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Biomedical subjects

Mark H Stoler

Publications and source records attributed to Mark H Stoler.

At least 19 recordsLinked to original sources
PubMed2006

Description of patients with squamous cell carcinoma in the atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion triage study.

BACKGROUND: The Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS) accumulated information regarding conventional and liquid-based Papanicolaou (Pap) cytology, 2 kinds of human papillomavirus (HPV) DNA testing, cervicography, and colposcopically directed biopsy. The prevalence of squamous cell carcinoma in these women, the efficacy of tests, and the time to detection were reviewed. METHODS: The ALTS data base was reviewed for all women with invasive carcinoma. All results of colposcopy, HPV testing, cytology, biopsies, and cervigrams were reviewed for all women in the ALTS trial who were diagnosed with squamous cell carcinoma. RESULTS: There were 7 diagnoses of invasive cancer (all squamous cell) during the 2 years of the ALTS trial. Although the enrollment studies isolated many high-grade lesions, none of those results were diagnostic of the underlying carcinoma. CONCLUSIONS: The prevalence of squamous cell carcinoma in the setting of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion cytology interpretation appears to be low (approximately 1 per 1000 women in the ALTS trial). Many of the carcinomas were not visible on the ectocervix by cervicography or colposcopy, which may explain in part the paucity of atypical cells detected on the Pap tests and the finding that the presenting cytology, although abnormal, was never diagnostic of cancer. HPV DNA tests were positive in all 7 cancers. Type-specific testing identified HPV type 16 in 6 of 7 cancers and HPV type 18 in 1 of 7 cancers.

Adult↗
PubMed2006

Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18.

Human papillomavirus (HPV) infection causes cervical cancer and genital warts. Young women (1106) were randomized to receive one of three formulations of a quadrivalent HPV (Types 6/11/16/18) L1 virus-like particle (VLP) vaccine or one of two placebo formulations. The goal was to assess vaccine safety and immunogenicity in baseline HPV 6/11/16 or 18-naïve and previously infected subjects. All three formulations were highly immunogenic. At Month 2 (postdose 1), among women with vaccine-type antibodies at baseline, vaccine-induced anti-HPV responses were approximately 12- to 26-fold higher than those observed in baseline-naïve women, suggesting an anamnestic response. Following an initial, similar sized decline, anti-HPV responses plateaued and remained stable through end-of-study (3.0 years). No vaccine-related serious adverse experiences were reported.

Adolescent↗
PubMed2006

cis-requirement for the maintenance of round spermatid-specific transcription.

Maintenance of strict developmental stage- and cell type-specific gene expression is critical for the progression of spermatogenesis. However, the mechanisms which sustain the spatiotemporal order of gene transcription within the seminiferous epithelium are poorly understood. Previous work has established that the proximal promoter of the mouse SP-10 gene was sufficient to maintain round spermatid-specific expression (Reddi, P.P., Shore, A.N., Shapiro, J.A., Anderson, A., Stoler, M.H., Acharya, K.K., 2003b. Spermatid-specific promoter of the SP-10 gene functions as an insulator in somatic cells. Dev. Biol. 262, 173-182). The present study addressed the cis-requirement for this regulation and sought to identify the cognate transcription factor(s). We found that mutation of two 5'-ACACAC motifs (at -172 and -160) within the -186/+28 SP-10 promoter led to premature and indiscriminate expression of a reporter gene in the seminiferous epithelium of transgenic mice, whereas the wild-type -186/+28 promoter retained spermatid specificity. Neither promoter showed ectopic expression in the somatic tissues. Expression cloning using the -186/-148 portion of the promoter yielded transcriptional repressors TDP-43 and Puralpha of which TDP-43 required the complementary 5'-GTGTGT elements located on the opposite strand for binding in vitro. Further, Northern analysis and immunohistochemistry of mouse testis showed the presence of TDP-43 in cell-types where the SP-10 gene remains repressed. Taken together, our results demonstrate that 5'-GTGTGT motifs on the complementary strand are required to prevent premature expression of SP-10 during spermatogenesis and implicate TDP-43 as the putative regulatory factor. The study also implied that additional level(s) of regulation keep the SP-10 gene silent in the somatic tissues.

Amino Acid Motifs↗
PubMed2006

Biologic targets for therapeutic intervention in endometrioid endometrial adenocarcinoma and malignant mixed müllerian tumors.

OBJECTIVE: The purpose of this study was to investigate the AKT signaling cascade in endometrial cancers and to assess its therapeutic potential. STUDY DESIGN: Western blotting and immunohistochemistry were used to investigate the expression of estrogen receptor, progesterone receptor, HER2, AKT, and 4EBP1 proteins in 27 atrophic endometria, 31 grade 1 and 24 grade 3 endometrioid endometrial cancers, and 19 malignant mixed müllerian tumors. Inhibition of the AKT signaling cascade was investigated in cell lines. RESULTS: Malignant mixed müllerian tumors and grade 3 endometrioid endometrial cancers demonstrated higher levels of AKT and 4EBP1 activation and hormone receptor loss compared with grade 1 endometrioid endometrial cancers and atrophic samples. HER2 over-expression was identified most often in grade 3 tumors without gene amplification. In endometrial cancer cell-lines, AKT cascade inhibitors decreased cell proliferation by apoptosis and cell cycle arrest. CONCLUSION: AKT cascade activation in grade 3 endometrioid endometrial cancers and malignant mixed müllerian tumors is a novel finding. Apoptosis and growth arrest that results from AKT inhibition expose opportunities for therapeutic intervention.

Carcinoma, Endometrioid↗
PubMed2006

The distribution of low and high-risk HPV types in vulvar and vaginal intraepithelial neoplasia (VIN and VaIN).

It has been proposed that low-grade vulvar and vaginal lesions (VIN 1 and VaIN 1) are flat condylomas and should be designated as such. Moreover, their relationship to high-grade lesions (VIN 3 and VaIN 3) is unclear. Accordingly, this study was undertaken to address these issues by comparing the distribution of human papillomavirus (HPV) types in vulvar and vaginal intraepithelial lesions. We identified 33 cases of VIN 1, 34 cases of VIN 3, 17 cases of VaIN 1, and 16 cases of VaIN 3. In addition, 36 cases of low-grade squamous intraepithelial lesion (LSIL) in the cervix and 116 cases of cervical high-grade squamous intraepithelial lesion were used for comparison. Polymerase chain reaction analysis was performed using both the Roche PGMY and DDL SPF 10 systems. In cases where HPV was detected, the majority of low-grade and high-grade lesions contained a single HPV type. However, a minority of cases were found to have multiple HPV types. Of the VIN 1 cases, a low-risk virus was seen in 22 (67%), with HPV 6 or 11 accounting for 14 (42%). A high-risk virus was detected in 14 (42%) of cases of which 2 (6%) contained HPV 16. Of the VIN 3 cases, all had high-risk HPV of which 31 (91%) were found to have HPV 16. Of the VaIN 1 cases, 6 (35%) were found to have low-risk HPV types. HPV 6 or 11 were not found in these cases. High-risk virus was seen in 13 (76%) VaIN 1 cases, with 1 (6%) containing HPV 16. HPV was detected in 15 of 16 (94%) VaIN 3 lesions, all of which had high-risk types. HPV 16 was found in 8 (50%). In contrast, 2 (6%) of cervical LSIL had low-risk HPV (HPV 6 and 11), whereas 34 (94%) of LSIL cases had high-risk HPVs. Of the cervical high-grade squamous intraepithelial lesion cases, 100% had high-risk HPVs of which 87 (75%) were found to have HPV 16. The findings demonstrate that a significant number of low-grade vulvar and vaginal lesions contain high-risk HPV types, supporting their designation as low-grade intraepithelial lesions rather than flat condylomas. The low frequency of HPV 16 in VIN 1 compared with VIN 3 suggests they are distinct lesions or that HPV 16 is critical in the progression to VIN 3. Finally, comparison of the distribution of HPV in the vagina and vulva suggests that VaIN is more closely related to cervical intraepithelial neoplasia than to VIN.

Carcinoma in Situ↗
PubMed2005

The utility of calretinin, inhibin, and WT1 immunohistochemical staining in the differential diagnosis of ovarian tumors.

Calretinin has been proposed as a novel marker of ovarian sex cord-stromal tumors (SCST); this study aims to determine whether calretinin can complement or supplant the established utility of inhibin in the differential diagnosis of SCST. WT1 has been shown to be expressed in ovarian serous, but not mucinous neoplasms; its expression in a variety of ovarian tumors is also examined. Formalin-fixed, paraffin-embedded archival tissues from 111 primary ovarian tumors were analyzed with commercially available antibodies using semi-automated immunohistochemistry. Results were graded on a 4-tiered scale with staining of more than 0 but less than 5% of cells considered focal. Of 27 SCST, 56% were calretinin and 56% inhibin positive overall; 90% of granulosa cell tumors, 57% of Sertoli-Leydig cell tumors, 33% of thecomas, and 14% of fibromas were calretinin positive. Inhibin was expressed in 60% of granulosa cell tumors, 71% of Sertoli-Leydig cell tumors, 43% of fibromas, and 33% of thecomas. Of 35 surface epithelial tumors (SET), 8% of serous papillary tumors were calretinin positive, whereas 8% of serous papillary tumors and 13% of poorly differentiated carcinomas expressed inhibin. WT1 was expressed in 29% of all endometrioid carcinomas, 10% of borderline mucinous tumors, and no mucinous carcinomas; however, most of the other SETs were positive (77% serous papillary and 88% poorly differentiated carcinomas). Among the SCST, WT1 stained only granulosa cell tumors (75%), though often weakly or variably. Calretinin has only slightly greater sensitivity (76% versus 65%) and equal specificity to inhibin (92%) in the differential staining of granulosa or Sertoli-Leydig cell tumors, that is, nonstromal SCST. Hence, calretinin cannot replace but could complement inhibin as part of an immunohistochemical panel used for diagnostically challenging SCST. Although WT1 should be reliably positive in non-mucinous SET, staining of granulosa cell tumors and lack of expression in a sizable subset of endometrioid carcinomas may confound interpretation.

Adenocarcinoma↗
PubMed2005

Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial.

BACKGROUND: A randomised double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus (HPV) types associated with 70% of cervical cancers (types 16 and 18) and with 90% of genital warts (types 6 and 11). METHODS: 277 young women (mean age 20.2 years [SD 1.7]) were randomly assigned to quadrivalent HPV (20 microg type 6, 40 microg type 11, 40 microg type 16, and 20 microg type 18) L1 virus-like-particle (VLP) vaccine and 275 (mean age 20.0 years [1.7]) to one of two placebo preparations at day 1, month 2, and month 6. For 36 months, participants underwent regular gynaecological examinations, cervicovaginal sampling for HPV DNA, testing for serum antibodies to HPV, and Pap testing. The primary endpoint was the combined incidence of infection with HPV 6, 11, 16, or 18, or cervical or external genital disease (ie, persistent HPV infection, HPV detection at the last recorded visit, cervical intraepithelial neoplasia, cervical cancer, or external genital lesions caused by the HPV types in the vaccine). Main analyses were done per protocol. FINDINGS: Combined incidence of persistent infection or disease with HPV 6, 11, 16, or 18 fell by 90% (95% CI 71-97, p<0.0001) in those assigned vaccine compared with those assigned placebo. INTERPRETATION: A vaccine targeting HPV types 6, 11, 16, 18 could substantially reduce the acquisition of infection and clinical disease caused by common HPV types.

Adolescent↗
PubMed2004

Borderline ovarian tumors: diverse contemporary viewpoints on terminology and diagnostic criteria with illustrative images.

The National Cancer Institute sponsored a Borderline Ovarian Tumor Workshop held in August 2003 in Bethesda, MD. This report was developed from discussions at the Workshop. The participants acknowledged several areas of disagreement on basic terminology issues and agreed that a glossary with example images would help clarify many commonly misunderstood issues. This report defines terminology used in the pathological description of borderline tumors and their variants, and illustrates examples of each of the most common entities. It also addresses controversial aspects of the definitions and issues involving specimen handling and reporting. For those issues where there is disagreement, the terminology and diagnostic approaches reflecting the differing views are presented.

Cystadenocarcinoma↗
PubMed2004

Serous borderline (low malignant potential, atypical proliferative) ovarian tumors: workshop perspectives.

Although the category of serous borderline ovarian tumor (S-BOT) was established more than 30 years ago, the nomenclature and prognostic significance of various histological features of these neoplasms continues to engender controversy. The Borderline Ovarian Tumor Workshop was held in Bethesda, MD, in August 2003 in an attempt to examine the existing data, establish areas of agreement, and identify areas needing further investigation. This report addresses 6 areas of controversy regarding S-BOT: (1) tumors with and without a micropapillary architecture (typical vs micropapillary type), (2) peritoneal implants, (3) stromal microinvasion, (4) ovarian surface involvement, (5) lymph node involvement, and (6) recurrent tumors. Each of these issues is addressed by summarizing the data in the literature on which the discussions were based, areas of agreement that emerged, divergent opinions and the reasoning behind them, and the conclusions of the participants with recommended nomenclature.

Cystadenocarcinoma, Serous↗
PubMed2004

Kaposiform hemangioendothelioma: a study of 33 cases emphasizing its pathologic, immunophenotypic, and biologic uniqueness from juvenile hemangioma.

Kaposiform hemangioendothelioma (KH) is a rare tumor of childhood often associated with Kasabach-Merritt phenomenon (KMP) and occasionally lymphangiomatosis. Although generally considered distinct from other vascular neoplasms, its rarity has precluded a thorough study of its immunophenotypic profile and long-term behavior. Thirty-three cases of KH were reviewed and immunostained for alpha-smooth muscle actin, various endothelial markers (CD31, CD34, vWf, FLI1), a platelet marker (CD61), and the juvenile hemangioma-associated markers GLUT-1 and Lewis Y antigen (LeY). In addition, the presence of HHV-8 was evaluated by RT-PCR. The patients (20 males and 13 females) ranged in age from 2 weeks to 20 years (mean 3 years 9 months). Tumors developed on the extremities (17 cases), head/neck (8 cases), and other sites (8 cases) and affected both superficial and deep soft tissue. Those in the skin presented as slightly raised blue-red lesions. More than half of the patients presented with KMP (14 of 25). Tumors consisted of irregular, infiltrating nodules of compressed vessels, which modulated between areas resembling a capillary hemangioma and Kaposi sarcoma (KS). Endothelial cells in nodules were CD31, CD34, and FLI1 positive but negative for GLUT1 and LeY. Scattered "epithelioid" or glomeruloid islands featuring endothelium associated with clusters of plump alpha-smooth muscle actin-positive pericytes, stippled hemosiderin, and CD61-positive fibrin thrombi likely represent the morphologic sites of platelet consumption. Small and large lymphatic channels occurred in 22 of 33 cases and were typically seen peripheral or deep to the main tumor mass. HHV-8 transcripts were not identified (0 of 3 cases). Follow-up information was available in 22 patients (range 8 months to 15 years; mean 2 years) and indicated that 3 died of disease, 8 were alive with disease, and 10 were alive without residual disease. Two patients developed regional perinodal soft tissue involvement, but none developed distant metastases. KH is a lesion having both a vascular and lymphatic component. Its common association with KMP probably relates in part to unique architectural features that favor turbulent blood flow and platelet activation. KH can also be reliably separated from JH by GLUT-1 and LeY immunostaining, indicating differences in the morphologic and functional attributes of the endothelium between the two lesions. The absence of HHV-8 in KH underscores a different pathogenesis from Kaposi sarcoma. Our study, the largest to date, emphasizes that mortality is due to KMP and not metastatic disease, which appears limited to regional perinodal soft tissue. Given this behavior, its continued classification as a vascular tumor of intermediate malignancy is warranted.

Adolescent↗
PubMed2003

Spermatid-specific promoter of the SP-10 gene functions as an insulator in somatic cells.

Spermatid differentiation markers such as the acrosomal protein SP-10 display remarkable testis- and germ cell-restricted gene expression. However, little is known about the mechanisms that prevent their expression in somatic tissues. We have previously noted that the -408/+28 or the -266/+28 promoter of SP-10 directed strictly spermatid-specific transcription in transgenic mice, Biol. Reprod. 61, 1256-1266). Lack of ectopic expression in these mouse lines implied that the SP-10 promoter might have protected the transgene from the influence of neighboring enhancers. The present study tested this directly by performing enhancer-blocking assays. In transiently transfected COS cells, the -408/-92 SP-10 promoter, but not stuffer DNA, blocked the transcriptional activity of a heterologous enhancer (CMV) in a position- and orientation-dependent manner. In transgenic mice, despite integration adjacent to the pan-active CMV enhancer, the -408/+28 promoter maintained spermatid-specificity and no ectopic expression of the transgene resulted. Enhancer blocking is a characteristic feature of insulators. Our results show that the SP-10 proximal promoter, which activates transcription in spermatids, functions as an insulator in somatic cells. Insulator activity mapped to the -186/-135 region and mutation of two ACACAC motifs compromised the insulator function. In conclusion, the evolutionarily conserved SP-10 insulator is novel and is the first one shown to regulate transcription of a germ cell differentiation marker.

Acrosome↗
PubMed2003

Large-scale molecular and tissue microarray analysis of mesothelin expression in common human carcinomas.

The 40-kilodalton processed glycoprotein, mesothelin, is highly expressed in epithelial mesotheliomas and adenocarcinomas of the ovary (serous papillary) and pancreas, but its expression in a large series of other common carcinomas has not been completely explored. In the present study, we used oligonucleotide and tissue microarrays to profile the expression of the mesothelin gene (MSLN) and encoded protein, respectively. Among 150 carcinomas of multiple anatomic sites, we found the highest average expression of MSLN in serous carcinomas of the ovary and adenocarcinomas of the pancreas, consistent with previous reports, as well as measurable but less-striking expression in pulmonary, gastric/esophageal, and colorectal adenocarcinomas. On tissue microarrays containing 621 carcinomas derived from the same and additional sites as those profiled by gene expression, mesothelin immunoreactivity was highest in cancers of the ovary (serous papillary, endometrioid, and undifferentiated) and pancreas, with less frequent staining seen in adenocarcinomas of the endometrium, lung, and stomach/esophagus. Some immunopositivity was observed in 42% of pulmonary adenocarcinomas, including 18% that had >50% of tumor cells that were immunoreactive. Some 14% of breast and 30% of colorectal adenocarcinomas showed immunopositivity, but no case contained >50% tumor cells that were immunoreactive. Mesothelin was either entirely absent or present in <5% of carcinomas of the prostate, bladder/ureter, liver, kidney, and thyroid. Overall, we observed good concordance between the results obtained by oligonucleotide and tissue microarrays. This large study of the MSLN gene and protein expression in common carcinomas provides data for future investigations that evaluate the utility of mesothelin/megakaryocyte potentiating factor as a potential serum tumor marker or target of immunotoxin-based therapy in human cancers.

Biomarkers, Tumor↗
PubMed2003

Testing for human papillomavirus: data driven implications for cervical neoplasia management.

The results of the National Cancer Institute-sponsored ASCUS-LSIL Triage Study (ALTS), the only randomized longitudinal trial in cytopathology, have provided a wealth of data to benchmark practice and stimulate discussion regarding the usefulness of human papillomavirus testing. These landmarks aided the American Society of Colposcopy and Cervical Pathology's broad-based consensus conference in integrating the Bethesda deliberations and ALTS data into clinical management. The outcomes of these open- and wide-ranging discussions have a direct impact on all who practice in this area. This article highlights the impact of these data on the contemporary practice of cytopathology and emphasizes the interaction between pathologists and clinicians.

Female↗
PubMed2003

Human papillomavirus biology and cervical neoplasia: implications for diagnostic criteria and testing.

Human papillomaviruses are necessary for the development of cervical neoplasia. Progress in our understanding of the epithelial biology of this common pathogen has greatly influenced current concepts of cervical carcinogenesis. This understanding has provided a framework for understanding the biologic basis of many diagnostic criteria. Furthermore, classification schemes, diagnostic testing, and clinical management have been modified and clarified in light of this knowledge.

Biomarkers↗
PubMed2002

Use of human papillomavirus DNA testing to compare equivocal cervical cytologic interpretations in the United States, Scandinavia, and the United Kingdom.

BACKGROUND: Human papillomavirus (HPV) DNA testing may be useful in clarifying equivocal cervical cytologic interpretations. One application might be to standardize the meaning of equivocal interpretations from laboratories in various regions. Because international differences may be particularly marked, international comparisons of emerging data will require clear translations of "equivocal" and similar terms. METHODS: To perform a three-country comparison, the authors selected a morphologically diverse set of 188 conventional Papanicolaou tests initially classified as "squamous atypia" from a study of more than 20,000 women in Portland, Oregon (1989-1990). Previously, five U.S. expert cytopathologists independently interpreted the slides with screening cytotechnologists' marks in place. For this comparison, one British and two Scandinavian reviewers involved in HPV research reviewed the slides after original marks had been removed. The authors compared all eight reviewers' classifications of negative, equivocal, or abnormal in a series of pairwise comparisons using the kappa statistic. They then compared cytologic interpretations with HPV DNA testing. RESULTS: Oncogenic HPV DNA detection was significantly associated with increasingly abnormal interpretations for each reader. The British reader tended to rate tests as more abnormal than the American pathologists did, whereas the Scandinavians tended to rate tests as more normal. Reference to the HPV DNA standard clarified the tendency of readers to render systematically more or less severe interpretations. For example, the Scandinavian cytologists discounted subtle (often HPV-associated) changes in favor of cytologic certainty, making HPV triage of equivocal tests less applicable there. CONCLUSIONS: International research on cytopathology, particularly on the possible uses of HPV DNA testing, will require calibration of local cytologic definitions.

Adolescent↗