Biomedical subjects

M H Stoler

Publications and source records attributed to M H Stoler.

At least 73 records · Page 4Linked to original sources

PubMed1994

Efficacy and safety of 0.5% podofilox solution in the treatment and suppression of anogenital warts.

PURPOSE: For the patient-administered treatment of anogenital warts, 0.5% podofilox (podophyllotoxin), one of the active compounds of podophyllin, has been shown to be more effective than the vehicle alone. This study was designed to evaluate the safety and efficacy of 0.5% podofilox treatment followed by prophylaxis. PATIENTS AND METHODS: A total of 103 patients were entered in stage 1 of the study. Stage 1 was an open label study, and patients self-administered 0.5% podofilox twice daily for 3 consecutive days per week for 4 weeks. A total of 100 patients remained available for efficacy and safety analyses. At the end of stage 1, patients who had a complete response proceeded to stage 2 of the study. Patients who had a 50% to 99% reduction in measured total wart area were offered cryotherapy every 10 days, up to 5 times. If cleared of warts, they were also entered into stage 2. A total of 57 patients were enrolled into stage 2, a double-blind, randomized, placebo-controlled prophylactic study of 0.5% podofilox self-administered once daily for 3 days per week for 8 weeks, on the sites of healed warts. A total of 45 patients in stage 2 were available for efficacy analysis. RESULTS: By the end of stage 1, 68% of the warts had disappeared, and 29 of 100 patients (29%) had a complete response. A total of 49 patients had a 50% or greater improvement in wart area and underwent cryotherapy. Rates of local side effects after 1 week of treatment were 57% for inflammation, 39% for erosion, 47% for pain, 48% for burning, and 44% for itching. However, these symptoms and signs were mostly mild to moderate in intensity and diminished over time. Therefore, overall treatment was well tolerated. In stage 2, only 4 of 21 patients (19%) in the podofilox group experienced a recurrence as opposed to 12 of 24 (50%) in the placebo group (P = 0.031). As in stage 1, the side effects were modest, and the drug was well tolerated. CONCLUSION: This study confirms the efficacy and good tolerance of 0.5% podofilox in the treatment of anogenital warts. It also establishes the safety and superior efficacy of patient-administered podofilox over the vehicle alone as prophylaxis against recurrence of lesions. Although long-term efficacy and tolerance remain to be established, podofilox appears to be a useful agent in the control of this disease.

Adult↗

PubMed1994

Induction of proliferating cell nuclear antigen in differentiated keratinocytes of human papillomavirus-infected lesions.

The expression of proliferating cell nuclear antigen (PCNA) was studied in human papillomavirus (HPV)-infected, benign and malignant lesions of the genital tract and larynx using immunocytochemical staining of formalin-fixed clinical specimens. We observed the induction of PCNA in squamous carcinomas and adenocarcinomas, as has been demonstrated with other malignancies. In addition, the differentiated keratinocytes of the upper spinous cells and granulocytes in condylomata acuminata and low-grade intraepithelial neoplasias showed a consistent induction of PCNA compared with the normal squamous epithelium, in which only some of the parabasal and basal cells were positive. This reactivation of PCNA synthesis correlated with the presence of high copy numbers of HPV DNA and was independent of the oncogenic risk potential of the infecting HPV genotype. We postulate that HPV gene products induce the expression of PCNA and other components of the host DNA replication machinery in differentiated cells of squamous lesions to facilitate vegetative viral replication.

Antigens, Neoplasm↗

PubMed1994

Isolated extragenital HPV-thirties-group-positive bowenoid papulosis in an AIDS patient.

We report a case of extragenital bowenoid papulosis in a man with AIDS. The lesions occurred on the anterolateral aspects of the neck, and were not associated with clinical genital or periungual involvement. In situ hybridization demonstrated abundant HPV DNA within the thirties group (31/33/35), in the absence of HPV-16 or -18.

Acquired Immunodeficiency Syndrome↗

PubMed1994

In situ hybridization analysis of lymphoproliferative disorders. Assessment of clonality by immunoglobulin light-chain messenger RNA expression.

Determination of clonality in B-cell lymphomas is a useful diagnostic adjunct. In situ hybridization (ISH) for the detection of kappa and lambda mRNAs has the potential to overcome some common specimen-related limitations in clonal assessment. Tritium-labeled antisense cRNA probes directed at conserved segments of the constant regions of the kappa and lambda mRNAs were used in an autoradiographic method to detect B-cell clonality. Using these probes, we analyzed 103 formalin-fixed, paraffin-embedded biopsy samples, and the results were subsequently compared to available immunophenotypic (all cases) and genotypic (50 cases) data. Of 103 samples, 82 (80%) had adequate RNA preservation as determined by actin RNA signals, and 73 (89%) of the 82 cases demonstrated concordant clonality assignment by both ISH and immunophenotyping. The remaining nine cases showed a specific form of discordance in that each exhibited no protein (Ig) expression but had evidence of mRNA immunoglobulin light-chain expression. Forty-five (90%) of 50 cases evaluated for immunoglobulin and T-cell receptor beta-gene rearrangements demonstrated concordant results with respect to clonality assignment by ISH. Thus, ISH demonstrates adequate sensitivity with respect to traditional methods of clonality assessment. However, its practical utility awaits the development of nonradioactive detection methods with adequate sensitivity to improve turnaround time.

Gene Rearrangement↗

PubMed1993

Astrocyte expression of mRNA encoding cytokines IP-10 and JE/MCP-1 in experimental autoimmune encephalomyelitis.

Mononuclear leukocytes preferentially accumulate in the central nervous system (CNS) during the course of experimental autoimmune encephalomyelitis (EAE). To address factors that govern leukocyte trafficking in EAE, we monitored expression of mRNAs encoding IP-10 and JE/MCP-1, which are members of a family of chemoattractant cytokines. A transient burst of IP-10 and JE/MCP-1 mRNA accumulation in the CNS occurred, in close relation to the onset of histologic and clinical disease. In situ hybridizations showed, unexpectedly, that astrocytes were the major source of mRNAs encoding IP-10 and JE/MCP-1. These observations implicate astrocyte-derived cytokines as potential chemoattractants for inflammatory cells during EAE.

Animals↗

PubMed1993

Penile intraepithelial neoplasia: clinical presentation and an analysis of the physical state of human papillomavirus DNA.

Forty-four men with penile intraepithelial neoplasia (PIN) and a matched control group of 88 men with condyloma acuminatum were evaluated in three centers studying anogenital human papillomavirus (HPV) infections. PIN and condyloma groups could not be distinguished on the basis of historical features or clinical presentation. Although PINs were more likely than condylomata to be pigmented (31/46 [67%] vs. 33/97 [34%], P < .001), 43% of PIN III were not pigmented, suggesting that pigmentation is not a sensitive indicator of high-grade PIN. HPV-16 infection, as determined by in situ hybridization, was closely associated with PIN III (0/24 PIN I contained HPV-16 vs. 12/13 PIN III, P < .001). Southern blot analysis demonstrated only episomal viral genomes, suggesting that integration is not an early event in penile neoplasia.

Adolescent↗

PubMed1993

Expression of the Wilms' tumor suppressor gene WT1 during mouse embryogenesis.

WT1 is a Wilms' tumor suppressor gene that maps to human chromosome 11p13 and encodes a putative transcription factor implicated in controlling normal urogenital development. Sporadic homozygous mutations in WT1 result in the development of Wilms' tumor (nephroblastoma), and heterozygous germline mutations can give rise to a phenotype which includes nephropathy and urogenital abnormalities (the Denys-Drash syndrome). Thus, inappropriate expression of WT1 results in developmental abnormalities affecting the urogenital system. To better define the temporal and spatial distribution of WT1 expression during embryogenesis, we have used in situ mRNA hybridization and immunohistochemistry to examine WT1 expression in murine embryos during the period prior to and throughout active organogenesis. Prior to embryological day 9.5 (E9.5), WT1 mRNA expression is absent in the embryo proper but is strongly expressed in the maternal uterus. During the initiation of organogenesis on E10.5, WT1 mRNA is localized within the pronephric and mesonephric tissues. By E11.5, the nephrogenic cord, urogenital ridge, and condensing metanephric tissue show intense WT1 hybridization signals, and increasingly centripetal expression of WT1 in the kidney correlates with renal differentiation from days E11.5 through E16.5. The stromal cell components in the developing gonad show expression of WT1 by E10.5, whereas in the remaining organs examined, WT1 expression is restricted to the uterus, spleen, abdominal wall musculature, and mesothelial lining of organs within the thoracic and abdominal cavities. Interestingly, there is also WT1 expression in the central nervous system which localizes to the ependymal layer of the ventral aspect of the spinal cord.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Human papillomavirus in penile squamous cell lesions. A comparison of an isotopic RNA and two commercial nonisotopic DNA in situ hybridization methods.

Sensitive isotopic in situ hybridization analysis of 34 paraffin-embedded penile squamous cell lesions for human papillomavirus (HPV) types 6, 11, 16, 18, and 31 revealed similar HPV detection rates, HPV-type specificity, and viral distribution patterns to those described in analogous cervical and vulvar lesions. Human papillomavirus was detected in six of six cases of condylomata acuminata (HPV type 6 [n = 4], HPV type 11 [n = 2]), in six of eight cases of squamous cell carcinoma in situ (HPV type 16 [n = 5], HPV type 31 [n = 1]), and in four of 10 cases of squamous cell carcinoma (all were HPV type 16). Interestingly, all 10 cases of penile verrucous carcinoma analyzed were HPV negative. Reevaluation of the HPV-positive penile lesions with two commercial nonisotopic HPV-typing in situ hybridization kits (Pathogene, Enzo, New York, NY; Viratype, Life Technologies, Gaithersburg, Md), revealed positive results for HPV type 6 and/or type 11 in all six cases of condylomata acuminata studied. However, only the Viratype assay detected HPV genome in the high-grade squamous cell lesions, with a relative sensitivity of 70% compared with that of the isotopic assay.

Carcinoma in Situ↗

PubMed1993

In situ hybridization. A research technique or routine diagnostic test?

In situ hybridization is the molecular method for localizing nucleic acid targets in the context of histomorphology. As such, it has tremendous potential application in research and diagnostic pathology. This essay attempts to briefly review the in situ method and to clarify its position as an emerging clinically useful technology.

Diagnostic Tests, Routine↗

PubMed1992

Precursor Langerhans cell histiocytosis. An unusual histiocytic proliferation in a patient with persistent non-Hodgkin lymphoma and terminal acute monocytic leukemia.

BACKGROUND: Langerhans cell precursors are considered to be identical to their mature counterparts except for the lack of Birbeck granules. Proliferations composed of such histiocytes appear to be uncommon. METHODS: Standard immunophenotypic, molecular genetic, and DNA content studies were used to characterize various hematopoietic disorders, including a proliferation of precursor Langerhans cells, which arose sequentially in a patient. RESULTS: The patient studied initially had a low-grade, B-cell, non-Hodgkin lymphoma and subsequently had an unusual histiocytic proliferation (precursor Langerhans cell histiocytosis) in cutaneous and lymph node sites. The patient eventually died of acute myelogenous leukemia (FAB, M5). CONCLUSIONS: A larger series is required to determine the significance of the precursor Langerhans cell phenotype, particularly with respect to the development of acute myelogenous leukemia.

Adult↗

PubMed1992

Expression of high-affinity laminin receptor mRNA correlates with cell proliferation rather than invasion in human papillomavirus-associated cervical neoplasms.

Induction of the expression of the Mr 67,000 high-affinity laminin receptor gene has been postulated as playing a role in the progression of human tumors to invasive cancers. We tested this hypothesis by examining histopathological sections of a large number of epithelial lesions of the genital tract associated with human papillomaviruses. In situ hybridization was performed with a riboprobe generated from a laminin receptor complementary DNA. Laminin receptor mRNA was expressed primarily in the less differentiated cells in normal squamous tissues and in a spectrum of squamous neoplasms. There was no net induction of mRNA per cell in intraepithelial or invasive squamous neoplasms relative to normal tissue. In contrast, laminin receptor mRNA was not expressed at a detectable level in normal glands of the uterine cervix but was dramatically induced in morphologically abnormal, human papillomavirus-positive glands, irrespective of the genotype of human papillomaviruses present. The induction occurred before any evidence of invasion, and there was no further increase during the transition from adenocarcinoma in situ to invasive carcinoma. We conclude that induction of high-affinity laminin receptor gene expression is associated with the development of malignancies of cervical glandular epithelia, but the increased expression appears to correlate with the proliferative rather than the invasive properties of these cells.

Blotting, Northern↗

PubMed1992

Tissue-specific expression of murine IP-10 mRNA following systemic treatment with interferon gamma.

We have examined the tissue distribution of 10-kd inflammatory protein (IP-10) mRNA expression in C57Bl/6 mice injected intravenously (i.v.) with various inflammatory stimuli. IP-10 mRNA was strongly induced by interferon-gamma (IFN-gamma) in liver and kidney but only poorly in skin, heart, and lung. IFN-gamma had nearly equivalent access to these tissues as indicated by the distribution of radiolabeled recombinant IFN-gamma 1 h after injection. The time course of IP-10 mRNA appearance was rapid and transient in both liver and kidney; maximal expression in the liver (2 h) preceded that in the kidney (3 h) and declined rapidly thereafter in both tissues. Expression of IP-10 mRNA in the liver and kidney was highly sensitive to IFN-gamma treatment; nearly maximal stimulation occurred with injection of 500 U of IFN-gamma per mouse. Comparable stimulation of IP-10 mRNA expression in splenic macrophages required 10,000 U of IFN-gamma administered i.v., indicating that liver and kidney responses are 10- to 20-fold more sensitive. IP-10 mRNA expression in both tissues was not restricted to stimulation by IFN-gamma but was also seen with injection of lipopolysaccharide (LPS) (25 micrograms/mouse) or IFN-beta (100,000 U/mouse). Two other members of the IP-10 gene family, KC (gro) and JE (MCP-1), were expressed at lower levels under similar treatment conditions. Analysis of IP-10 mRNA distribution in the liver and kidney by in situ hybridization indicated that expression in both tissues was most prominent in the reticuloendothelial cell system, particularly in the endothelial lining of the microvascular circulation. Although the function of the IP-10 gene product has not been defined, these results suggest that it may play an important role in the response of both the liver and kidney to systemic inflammation.

Animals↗

PubMed1992

Human papillomavirus type 16 and 18 gene expression in cervical neoplasias.

Human papillomavirus (HPV) types 16 and 18 are strongly implicated in the generation of progressive cervical neoplasms. The viruses produce complex families of overlapping messenger RNAs that are linked to differentiation, making it necessary to analyze gene expression in the context of morphology. We have developed HPV type 16 and type 18 subgenomic clones from which 3H-labeled riboprobes specific to individual mRNA families can be generated in vitro. Using these probes for in situ hybridization, we examined serial sections of archival biopsy specimens of the spectrum of genital lesions. In low-grade squamous lesions, all viral open reading frames were expressed, and the most abundant transcription spanned the E4 and E5 open reading frames at the 3' end of the E region. L region transcription coding for the capsid proteins was restricted to terminally differentiated keratinocytes. As the grade of neoplasia increased, cellular differentiation and overall viral transcription decreased and, with few exceptions, the L2 and L1 transcripts ceased to exist. The E6-E7 transforming region was invariably derepressed. Interestingly, the patterns of HPV-16 gene expression suggested the coexistence of episomal and integrated viral DNAs. In contrast, in HPV-18 lesions, all the viral template DNA appeared to have integrated. Integration was deduced to have occurred near the boundary of the E1 and E2 open reading frames. Viral transcription patterns were similar in carcinomas in situ and in invasive carcinomas, regardless of the histologic cell types or the associated virus types, consistent with the notion that additional host gene alterations were necessary for progression. On the basis of viral gene expression in vivo and the E6 promoter regulation previously characterized in vitro, we discuss a molecular mechanism for HPV-associated carcinogenesis.

Adenocarcinoma↗

PubMed1992

The "CD43 only" phenotype. An aberrant, nonspecific immunophenotype requiring comprehensive analysis for lineage resolution.

Paraffin section immunohistology of leukocytic proliferations is a routine method of immunophenotyping in many clinical laboratories. Furthermore, a relatively standard antibody screening panel that includes L26 (CD20), Leu22 (CD43), and UCHL1 (CD45RO) appears to be widely used. Although paraffin section immunophenotyping in general, and this panel in particular, have been shown to be very reliable in defining B-cell lineage, characterization of T-cell lineage is less definitive. This is related primarily to the relatively poor specificity of the commercially available T-cell-associated reagents. CD43 (Leu22) in particular has a broad immunoreactivity profile that has not been stressed adequately in some reports. Seventeen cases with a "CD43 only" phenotype were identified during the last several years while using the relatively standard screening panel mentioned above. These cases were quite heterogeneous with respect to cellular differentiation and most were not T-cell proliferations. Specifically, eight cases were extramedullary leukemic infiltrates (five myeloid, two monocytic, one mixed lineage), four cases were T-cell lymphomas, three cases were B-cell lymphomas and two cases were plasmacytomas. Although CD43 has demonstrable utility in a leukocyte screening panel, this report stresses the aberrancy and lack of specificity of the "CD43 only" phenotype. Caution is recommended in assigning a specific lineage to such cellular proliferations without additional immunologic or genotypic analysis. Recommendations for comprehensive diagnostic evaluation of these proliferations are provided.

Antigens, CD↗

PubMed1992

Human papillomavirus identified by nucleic acid hybridization in concomitant nasal and genital papillomas.

Presence of human papillomavirus (HPV) as the etiologic agent in nearly all upper respiratory tract recurrent papillomas is well-established. The technique of nucleic acid hybridization now allows specific typing of HPV with a high degree of accuracy. This article reports a series of nine consecutive patients treated for nasal papillomas over the past 9 years. Eight of these patients had a personal history of genital papillomas (seven patients) or exposure (one patient). With the use of in situ hybridization and autoradiographic technique on paraffin-embedded tissue sections, HPV RNA type 6/11 was expressed in eight of nine nasal papillomas, and corresponding HPV types were also found in the two cases with which concurrent anogenital papilloma tissue was also available for analysis. Human papillomavirus RNA types 16 and 18 were not detected in any of the specimens. Signals of HPV messenger RNA type 6/11 were stronger in the fungiform areas than in the inverted areas of papillomas.

Adult↗

PubMed1992

Penile verrucous carcinoma: a clinicopathologic, human papillomavirus typing and flow cytometric analysis.

The relationship of various verruciform squamous cell proliferations of the penis such as verrucous carcinoma, with or without anaplasia and giant condyloma, is uncertain. We conducted clinicopathologic, flow cytometric, and HPV typing studies on 15 cases of penile verrucous carcinoma to investigate its place in the spectrum of genital squamous proliferations. The results show a high degree of morphologic uniformity with respect to Ackerman's original diagnostic criteria, as well as to several other histopathologic features evaluated. The latter include polygonal squamous cells with glassy cytoplasm, centrally located vesicular nuclei, intercellular edema, well-formed cellular bridges, and absence or paucity of koilocytes, true fibrovascular cores, and keratohyalin granules. Intraepithelial abscesses and crust-formation were present in many cases. Four cases contained microscopic foci of cellular anaplasia. These hybrid verrucous-squamous carcinomas presented and behaved similarly to the pure verrucous carcinomas. Tumor recurrence was correlated with extent of initial surgical management. DNA ploidy analysis by flow cytometry performed on eight pure and two hybrid tumors showed uniform diploid populations with similar G1/G2 fractions in both groups. Eight pure and two hybrid tumors evaluated for HPV by isotopic in situ hybridization were uniformly negative for HPV types 6, 11, 16, 18, and 31. The results show that penile verrucous carcinoma demonstrates characteristic and uniform morphologic features and does not contain the HPV types typically associated with condyloma acuminatum, giant condyloma of Buschke-Löwenstein, and condylomatous carcinoma.

Adult↗

PubMed1992

Identification of monoclonal B-cell populations by rapid cycle polymerase chain reaction. A practical screening method for the detection of immunoglobulin gene rearrangements.

Alternatives to Southern blot hybridization for gene rearrangement analysis are being studied because of the time, labor, cost, and radioisotopes required for this technique. We have utilized a rapid, hot air, thermocycling polymerase chain reaction (PCR) system to examine various lymphoproliferative disorders for immunoglobulin heavy chain (IgH) gene rearrangements. This unique system amplifies DNA from 10 microliters samples placed in glass capillary tubes, over a total cycle time of about 30 minutes. Amplified bands are easily visualized on ethidium bromide-stained agarose gels. Forty-one monoclonal B-cell proliferations, 27 reactive lymphoid hyperplasias, 17 T-cell lymphomas and 3 cases of Hodgkin's disease were studied. All 88 cases were fully characterized by morphologic, immunophenotypic, and genotypic (Southern blot) analyses. Each case was separately evaluated by PCR with two primer pairs: 1) IgH variable region (VH) and IgH joining region (JH) and 2) bcl-2 and JH. Thirty-four of 41 monoclonal B-cell proliferations revealed a distinct band (within an expected base pair range) with 1 or both primer combinations supporting B-cell monoclonality; the other 7 cases were considered false negatives. The 47 entities without IgH gene rearrangements detectable by Southern analysis demonstrated no amplified product or a smear of amplified DNA with no distinct band. The overall specificity of PCR was 100%, and the sensitivity was 83% when directly compared with Southern blot analysis. Although its sensitivity is currently less than optimal, PCR is a rapid and practical screening method for the detection of IgH gene rearrangements. If a positive result is obtained no further analysis is required; however, if there is a negative result, standard Southern blot analysis should be performed to definitively exclude the presence of a monoclonal B-cell population in the sample.

B-Lymphocytes↗

PubMed1991

Developmental expression of mRNAs encoding platelet proteins in rat megakaryocytes.

The committed bone marrow megakaryocyte (MK) progenitor undergoes a series of highly regulated stages of development resulting in a large multi-nucleated platelet-producing cell. We studied the developmental expression of the mRNA for two alpha granule proteins, fibronectin (FN) and fibrinogen gamma chain (gamma-FIB), and a cytoskeletal protein, actin, in MKs from marrow of Sprague-Dawley rats. By the method of in situ RNA:RNA hybridization, we showed that mRNAs for the alpha granule proteins were expressed most abundantly in a population of 15-microns diameter promegakaryocytes and in cells as small as 10 microns whose identity as immature MKs was inferred by positive staining for platelet- and MK-specific markers. gamma-FIB and FN mRNAs were present in reduced abundance in a small proportion of intermediate MKs; however, little or no expression was seen in mature platelet-producing MKs. In contrast, high levels of actin mRNA were expressed predominantly in mature, multi-nucleated MKs, and less abundantly in the immature forms. These results suggest that FN and gamma-FIB are transcribed early in MK development to permit translation and packaging of the protein into alpha granules, after which transcription ceases. On the other hand, transcription of actin occurs continuously throughout development, with highest levels in mature platelet-producing MKs, in which actin is needed for shape changes and intracellular movement of organelles. Our data suggest that in situ RNA:RNA hybridization for platelet-specific markers will provide additional criteria by which to establish MK lineage in immature marrow progenitors.

Actins↗