Oncocytic adrenocortical neoplasm of borderline uncertain malignant potential diagnosed after robot-assisted adrenalectomy case report.

BACKGROUND: Adrenal incidentalomas are radiologically discovered tumors that represent a variety of pathologies, with the diagnosis clinched only on surgical pathology. These tumors may be clinically monitored, but triggers for surgery include size > 4 cm, concerning features on radiology, or hormonally functioning. Adrenal oncocytic neoplasms (AONs) are notably rare and typically nonfunctional tumors that are discovered as incidentalomas and exist on a spectrum of malignant potential. CASE PRESENTATION: We discovered an exceptionally large (15 cm in the greatest dimension) incidentaloma in a 73-year-old man with left back pain and he was treated with robotic-assisted adrenalectomy. Surgical pathology was consistent with AON of borderline uncertain malignant potential; adjuvant mitotane and radiation were omitted based on shared decision-making. CONCLUSION: Large AONs are rare, usually benign tumors that can be safely treated with robotic-assisted adrenalectomy. Surgical pathology is the crux of diagnosis and post-operative management, as it informs both the initiation of adjuvant therapy and the stringency of post-operative surveillance.

Post-therapeutic squamous cell transformation of a metastatic prostate adenocarcinoma with comparison of molecular profiles: a case report and review of the literature.

Transformation of primary prostate adenocarcinoma to squamous cell carcinoma after initial treatment with chemotherapy and hormonal therapy is extremely rare and typically results in rapid treatment-refractory disease progression and death. Here, we present a case of a 64-year-old man who was initially diagnosed with metastatic prostate adenocarcinoma (positive PSA and NKX3.1 stains, total PSA 747.2 ng/ml) to the thoracic spine (T8) in 2019. The patient received androgen deprivation therapy and chemotherapy with good response (PSA 2.53 ng/ml). In 2022, the patient had a tumor resection from the left humerus with a consequent fracture. Pathology showed pure squamous carcinoma without any adenocarcinoma component (PSA and NKX3.1 stains negative and weak p504s stain, PSA 19.82 ng/ml). Given the patient's history of metastatic prostate adenocarcinoma and no history of any other malignancies, a diagnosis of squamous carcinoma transformed from prostate adenocarcinoma was rendered. The patient passed away in 2023. Molecular profiling identified the same TP53 mutation and two variants of uncertain significance in both specimens, suggesting the same primary. However, there was CCND3 amplification and absence of the TMPRSS2::ETV4 fusion in the 2022 specimen, which may be associated with squamous transformation and poor prognosis. A microarray might be beneficial to confirm loss of the TMPRSS2::ETV4 fusion. This case illustrates the rare occurrence of squamous transformation in prostate adenocarcinoma and the aggressive clinical course, and need for more therapy guidance and prognostic studies. It also highlights the importance of molecular profiling to provide insights into the pathogenesis of histologic transformation.

Targeted biopsy added to systematic biopsy improves cancer detection in prostate cancer screening.

BACKGROUND: Magnetic resonance imaging (MRI)/ultrasound targeted biopsy has frequently been used together with a 12-core systematic biopsy for prostate cancer screening in the past few years. However, the efficacy of targeted biopsy compared to systematic biopsy, as well as its clinical-histologic correlation, has been assessed by a limited number of studies and is further investigated in this study. DESIGN: We collected 960 cases with both targeted and systematic prostate biopsies from 04/2019 to 04/2022 (Table 1). We compared cancer detection rates between targeted and systematic prostate biopsies in different grade groups. Correlations with the size of prostate lesions, prostate-specific antigen (PSA) level, and Prostate Imaging-Reporting and Data System (PI-RADS) scale were also analyzed for each of these biopsy methods. RESULTS: Among the 960 men who underwent targeted biopsy with systematic biopsy, prostatic adenocarcinoma was diagnosed in 652 (67.9%) cases. 489 (50.9%) cases were diagnosed by targeted biopsy and 576 (60.0%) cases were diagnosed by systematic biopsy. In the 384 cases diagnosed negative by systematic biopsy, targeted biopsy identified cancer in 76 (8%) cases. Systematic biopsy was able to detect 163 cancer cases that were missed by targeted biopsy. Systematic biopsy detected more grade group 1 cancers compared to targeted biopsy. However, for higher grade cancers, the differences between the cancer detection rates of targeted biopsy and systematic biopsy became negligible. Targeted biopsy upgraded the grade group categorized by systematic biopsy in several cases (3.8%, 7.0%, 2.6%, 1.1% and 0.9% in Grade Groups 1, 2, 3, 4, and 5 respectively). Targeted biopsy was more likely to detect cancer in larger lesions (13.17 mm VS 11.41 mm, P=0.0056) and for higher PI-RADS scales (4.19 VS 3.68, P<0.0001). The cancers detected by targeted biopsy also had higher PSA levels (10.38 ng/ml VS 6.39 ng/ml, P=0.0026). CONCLUSION: Targeted biopsy with systematic biopsy improved cancer detection rate compared to systematic biopsy alone. Targeted biopsy is not more sensitive for grade groups 1, 4, or 5 cancers but is as sensitive as systematic biopsy for detecting grade group 2 and 3 cancers. Targeted biopsy is more effective at detecting cancers when patients have larger lesions, higher PI-RADS scales, and higher PSA levels.

Expression and clinicopathologic significance of HER2 and PD-L1 in high grade urothelial carcinoma of the urinary tract.

BACKGROUND: Urothelial carcinoma (UC) is an aggressive tumor with high recurrence rates and poses a great challenge for clinical management. Programmed death ligand-1 (PD-L1) inhibitors and human epidermal growth factor receptor 2 (HER2) blockers have been approved for the treatment of advanced urothelial carcinoma. PD-L1 and HER2 expression in UC will determine whether patients are likely to respond to these targeted treatments. This study assessed the expressions of HER2 and PD-L1 in UC at our institution and investigated their correlations with gender, tumor location (upper genitourinary (GU) tract vs. lower GU tract), tumor stage, and histologic divergent subtypes. DESIGN: Patients with UC who had PD-L1 or HER2 immunostains performed in the past 3 years at our institution were included in our analysis. A total of 97 cases were identified. PD-L1 and HER2 scores were provided by two experienced GU pathologists. HER2 scores were given according to the criteria used in breast cancer, while PD-L1 scores were reported as the combined positive score. We assessed correlation of the scores with the patients' gender, tumor location, tumor stage, and histologic divergent subtypes. The data for PD-L1 expression were analyzed using the Mann-Whitney U Test for gender and urinary tract location, and one-way analysis of variance (ANOVA) for stage and histology. The data for HER2 expression were analyzed using the chi-square test. For all analyses, significance was set at P<0.05. RESULTS: Of the 97 patients, the average age was 69 years. There were 95 patients who had previously reported HER2 results and 86 patients who had PD-L1 results. PD-L1 expression did not show a significant difference among the histological divergent subtypes (P=0.36). However, HER2 status exhibited a significant difference, with more HER2-positive cases observed in the conventional histology (P=0.008). No correlation between HER2 status and either gender or tumor stage was identified. The median PD-L1 combined positive score was significantly higher in lower urinary tract UC than upper (10 and 2, respectively; P=0.049). No significant differences were observed for gender or pathologic stage. CONCLUSION: Our data suggest that HER2 is more frequently expressed in conventional UC than in divergent subtypes. Additionally, PD-L1 has a higher expression level in lower urinary tract UC compared to upper. However, PD-L1 and HER2 expression are not related to gender or tumor stage in UC.

Melanotic medullary thyroid carcinoma: A case report with review of the literature.

Melanotic medullary thyroid carcinoma is morphologically defined by the presence of melanin deposits in the cytoplasm of tumor cells. It is an extremely rare variant with only 15 cases described in the literature to date and only one report of diagnosis by fine needle aspiration (FNA) biopsy. A 51-year-old woman presented with neck swelling. An ultrasound examination revealed a single solid nodule in the right thyroid lobe that measured 5.4 × 4.7 × 4.3 cm. Laboratory examination revealed elevated levels of serum calcitonin (8643.0 pg/ml), carcinoembryonic antigen (CEA) (86.2 ng/ml), and chromogranin A (123.2 ng/ml). An FNA biopsy of the thyroid nodule revealed predominantly single plasmacytoid cells with round to oval eccentric nuclei and dark brown intracytoplasmic granules. Immunohistochemical studies with Melan-A performed on a cell block slide confirmed that the granules contained melanin. The tumor cells were also positive for calcitonin, CEA, synaptophysin, AE1/AE3, CAM5.2, and HMB-45(focal); the tumor cells were negative for chromogranin, thyroglobulin, PAX8 and TTF-1. The diagnosis was reported as melanotic variant of medullary thyroid carcinoma. The patient underwent a total thyroidectomy which revealed tumor cell expression of insulinoma-associated protein 1 and confirmed neuroendocrine differentiation. Shortly after she presented with tumor recurrence in the thyroidectomy bed. The tumor cells were positive for only S100, SOX10, and Melan-A. Molecular analysis with the SEMA4 Solid Tumor Panel revealed mutations in the HRAS, PIK3CA, PIK3R1, MYC, and CCND3 genes. The final diagnosis was reported as melanocytic medullary thyroid carcinoma with high grade transformation and loss of epithelial and neuroendocrine expression.

Primary renal glomus tumor with concurrent papillary renal cell carcinoma and multiple papillary adenomas in a patient with end stage renal disease: a case report and clinicopathologic analysis.

Glomus tumors are mesenchymal tumors commonly seen in the extremities, and rarely seen in deep visceral organs. This is due to the lack of glomus bodies in visceral organs. Here, we describe an unusual association between glomus tumor and co-existing papillary renal cell carcinoma, multiple papillary adenomas, and end stage renal disease. We discuss our diagnostic approach and differential diagnoses, along with an extensive review of all reported benign and malignant primary glomus tumors. A 63-year-old male with a known history of a kidney transplant, end-stage renal disease, and previous nephrectomy of his right kidney due to a renal mass (papillary renal cell carcinoma) presented with a renal mass. Microscopic examination showed papillary carcinoma, multiple papillary adenomas, and a small nodule with uniform, round to oval cells. Immunohistochemical work-up revealed the small nodule to be a glomus tumor. Only 28 cases of primary renal glomus tumors have been reported in the literature. Most were discovered incidentally. None of the reported cases have occurred along with other renal tumors. This is the first case of the unusual combination of primary renal glomus tumor arising in the native kidney of a renal transplant patient with concurrent papillary renal cell carcinoma and multiple papillary adenomas (renal adenomatosis). We also explore the possible genetic basis behind this association.

Primary hemangioblastoma of the kidney with molecular analyses by next generation sequencing: a case report and review of the literature.

BACKGROUND: Hemangioblastoma is an indolent mesenchymal tumor most frequently occurring in the central nervous system (CNS), but can also arise extraneuraxially, as part of Von Hippel-Lindau (VHL) disease or in sporadic tumors. Extraneuraxial hemangioblastomas occur outside the central nervous system. It includes tumors arising from the nervous paraneuraxial structures and visceral organs. Sporadic hemangioblastoma of the kidney, a rare subset of extraneuraxial hemangioblastomas, is an under-recognized renal neoplasm. There have been only 25 cases described to date in the English language literature. We report herein one additional sporadic tumor in a patient without VHL disease. CASE PRESENTATION: A 61 year old male presenting with gross hematuria was found to have a 3.5 cm renal mass at the lateral mid to lower pole of the left kidney on computed tomography urogram. The patient underwent a partial nephrectomy for the mass. Pathological examination showed a well-circumscribed non-encapsulated tumor composed of sheets of large polygonal cells traversed by a rich vascular network. The tumor cells showed clear to eosinophilic cytoplasm and overall bland nuclei. The diagnosis of hemangioblastoma was confirmed by positive immunostaining for alpha-inhibin, S100, neuron-specific enolase, and PAX8. No significant gene mutations, including VHL gene and copy number changes were detected in the tumor using next generation sequencing supporting the diagnosis of sporadic renal hemangioblastoma. CONCLUSION: Sporadic renal hemangioblastoma is a rare subset of extraneuraxial hemangioblastomas. We report one such tumor in a patient without clinical or molecular evidence of VHL disease. The literature was reviewed to better understand the clinical, radiological, pathological, and molecular features of this neoplasm. The majority of renal hemangioblastomas showed positive immunostaining for PAX8, which supports the idea that the immunoprofiles of extraneuraxial hemangioblastomas can vary depending on sites of origin. Diagnosis of renal hemangioblastoma is challenging because of its rarity and overlapping microscopic and immunophenotypic features with other renal tumors, including clear cell renal cell carcinoma. In some cases, molecular or genetic studies may be necessary to obtain an accurate diagnosis. Since renal hemangioblastoma is clinically benign, recognition of this pathological entity is important to avoid unnecessary over-treatment.

A comparative study of the genotype profiles of high-risk human papillomavirus infection in male and female HIV-positive patients and their correlation with anal cytology and biopsy.

INTRODUCTION: Although anal cancer is more common in women, most of the studies on the role of high-risk human papillomavirus (hrHPV) infection in anal squamous lesions have focused on high-risk male patients. Therefore, we compared the genotype profile and clinicopathologic correlation of hrHPV infection in human immunodeficiency virus-positive (HIV+) men and women. MATERIALS AND METHODS: We retrospectively analyzed 2254 HIV+ patients (1931 men and 323 women) who had undergone anal Papanicolaou tests at our institution; 1189 of them also had follow-up biopsy data available. HPV genotyping was performed using the Roche Cobas system and correlated with the cytologic and histologic diagnosis. RESULTS: Compared with the HIV+ men, the HIV+ women had a significantly lower rate of hrHPV infection (67.5% versus 78.5%; P < 0.0001) but a significantly higher rate of high-grade squamous intraepithelial lesions (HSILs) on anal Papanicolaou tests (4.6% versus 2.5%; P < 0.05). Other high-risk HPV (ohrHPV), as a group, is much more common than HPV16 or HPV18 in both genders. HIV+ women had significantly lower HPV16 and ohrHPV infection rates than did HIV+ men. However, the HPV18 infection rates were similar between HIV+ women and HIV+ men. For both genders, the rates of HSILs or high-grade anal intraepithelial neoplasia (AIN2-3) were significantly increased when coinfection of ohrHPV with either HPV16 or HPV18 was present. CONCLUSIONS: Although both HIV+ men and HIV+ women have an increased risk of hrHPV infection, HIV+ women have different hrHPV genotype profiles and higher rates of high-grade lesions. Coinfection with different genotypes of hrHPV can significantly increase the risk of HSILs or AIN2-3 in both genders and could requires vigilant clinical and laboratory follow-up.

An accessible, efficient, and accurate natural language processing method for extracting diagnostic data from pathology reports.

Context: Analysis of diagnostic information in pathology reports for the purposes of clinical or translational research and quality assessment/control often requires manual data extraction, which can be laborious, time-consuming, and subject to mistakes. Objective: We sought to develop, employ, and evaluate a simple, dictionary- and rule-based natural language processing (NLP) algorithm for generating searchable information on various types of parameters from diverse surgical pathology reports. Design: Data were exported from the pathology laboratory information system (LIS) into extensible markup language (XML) documents, which were parsed by NLP-based Python code into desired data points and delivered to Excel spreadsheets. Accuracy and efficiency were compared to a manual data extraction method with concordance measured by Cohen's κ coefficient and corresponding P values. Results: The automated method was highly concordant (90%-100%, P<.001) with excellent inter-observer reliability (Cohen's κ: 0.86-1.0) compared to the manual method in 3 clinicopathological research scenarios, including squamous dysplasia presence and grade in anal biopsies, epithelial dysplasia grade and location in colonoscopic surveillance biopsies, and adenocarcinoma grade and amount in prostate core biopsies. Significantly, the automated method was 24-39 times faster and inherently contained links for each diagnosis to additional variables such as patient age, location, etc., which would require additional manual processing time. Conclusions: A simple, flexible, and scaleable NLP-based platform can be used to correctly, safely, and quickly extract and deliver linked data from pathology reports into searchable spreadsheets for clinical and research purposes.

Urothelial carcinoma of the graft kidney with molecular analyses: a rare case report.

BACKGROUND: Malignancy after transplantation is a leading cause of death among kidney transplant recipients. However, donor-derived malignancies are rare. We report a case of a high grade papillary urothelial carcinoma arising in a transplanted kidney. CASE PRESENTATION: A 62-year-old female who received a kidney transplantation more than 30 years ago presented with urinary tract infection, acute renal failure, and hydronephrosis of the transplant kidney. Anterograde nephrostogram showed a large filling defect in the lower pole of the transplant kidney and in the proximal 3-4 cm of the ureter. A biopsy from the renal pelvic mass showed a high grade urothelial carcinoma. She underwent an anterior exenteration, resection of both transplant and native kidneys and bilateral pelvic lymph node dissection. Pathologic examination showed a high grade papillary urothelial carcinoma which appeared to arise in the pelvis of the graft kidney, involve the graft ureter and native urinary bladder. The tumor had metastasized to one left obturator lymph node but spared the two native kidneys and ureters. Short tandem repeat (STR) analysis confirmed the tumor to be of donor origin. Next-generation sequencing identified amplification of TERT and loss of CDKN2A/CDKN2B in the primary tumor. CONCLUSION: While it is known that transplant recipients have an increased risk of urothelial carcinoma compared to the general population, the lack of the well-documented risk factors, such as older age at transplantation, BK polyomavirus infection, and prolonged post-transplantation history and dissemination of the tumor in this case shed light on the de novo tumorigenesis of the graft kidney within the host microenvironment. Amplification of Telomerase reverse transcriptase (TERT) and loss of cyclin dependent kinase inhibitor 2A/2B (CDKN2A/CDKN2B) detected in the tumor by next gene sequencing suggests that they may play an important role in this case.

Liquid phase human papillomavirus genotype analysis of aspirated metastatic head and neck squamous cell carcinoma: Fine needle aspiration supernatant is a rich source of tumor DNA that can increase the diagnostic yield.

BACKGROUND: Most patients with human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSC) present with lymph node metastasis. In these patients, fine needle aspiration (FNA) is not only a diagnostic tool, but a means for determining HPV status. HPV status, in turn, is used to determine tumor origin, prognosis, and even guide therapy. Thus, the limited sampling afforded by FNA must be optimized to meet heavy clinical demands. PURPOSE: The purpose of this study was to determine whether the residual supernatant portion of the FNA could serve as a resource for reliable determination of HPV status DESIGN/METHOD: 25 FNAs from 24 patients with metastatic HNSC underwent HPV genotyping of post-centrifuged supernatant fluid from FNA needle rinses. HPV genotyping was performed using two real time PCR-based assays, the two-step LightCycler and the one-step automated cobas HPV tests. HPV status of the supernatant was compared with the paired FNA cell blocks and/or surgical tissue samples. RESULTS: The supernatant was adequate for HPV testing in 24 (96%) of 25 cases. Of these, 14 (56%) were HPV positive and 11 (44%) negative by the LightCycler assay. HPV16 was the most commonly detected genotype (n = 12). When results of supernatant and paired cell block testing were compared, HPV status was concordant in all cases. The LightCycler method was more sensitive than the cobas assay due to its ability to detect an expanded profile of HPV variant genotypes. CONCLUSION: The current standard of practice for patients with HNSC who undergo FNA is to construct a cell block and then discard the supernatant. This supernatant is a rich source of tumor DNA that can be used to detect HPV status. It should not be wasted.

Modulation of astrocyte proliferation by HIV-1: differential effects in productively infected, uninfected, and Nef-expressing cells.

Although quiescent in normal brain, reactive astrocytes can proliferate in various disorders. We examined the impact of HIV-1 on astrocyte proliferation in cultures exposed to VSVg env-pseudotyped HIV-1 which yields high levels of infection. HIV-1, while increasing the proliferation of uninfected (p24-) astrocytes, strongly inhibited proliferation of productively infected (p24+) cells. The cell cycle arrest was G1/S rather than G2/M, a type commonly attributed to Vpr. No clear role of Vpr or Nef could be identified. Adenovirus-mediated expression of Nef (a model of "restricted" infection) induced M-phase arrest of astrocytes. We speculate that HIV-1 is a significant modulator of astrocyte proliferation in vivo.

Fine-needle aspiration of small pulmonary nodules yields material for reliable molecular analysis of adenocarcinomas.

INTRODUCTION: Early molecular characterization with Kirsten rat sarcoma factor, epidermal growth factor, and anaplastic lymphoma kinase are critical to manage pulmonary adenocarcinoma. Fine-needle aspiration (FNA) of lesions <2 cm are routine in our institution and are used in molecular analysis. We report our experience. MATERIALS AND METHODS: We searched our databank for primary pulmonary adenocarcinomas diagnosed by FNA between January 2009 and April 2013. Size of the lesion aspirated, molecular results, and sample source (FNA versus surgical specimen) were recorded. We compared the frequency of mutations identified by FNA versus surgical specimens and the frequency of mutations in lesions by size (<1 cm, 1-2 cm, >2 cm). RESULTS: We identified 397 primary pulmonary adenocarcinomas. Molecular studies were requested by the clinician in 89 (22%) of primary adenocarcinomas. FNAs were used in 55 cases; 51 (93%) yielded sufficient material for molecular studies; surgical tissue were used in 34 cases; 33 (97%) yielded sufficient material for molecular studies. The insufficient specimens came from 2 FNAs of 0.6 cm nodules, an FNA of a 2 cm nodule, and a core biopsy. CONCLUSIONS: FNA was adequate for molecular analysis of small nodules. In nodules greater than 0.6 cm, the adequacy is comparable to surgical tissue. There was no statistically significant change in mutation rate by size (53%-58%). Importantly, FNA of small lesions for cytological diagnosis and molecular analysis is encouraged by our data and experience in order to provide early treatment.

Radiographic Thrombus within the External Jugular Vein: Report of a Rare Case and Review of the Literature.

We are reporting a case of a 91-year-old male with a primary malignancy of the right parotid gland with radiographic thrombus extension within the right external jugular vein. He was treated with palliative radiation therapy to the right parotid mass with a marked clinical response. The rarity of this occurrence as documented in the review of the literature provides for uncertainty with regard to proper management. Radiographic evidence of thrombus in the absence of clinical manifestations, the role of anticoagulation, and the proper radiation target delineation were all challenges encountered in the care of this patient. Our case represents a rare occurrence with unique radiologic findings that has implications for management.

Prior high-risk human papillomavirus testing and Papanicolaou test results of 70 invasive cervical carcinomas diagnosed in 2012: results of a retrospective multicenter study.

CONTEXT: Persistent high-risk human papillomavirus (hrHPV) infection is essential for the development of cervical cancer and its precursor lesions. High-risk HPV testing has a higher sensitivity than cytology does for detecting cervical epithelial lesions. However, a large study from a single institution showed 31% of patients with invasive cervical cancer had negative baseline hrHPV testing within 5 years preceding the diagnosis. OBJECTIVE: To investigate the limitation of hrHPV testing in detecting invasive cervical cancer. DESIGN: Cases from 2012 with a histologic diagnosis of invasive cervical carcinoma were retrieved from multiple institutions. From those records, prior hrHPV testing and Papanicolaou test results in the 5 years before the cancer diagnosis were recorded. RESULTS: Seventy patients with cervical carcinoma were included in the study. Negative HPV test result rates were 9% (5 of 53), 23% (6 of 26), and 25% (2 of 8) during the periods of less than 1 year, 1 to 3 years, and 3 to 5 years before the histologic diagnoses, respectively. Negative Papanicolaou testing results in the same time intervals were 3.4% (2 of 59), 33% (10 of 30), and 40% (6 of 15). Although the HPV(-) rate seemed to be different among different HPV test methods, no statistical significance was detected because of small sample size. Negative hrHPV rates in patients with adenocarcinoma were similar to those in patients with squamous cell carcinoma. CONCLUSIONS: These data expose limitations for the potential use of primary HPV testing. In addition, current screening guidelines recommending cotesting at 5-year intervals should be evaluated further with additional historic data collection because there are women with negative results for both Papanicolaou tests and hrHPV testing within the period of 3 to 5 years before an invasive carcinoma diagnosis.

Human brain parenchymal microglia express CD14 and CD45 and are productively infected by HIV-1 in HIV-1 encephalitis.

Microglia are endogenous brain macrophages that show distinct phenotypes such as expression of myeloid antigens, ramified morphology, and presence within the neural parenchyma. They play significant roles in a number of human CNS diseases including AIDS dementia. Together with monocyte-derived (perivascular) macrophages, microglia represent a major target of HIV-1 infection. However, a recent report challenged this notion based on findings in SIV encephalitis. This study concluded that perivascular macrophages can be distinguished from parenchymal microglial cells by their expression of CD14 and CD45, and that macrophages, but not microglia, are productively infected in SIV and HIV encephalitis. To address whether parenchymal microglia are productively infected in HIV encephalitis, we analyzed expression of CD14, CD45 and HIV-1 p24 in human brain. Microglia were identified based on their characteristic ramified morphology and location in the neural parenchyma. We found that parenchymal microglia are CD14+ (activated), CD45+ (resting and activated), and constitute approximately two thirds of the p24+ cells in HIV encephalitis cases. These results demonstrate that microglia are major targets of infection by HIV-1, and delineate possible differences between HIVE and SIVE. Because productively infected tissue macrophages serve as the major viral reservoir, these findings have important implications for AIDS.

Small cell carcinoma of the kidney: a clinicopathologic study of 14 cases.

Small cell carcinoma of the kidney is distinctively rare. We searched pathology files in 2 institutions and found 14 cases of renal small cell carcinoma. The patients' mean age at diagnosis was 59 years (range, 22-75 years); 8 were women, and 6 were men. Patients usually presented with hematuria (n = 6) and abdominal pain (n = 5). The mean tumor size was 7.1 cm (range, 3.5-14.0 cm). The small cell carcinoma was pure in 9 cases and mixed with high-grade urothelial carcinoma in 5 cases. None was associated with any type of renal cell carcinoma. Tumor necrosis was present in all cases, and lymphovascular invasion was identified in 6 cases. The tumor invaded the perinephric adipose tissue in 13 cases and was confined to the kidney in only 1 case. Lymph node metastases were identified in all patients who underwent lymph node dissection (5/5). On immunostains, the small cell carcinoma cells were positive for pancytokeratin (11/12), chromogranin (6/9), and synaptophysin (8/9). Follow-up data were available for 13 patients, and 11 died of small cell carcinoma at a mean of 15 months (range, 4-31 months) after diagnosis. Of the 2 surviving patients, 1 was alive at 5 months after diagnosis, and the other, whose disease was confined to the kidney, was alive with no evidence of disease at 137 months. In summary, renal small cell carcinoma is a highly aggressive disease that often presents at an advanced stage with widespread metastases. Patients usually have a poor clinical outcome despite multimodal therapy. The frequent coexistence of small cell carcinoma with urothelial carcinoma suggests that renal small cell carcinomas may evolve from a preexisting urothelial carcinoma.

Diabetic downregulation of Nrf2 activity via ERK contributes to oxidative stress-induced insulin resistance in cardiac cells in vitro and in vivo.

OBJECTIVE: Oxidative stress is implicated in cardiac insulin resistance, a critical risk factor for cardiac failure, but the direct evidence remains missing. This study explored a causal link between oxidative stress and insulin resistance with a focus on a regulatory role of redox sensitive transcription factor NF-E2-related factor 2 (Nrf2) in the cardiac cells in vitro and in vivo. RESEARCH DESIGN AND METHODS: Chronic treatment of HL-1 adult cardiomyocyte with hydrogen peroxide led to insulin resistance, reflected by a significant suppression of the insulin-induced glucose uptake. This was associated with an exaggerated phosphorylation of extracellular signal-related kinase (ERK). Although U0126, an ERK inhibitor, enhanced insulin sensitivity and attenuated oxidative stress-induced insulin resistance, LY294002, an inhibitor of phosphoinositide 3-kinase (PI3K), worsened the insulin resistance. Moreover, insulin increased Nrf2 transcriptional activity, which was blocked by LY294002 but enhanced by U0126. Forced activation of Nrf2 by adenoviral over-expression of Nrf2 inhibited the increased ERK activity and recovered the blunted insulin sensitivity on glucose uptake in cardiomyocytes that were chronically treated with H(2)O(2). In the hearts of streptozotocin-induced diabetic mice and diabetic patients Nrf2 expression significantly decreased along with significant increases in 3-nitrotyrosine accumulation and ERK phosphorylation, whereas these pathogenic changes were not observed in the heart of diabetic mice with cardiac-specific overexpression of a potent antioxidant metallothionein. Upregulation of Nrf2 by its activator, Dh404, in cardiomyocytes in vitro and in vivo prevented hydrogen peroxide- and diabetes-induced ERK activation and insulin-signaling downregulation. CONCLUSIONS: ERK-mediated suppression of Nrf2 activity leads to the oxidative stress-induced insulin resistance in adult cardiomyocytes and downregulated glucose utilization in the diabetic heart.

Inhibiting the function of ABCB1 and ABCG2 by the EGFR tyrosine kinase inhibitor AG1478.

The tyrphostin 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) is a potent and specific EGFR tyrosine kinase inhibitor (TKI); its promising pre-clinical results have led to clinical trials. Overexpression of ATP-binding cassette (ABC) transporters such as ABCB1, ABCC1 and ABCG2 is one of the main causes of multidrug resistance (MDR) and usually results in the failure of cancer chemotherapy. However, the interaction of AG1478 with these ABC transporters is still unclear. In the present study, we have investigated this interaction and found that AG1478 has differential effects on these transporters. In ABCB1-overexpressing cells, non-toxic doses of AG1478 were found to partially inhibit resistance to ABCB1 substrate anticancer drugs as well as increase intracellular accumulation of [3H]-paclitaxel. Similarly, in ABCG2-overexpressing cells, AG1478 significantly reversed resistance to ABCG2 substrate anticancer drugs and increased intracellular accumulation of [3H]-mitoxantrone as well as fluorescent compound BODIPY-prazosin. AG1478 also profoundly inhibited the transport of [3H]-E(2)17betaG and [3H]-methotrexate by ABCG2. We also found that AG1478 slightly stimulated ABCB1 ATPase activity and significantly stimulated ABCG2 ATPase activity. Interestingly, AG1478 did not inhibit the photolabeling of ABCB1 or ABCG2 with [125I]-iodoarylazidoprazosin. Additionally, AG1478 did not alter the sensitivity of parental, ABCB1- or ABCG2-overexpressing cells to non-ABCB1 and non-ABCG2 substrate drug and had no effect on the function of ABCC1. Overall, we conclude that AG1478 is able to inhibit the function of ABCB1 and ABCG2, with a more pronounced effect on ABCG2. Our findings provide valuable contributions to the development of safer and more effective EGFR TKIs for use as anticancer agents in the clinic.