who presented with a progressively enlarging left lower eyelid lesion. An excisional biopsy with wide margins revealed a diagnosis of primary adenoid cystic carcinoma of the eyelid with perineural invasion. Because of the high risk of recurrence associated with perineural invasion, the patient received postoperative adjuvant radiation in the form of 50 Gy relative biological effectiveness of proton beam therapy to the postoperative tumor bed and to the infraorbital nerve tracking back to the apex of the orbit, followed by a 10-Gy boost to the lower eyelid tumor bed with orthovoltage x-rays.

p16 expression in cutaneous squamous carcinomas with neck metastases: a potential pitfall in identifying unknown primaries of the head and neck.

BACKGROUND: Human papillomavirus (HPV) positivity (+) has been used to identify oropharyngeal squamous carcinomas (SCCs) presenting as unknown primaries in the neck. p16 overexpression correlates with HPV+ in the oropharynx; however, the use of p16 alone as a surrogate marker of oropharyngeal HPV+ tumors has not been validated. METHODS: We immunohistochemically analyzed p16 expression in surgically resected aggressive cutaneous head and neck SCC primaries and their nodal metastases from 24 patients to determine the potential overlap of p16 expression outside of the oropharynx. RESULTS: Five of 24 primary tumors (20.8%) and 3 lymph node metastases (12.5%) in levels II, III, and V, and the periparotid region diffusely expressed p16. HPV (high-risk types by in situ hybridization) was negative. CONCLUSIONS: p16 expression is relatively common in lymph node-positive cutaneous head and neck SCCs; thus, p16 expression as an independent biomarker and mechanism to determine the oropharyngeal source of an unknown primary is not advised.

Anaplastic oligodendroglioma involving the subcutaneous tissue of the scalp: report of an exceptional case and review of the literature.

Anaplastic oligodendroglioma [AO, World Health Organization (WHO) grade III] is an uncommon but aggressive tumor of the central nervous system that typically arises in adults. Clinically, patients present with seizures, and the prognosis is considered poor. Metastatic spread is extremely rare. We report an exceptional case of AO with extracranial scalp involvement, which arose in a patient with recurrent primary AO of the brain after chemoradiation, multiple cranial surgical resections, and subsequent scalp reconstruction. On histopathology, the subcutaneous tissue of the scalp contained several clusters and infiltrating cords of relatively small, epithelioid cells with hyperchromatic nuclei, scant eosinophilic cytoplasm, and perinuclear halos, which gave the cells a characteristic fried-egg appearance. By immunohistochemistry, the lesional cells were positive for glial fibrillary acidic protein and S-100. It is likely that surgical implantation and direct extracranial extension after craniotomy were the mechanisms responsible for dissemination of the patient's tumor.

Cutaneous epithelioid angiomatous nodule of the chest wall with expression of estrogen receptor: a mimic of carcinoma and a potential diagnostic pitfall.

Cutaneous epithelioid angiomatous nodule (CEAN) is a rare vascular proliferation that develops on the trunk and extremities. The lesion arises over weeks to months and affects both sexes without age predilection. Histologically, CEAN is characterized by a circumscribed proliferation of epithelioid endothelial cells in the superficial dermis with a background of lymphocytes, plasma cells and eosinophils. The epithelioid cells are positive for CD31, CD34 and/or D2-40. We report a case of CEAN that had remained stable for more than 30 years on the chest wall of a woman with a history of breast cancer. The lesional cells were epithelioid in appearance and positive for estrogen receptor (ER), raising suspicion for breast carcinoma. However, the cells were positive for CD31, CD34, D2-40 and EMA (epithelial membrane antigen); they were negative for cytokeratins, carcinoembryonic antigen (CEA), CD1a, gross cystic disease fluid protein (GCDFP-15), S-100, a melanocytic cocktail, HHV-8 and progesterone receptor. The histologic and immunohistochemical features, including a low proliferation index (10% by Ki-67), helped to distinguish this lesion from carcinoma and other vascular lesions. This is the most comprehensive immunohistochemical profile reported for CEAN to date and the first time that ER expression has been described.

Head and neck squamous cell carcinomas in HIV-positive patients: a preliminary investigation of viral associations.

Oncogenic human papillomaviruses (HPVs) are associated with oropharyngeal squamous cell carcinoma (SCC). Infection with human immunodeficiency virus (HIV) increases susceptibility to opportunistic infections and viral-promoted cancers. The prevalences of HPV, herpes simplex virus (HSV), Epstein-Barr virus (EBV), and human herpesvirus-8 (HHV-8) have not been established for head and neck squamous cell carcinoma in HIV-positive patients (HIV+ HNSCC). We have observed that HIV+ HNSCC tend to contain numerous multinucleated tumor giant cells, this finding has not been described previously. The goal of this study is to test for these oncogenic viruses in a small cohort of retrospectively identified patients with HIV infection, and to compare histologically these cancers to a control group of HNSCC patients. Tumors were reviewed histologically and compared to a control group of 102 patients with HNSCC (serologically untyped or HIV negative). Polymerase chain reaction (PCR) was performed on formalin-fixed, paraffin-embedded HIV+ HNSCC samples from combined 25 patients in two institutions. In situ hybridization was performed to identify EBV (EBER) and immunohistochemistry was performed to detect HSV-1, HSV-2, HHV-8, and HIV-related proteins (Nef, p24). The study sample consisted of 34 HIV+ patients with HNSCC from Montefiore Medical Center, and six HIV+ HNSCC patients from Hospital Clinic, University of Barcelona; 24 (60%) men and 16 (40%) women. The larynx was most commonly involved (65%, n = 26); followed by the oropharynx (22.5%, n = 9). Four carcinomas arose from the oral cavity (10%) and one from the nasal cavity (2.5%). Histologically, multinucleated tumor giant cells were more common in the HIV+ group (39/40, 97.5%) than the control group (27/102, 26%, p 0.001, chi-square). HPV was detected in 6 of 25 (24%) HNSCC tumors by PCR, five were typed as HPV 16 and one as HPV 26/69; five of these tumors (83%) were located in the oropharynx. EBV, HSV-1, HSV-2, and HHV-8 were detected only infrequently in tumor cells. Nef protein was detected in tumor cells in 7 of 21 (33.3%) cases; p24 was not detectable in 6 tumors studied. There were no significant associations between HPV positive tumors and co-infections with other viruses. This study is consistent with other reports that suggest an increased incidence of laryngeal carcinoma for HIV+ patients. HPV was detected in 24% of HIV+ HNSCC, however, the number of tumors with amplifiable DNA (n = 25) is too small to allow for conclusions. EBV, HSV-1, HSV-2, and HHV-8 are uncommon in HIV+ HNSCC; it is unlikely that these viruses have a promoting effect. MNTCG are significantly common in HIV+ HNSCC, but there is overlap in MNTCG counts with the control group and therefore this finding cannot be used as a biomarker of HIV infection.