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P A McCue

Publications and source records attributed to P A McCue.

At least 19 recordsLinked to original sources
PubMed1998

Molecular alterations to human chromosome 3p loci in neuroendocrine lung tumors.

BACKGROUND: The origins of and interrelations between low grade and high grade neuroendocrine lung tumors, typical and atypical carcinoids, and small cell lung carcinoma (SCLC) have not been elucidated. Karyotypic and molecular genetic studies have demonstrated deletions in 3p in 100% of SCLCs and the candidate lung tumor suppressor gene, FHIT, at 3p14.2 is not expressed in the majority of SCLCs. Similar studies of typical and atypical carcinoids could clarify the interrelations among these tumors. METHODS: For molecular genetic analyses, archival carcinoids and paired normal cells were microdissected from paraffin sections, deparaffinized, and DNA prepared. Oligonucleotide primer pairs for 12 microsatellite markers mapping between 3p14.2 and 3p21.3 were used to amplify allelic DNA fragments from 13 typical and 6 atypical carcinoids. In addition, an independent series of archival sections of carcinoids and SCLCs was tested by immunohistochemistry for expression of Fhit protein. RESULTS: Of the six atypical carcinoids examined, three had lost an allele at all informative markers, whereas one had lost alleles in two distinct regions and two showed allele loss in a subregion of the chromosome region tested. Of the 13 typical carcinoids, 3 showed allele loss at only 1 or 2 loci each. Typical carcinoids, similar to normal lung epithelia, were strongly positive for the cytoplasmic Fhit protein, SCLCs were uniformly negative, and atypical carcinoids appeared to express an intermediate level of Fhit protein. CONCLUSIONS: Loss of heterozygosity at 3p14.2-p21.3 is significantly more extensive in all atypical carcinoids. Atypical carcinoids, which exhibit clinicopathologic features intermediate between typical carcinoids and small cell carcinomas and have been considered well differentiated neuroendocrine carcinomas, also are intermediate between typical carcinoids and SCLC on the basis of extent of loss of 3p alleles and reduced expression of Fhit protein.

Acid Anhydride Hydrolases↗
PubMed1998

Absence or reduction of Fhit expression in most clear cell renal carcinomas.

The FHIT gene at human chromosome region 3p14.2 straddles the common fragile site, FRA3B, and numerous homozygous deletions in cancer cell lines and primary tumors. Also, the 3p14.2 chromosome breakpoint of the familial clear cell kidney carcinoma-associated translocation, t(3;8)(p14.2;q24), disrupts one FHIT allele between exons 3 and 4, fulfilling one criterion for a familial tumor suppressor gene: that one allele is constitutionally inactivated. Because the FHIT gene sustains biallelic intragenic deletions rather than mutations, there has not been evidence that the FHIT gene frequently plays a role in kidney cancer, although replacement of Fhit expression in a Fhit-negative renal carcinoma cell line suppressed tumor growth in nude mice. We have now assessed 41 clear cell renal carcinomas for expression of Fhit by immunohistochemistry. Normal renal tubule epithelial cells express Fhit uniformly and strongly, whereas 51% of the tumors are completely negative, 34% of tumors show a mixture of positive and negative cells, and 14% are uniformly positive, although usually less strongly positive than the normal epithelial cells. Most interestingly, there was a correlation between complete absence of Fhit and the G1 morphological grade and early clinical stage. Morphological grades G2 and G3 exhibited a mixture of positive and negative cells with a tendency for a higher fraction of negative cells in G3. Fhit inactivation is likely to be an early event in G1 tumors and may be associated with progression in G2 and G3 tumors.

Acid Anhydride Hydrolases↗
PubMed1998

The role of deletions at the FRA3B/FHIT locus in carcinogenesis.

The FHIT gene, which encodes a 1-kb message and a 16.8-kDa protein that hydrolyses diadenosine triphosphate (ApppA) to ADP and AMP in vitro, covers a megabase genomic region at chromosome band 3p14.2. The gene encompasses the most active of the common human chromosomal fragile regions, FRA3B. Over the years, it has been suggested that fragile sites might be especially susceptible to carcinogen damage and that chromosomal regions of nonrandom alterations in cancer cells may coincide with defined fragile sites. Within the FRA3B region, the characteristic induced chromosome gaps can occur across the entire region, but 60% of the gaps are centered on a 300-kb region flanking FHIT exon 5, the first protein-coding exon. Numerous hemizygous and homozygous deletions, translocations and DNA insertions occur within FHIT in cancer cell lines, uncultured tumors, and even in preneoplastic lesions, especially in tissues such as lung that are targets of carcinogens. This supports the proposed cancer-fragile site connection and suggests that the FHIT gene, expression of which is frequently altered in cells showing FHIT locus damage, is a tumor suppressor gene whose inactivation may drive clonal expansion of preneoplastic and neoplastic cells. Replacement of Fhit expression in Fhit-negative cancer cells abrogates their tumorigenicity in nude mice. Analysis of the approximately 300-kb DNA sequence encompassing FHIT exon 5 in the FRA3B epicenter has provided clues to the mechanism of repair of the fragile site double strand breaks. The mechanism involves recombination between LINE 1 elements with deletion of the intervening sequence, often including FHIT exons. These studies have also shown that FHIT alterations generally entail independent deletion of both FHIT alleles. Future studies will focus on two objectives: study of (1) the in vivo function of the Fhit protein and (2) mechanisms of break and repair in the FRA3B fragile region.

Acid Anhydride Hydrolases↗
PubMed1997

Hyaline globules in renal cell carcinomas and oncocytomas.

Hyaline globules (extracellular collections of amorphous material) are identified in 10 of 59 renal cell carcinomas (RCC) and in 2 of 9 oncocytomas. Immunohistochemical characterization of these PAS-positive structures revealed the presence of basement membrane material in most cases. Collagen type IV and laminin were the predominant constituents, whereas fibronectin was detected only occasionally. Electron microscopic examination of the globules showed concentric multilayered accumulations of basement membrane material. No such structures were recognized in 8 renal pelvic transitional cell carcinomas nor in 2 metanephric adenomas. RCC associated hyaline globules were always negative for alpha1-antitrypsin (AAT), alpha-fetoprotein (AFP), amyloid A, cytokeratin, vimentin, or lysozyme. These features differ from those of the hyaline globules previously described in other malignant neoplasms, notably AAT-positive hyaline globules in ovarian tumors, and AFP-positive globules in yolk sac tumors. Identification and immunohistochemical characterization of hyaline globules in metastases may be helpful in determining the origin of occult primary tumors.

Adenoma↗
PubMed1997

Use of p53 in the diagnosis of upper-tract transitional cell carcinoma.

OBJECTIVES: To assess the usefulness of p53 staining of cytology specimens obtained ureteroscopically in the diagnosis of upper-tract transitional cell carcinoma (TCC). METHODS: We collected specimens from 43 patients undergoing a total of 50 ureteroscopic procedures for a variety of indications, including the diagnosis of TCC. Specimens were obtained by direct biopsy with forceps or basket whenever possible. We examined specimens for evidence of TCC by cytospin as well as cell block for any visible fragments. Each specimen was then stained for overexpression of p53 by immunohistochemical staining, and the degree of staining was graded. Eight patients subsequently underwent nephroureterectomy; the pathologic specimens were stained for p53 and compared with the cytology results. RESULTS: Staining for p53 was positive in specimens from 36 of 50 procedures, including all 28 with ureteroscopic or cytologic evidence of TCC (P < 0.0001). By contrast, cytology accurately diagnosed only 23 of the 28. Specimens from all 14 procedures that were negative also stained negative for p53. Specimens from all 8 procedures with no tumor seen and atypical cytology stained positive for p53; 4 of 5 patients with adequate follow-up have had a tissue diagnosis of TCC at that site. Overall, 35 of the 36 specimens that stained positive for p53 were obtained from patients with some history of TCC (P < 0.0001). No significant association could be found between degree of staining and grade (P = 0.3034). The degree of staining of ureteroscopic biopsy specimens was identical to that of the nephroureterectomy specimen in 6 of 8 cases. CONCLUSIONS: p53 nuclear protein staining of cytology specimens obtained ureteroscopically appears to correlate well with the presence of upper-tract urinary TCC. Further study is needed to determine if it can provide a definitive diagnosis in cases with indeterminate cytologic findings.

Carcinoma, Transitional Cell↗
PubMed1997

Grading of upper urinary tract transitional cell carcinoma by computed DNA content and p53 expression.

OBJECTIVES: Transitional cell carcinomas of upper urinary tract (uttTCC) constitute 5% to 6% of all urothelial tumors. Ureteropyeloscopy has become the standard for clinical evaluation of uutTCC. Moreover, endoscopic treatments have been advocated as a conservative approach for low grade tumors or patients with intermediate grade tumors whose renal function is compromised. Therefore, grading has become the most predictive variable in defining therapeutic approach. In addition to morphologic evaluation, a series of biologic markers may be used to increase the accuracy of grading such as DNA analysis and p53 protein expression. In this study, we have evaluated these markers by means of cell image analysis with the SAMBA 400 system. METHODS: Thirteen cases of uttTCC were studied with cytologic smear, cell block, and histologic confirmation. DNA analysis was performed on cytologic smear. Immunostaining was performed on cell blocks. A grade was assigned on the basis of DNA evaluation and p53 expression quantitation. These grades were combined for each case and compared with the initial cytologic grading and the final histologic grading. RESULTS: Cytology alone diagnosed TCC in all but 1 case that was diagnosed atypical. Discrepancies were found in primary grading: cytologic grading concurred with histologic grading in 6 of the 13 cases. CONCLUSIONS: These results, although in a limited but selected number of cases, show the potential of computerized evaluation of biologic markers as parameters for a more objective grading of tumors.

Biomarkers, Tumor↗
PubMed1997

Diagnostic accuracy of ureteroscopic biopsy in upper tract transitional cell carcinoma.

PURPOSE: Our aim was to determine the accuracy of ureteroscopic biopsies and cytological techniques compared to open surgical specimens of upper tract transitional cell carcinoma. MATERIALS AND METHODS: From 1985 to 1995, 51 cases of upper tract transitional cell carcinoma were diagnosed ureteroscopically and distal ureterectomy or nephroureterectomy was performed. Each patient underwent direct ureteroscopic inspection and biopsy. Fresh samples were delivered to the cytopathology laboratory, where they were examined using cytospin and smear. A cell block was prepared when visible tissue was present. Grades of ureteroscopic biopsies were compared to grades and stages of surgical specimens in 42 cases. RESULTS: Cytological evaluation was positive for malignancy in 48 of the 51 cases (94.1%). Grading of ureteroscopic specimens was possible in 42 cases (82.4%). Transitional cell carcinoma grade on ureteroscopy accurately predicted tumor grade and stage in the surgical specimens. Of 30 low or moderate grade ureteroscopic specimens 27 (90%) proved to be low or moderate grade transitional cell carcinoma in the surgical specimens, while 11 of the 12 high grade ureteroscopic specimens (91.6%) proved to be high grade transitional cell carcinoma (p < 0.0001). Of 30 low or moderate grade ureteroscopic specimens 26 (86.6%) had a low stage (Ta or T1) tumor. In contrast, 8 of 12 high grade ureteroscopic specimens (66.7%) had invasive tumor (stage T2 or T3) in the surgical specimen (p = 0.0006). CONCLUSIONS: Ureteroscopic inspection and biopsy combined with cytological techniques provide accurate information regarding grade and stage of upper tract transitional cell carcinoma.

Adult↗
PubMed1997

Coexistence of atheroemboli and minimal-change disease.

We report the first case of coexistent cholesterol emboli and minimal-change disease in an elderly individual with acute renal failure and the nephrotic syndrome. Renal insufficiency heavy proteinuria improved rapidly with oral steroids.

Acute Kidney Injury↗
PubMed1996

Gastric antral vascular ectasia (watermelon stomach) in patients with systemic sclerosis.

This report describes 5 patients with systemic sclerosis (SSc) who developed severe, recurrent upper gastrointestinal (GI) bleeding due to gastric antral vascular ectasia (GAVE). The clinical records, the endoscopic findings, and the histologic appearance of biopsy specimens and surgically resected gastric tissue from the patients were reviewed. All 5 patients developed severe and recurrent episodes of upper GI bleeding leading to severe anemia requiring multiple transfusions. The cutaneous involvement was diffuse in 3 patients and limited in 2. All but 1 had cutaneous telangiectasias. The diagnosis of GAVE was established by endoscopy within 3 years of the diagnosis of SSc in all cases. One patient required heater probe cautery, 2 required laser coagulation, and 2 underwent surgical resection of the gastric antrum for control of the GI bleeding. The possibility of GAVE should be considered in SSc patients who have recurrent upper GI bleeding. It is suggested that the antral vascular lesions in these patients may represent a component of the spectrum of vascular alterations of SSc.

Adult↗
PubMed1996

Correlation of flow cytometry to clinical factors, hormone receptors, and histopathological grade in stage I and II invasive breast carcinoma.

DNA index (ploidy) and S-phase fraction (SPF) were measured by flow cytometry in 131 invasive stage I and II breast carcinomas. Ploidy showed a strong correlation with SPF (p = 0.0001), with aneuploid tumors having a high SPF. Both cytometric parameters correlated with tumor size and hormonal receptor status. Smaller tumors tended to be diploid and have low SPF. Nodal status did not demonstrate an association with cytometric findings. There was a highly significant connection between tumor grade, especially nuclear grade, and SPF (p = 0.0001). The study demonstrates the relationship between conventional prognostic factors, DNA content, and proliferative activity of breast tumors.

Breast Neoplasms↗
PubMed1996

Development of secondary structure, growth characteristics and cytogenetic analysis of human transitional cell carcinoma xenografts in scid/scid mice.

PURPOSE: The growth of human bladder transitional cell carcinoma (TCC) in scid/scid mice was examined. MATERIALS AND METHODS: Cystocopically obtained TCC biopsies were implanted in scid/scid mice, and successful xenografts were compared with original tumors for growth and genetic characteristics. RESULTS: Low grade papillary tumors formed fluid-filled pseudobladders lined with malignant urothelium and papillary fronds containing fibrovascular cores recruited from the murine host. High grade xenografts grew without these secondary structures. When compared with the patient tumors, xenograft growth fractures, as measured by proliferating cell nuclear antigen, p53 expression and ploidy, were similar in each. CONCLUSIONS: The scid/scid xenografts maintain phenotype and architecture. This model may be useful for studying factors determining tumor grade, angiogenesis and tissue organization.

Animals↗
PubMed1996

Role of computed quantitation of immunohistochemical staining of Ki-67 antigen in diagnosing ampullary lesions.

OBJECTIVE: To determine the possible role of Ki-67 antigen expression by visual and computed quantitation in diagnosing ampullary lesions. STUDY DESIGN: Twenty-two cases of ampullary lesions treated at Thomas Jefferson University Hospital between 1989 and 1994 were analyzed. Four cases of adenoma, 4 of epithelial dysplasia in adenoma, 7 of well-differentiated adenocarcinoma and 7 of high grade adenocarcinoma were included. For each case three consecutive sections were obtained from the paraffin-embedded blocks. The first slide was stained with hematoxylin & eosin for visual diagnosis; the other two were immunoprocessed to evaluate the expression of Ki-67 antigen. Visual quantitation of Ki-67 was evaluated by light microscopy, and computed quantitation was performed utilizing the SAMBA 4000 cell image analysis system. RESULTS: Immunohistochemical analysis of the ampullary lesions showed a positive correlation of Ki-67 expression, both by visual and computed quantitation, with biologic grade. The cell proliferation sequence was carcinoma, adenoma with dysplasia and adenomia. CONCLUSION: Ki-67 antigen expression correlated highly with the progression of malignancy in ampullary lesions. Computed quantitation of Ki-67 was more sensitive than visual quantitation, especially in differentiating between low and high grade adenocarcinomas.

Adenocarcinoma↗
PubMed1994

Intravesical gene therapy: in vivo gene transfer using recombinant vaccinia virus vectors.

Intratumoral gene transfer may be a significant tool in active immunotherapy. The ability to insert functional genes into a tumor in vitro and in vivo using recombinant vaccinia vectors was examined in the murine bladder tumor model. Vaccinia recombinants expressing the influenza hemagglutinin or nucleoprotein antigens infected/transfected murine (MB-49 and MBT-2) and human (T24) bladder tumor cell lines in vitro. Systemic vaccinia immunity was induced with as few as 10 plaque-forming units of recombinant vaccinia instilled intravesically, and the encoded protein was expressed in vivo in tumor and urothelium. However, preimmunity to vaccinia did not inhibit intravesical tumor transfection. Thus, recombinant vaccinia virus is effective in introducing foreign antigens locally into tumor in vivo, supporting its use in clinical immunotherapy.

Animals↗
PubMed1994

Effect of human natural killer cells on the metastatic growth of human melanoma xenografts in mice with severe combined immunodeficiency.

An in vivo model for human melanoma was established with the growth of CR3 and DE5 human melanoma tumor cells following i.v. injection into C.B.-17 severe combined immunodeficient mice depleted of murine natural killer (NK) cells. The ability of human NK cells to mediate antitumor activity in vivo was investigated by evaluating the number of lung nodules and survival of mice given injections of human NK cells i.v. early after injection of CR3 tumor cells. Under these conditions, human NK cells effectively reduced lung nodule counts and prolonged survival when coinjected with interleukin 2 (IL-2). Multiple injections of IL-2 given during the first 16 h post-NK injection did not further enhance the tumor reduction. Significantly increased antitumor activity against CR3 tumor cells in vivo was observed in mice receiving NK cells coinjected with IL-2 and interleukin 12 (IL-12) in comparison to NK cells and IL-2 only. However, coinjection of IL-12 with human NK cells alone did not reduce the tumor burden. These results demonstrate the antitumor activity of human NK cells against human melanoma in severe combined immunodeficient mice and its augmentation by IL-2, alone or in combination with IL-12, suggesting that this model can be used to further investigate the interaction between human NK cells and human tumors.

Animals↗
PubMed1994

Deletion of chromosome arm 1p in a Merkel cell carcinoma (MCC).

A case of neuroendocrine skin carcinoma (Merkel cell carcinoma) with a deletion of the short arm of chromosome 1 (1p) as the sole chromosomal abnormality was examined. The tumor originated in the skin of the left knee of a 67-year-old man. Histopathologic study showed an undifferentiated small cell tumor which expressed neuron-specific enolase, chromogranin, and cytokeratin (CAM 5.2). Cytogenetic analysis of a lymph node metastasis from the groin showed a pseudodiploid cell population with a deletion of the short arm of chromosome 1 as the only abnormality: 46,XY,del(1)(p36.1). In situ hybridization with the D1Z2 probe specific for the terminal band of 1p confirmed the terminal deletion. This is the first case of Merkel cell carcinoma in which only one chromosomal abnormality has been observed. Loss of the terminal portion of 1p suggests that a tumor suppressor gene on 1p plays a role in the pathogenesis of Merkel cell carcinoma.

Carcinoma, Merkel Cell↗
PubMed1993

Screening for occult nodal metastasis in localized carcinoma of the prostate.

Metastatic involvement of pelvic lymph nodes in carcinoma of the prostate alters the prognosis and treatment of this disease. Our goal was to determine if additional techniques, such as immunohistochemical staining, could detect occult microscopic metastatic nodal disease not seen with routine hematoxylin and eosin staining. We examined paraffin embedded lymph nodes from 43 patients with clinical stage A or B carcinoma of the prostate who were candidates for radical prostatectomy and who underwent modified pelvic lymph node dissection with frozen section hematoxylin and eosin staining. Immunohistochemical staining for prostate specific antigen and prostate specific acid phosphatase was performed on the lymph nodes. Monoclonal antibodies to cytokeratins were used to confirm the epithelial origin of the prostate cells. An average of 9 lymph nodes and 42 histological sections per patient were stained. Based on routine hematoxylin and eosin staining the pathological staging was stage A in 3, stage B in 20, stage C in 9 and stage D1 in 11 cases. There were 17 well, 16 moderately and 10 poorly differentiated carcinomas. In 31 of 32 patients with negative nodes no occult metastases could be identified. One patient with poorly differentiated stage C cancer demonstrated occult nodal deposits by prostate specific acid phosphatase and not by prostate specific antigen. In the 11 stage D1 cancer patients immunohistochemical staining confirmed all malignant deposits and additional metastatic lesions were detected in only 1 patient. Unlike other carcinomas, such as breast, in which immunohistochemical staining yields a 14 to 37% occult metastasis rate, these data suggest that occult nodal metastases are infrequently seen in carcinoma of the prostate.

Acid Phosphatase↗
PubMed1993

High efficiency DNA transfection in murine embryonal carcinoma cells: expression of pSV3neo in wild type and retinoid-resistant cell lines.

Embryonal carcinoma cells provide a convenient and manipulable model for early embryogenesis. Like their counterparts in the inner cell mass, they are refractory to infection by several viruses. In their undifferentiated state, EC cells are resistant to calcium-phosphate DNA transfection. This resistance is compounded by the inefficient and/or actively inhibited expression of transfected genes driven by certain viral promoters. Conversely, the differentiated derivatives do not share this resistance and readily express virally promoted genes. We have developed a protocol for liposome-mediated gene transfer in EC cells and compared its efficiency in wild-type and retinoid-resistant variants. Dose response experiments with the EC cell line PCC4.aza1R showed a linear progression of colony formation when transfected with the vector pSV3neo and selected in medium containing the antibiotic G418. DNA concentrations of 10 micrograms per plate resulted in over 600 colonies per 10(6) cells. This represents a 20-30 fold greater efficiency over reported values for calcium-phosphate methods even though the neomycin resistance gene in this plasmid is driven by the SV40 viral promoter. The retinoid-resistant line PCC4(RA)-2 also showed enhanced transformation by lipofection, but despite the relatively high efficiency, colony formation rate for the differentiation-defective cells was less than 25% of the parental line. Our data indicates that there is no absolute block of genes driven by the SV40 early region promoter in murine EC cells if enough DNA is introduced to titrate out negative regulatory factors.

Animals↗