Georgette A. Dent

Focal adhesion kinase as a marker of invasive potential in differentiated human thyroid cancer.

AbstractBackground: The FAK gene encodes a 125-kDa tyrosine kinase (p125FAK) involved in signal transduction pathways used in cell adhesion, motility, and anchorage-independent growth. Because thyroid carcinomas have a wide variability in their propensity for invasion and metastasis, we studied the expression of FAK in a variety of thyroid tissues. Methods: We synthesized a recombinant N-terminal fragment of the human FAK protein and developed a specific polyclonal antisera. Using Western blot analysis, we assessed the levels of p125FAK expression in 30 human thyroid tissue samples from 27 patients that included paired normal and malignant specimens. Levels of FAK protein in individual tumors were quantitated by densitometric scanning of the immunoblots, and the results were correlated with tumor histology and biologic behavior. Results: The levels of FAK expression were directly correlated with thyroid carcinomas demonstrating the most aggressive phenotypes. The highest levels of p125FAK were seen in follicular carcinomas and tumors associated with distant metastatic foci. In contrast, neoplastic thyroid tissues with limited invasive potential, such as papillary carcinomas, follicular adenomas, and other nonmalignant thyroid lesions, showed minimal p125FAK expression. Conclusions: Overexpression of FAK may be part of a mechanism for invasion and metastasis of thyroid cancer. Furthermore, the levels of p125FAK may serve as a marker of biologic behavior in this disease.

Agricultural risk factors for t(14;18) subtypes of non-Hodgkin's lymphoma.

The t(14;18) translocation is a common somatic mutation in non-Hodgkin’s lymphoma (NHL) that is associated with bcl-2 activation and inhibition of apoptosis. We hypothesized that some risk factors might act specifically along t(14;18)-dependent pathways, leading to stronger associations with t(14;18)-positive than t(14;18)-negative non-Hodgkin’s lymphoma. Archival biopsies from 182 non-Hodgkin’s lymphoma cases included in a case-control study of men in Iowa and Minnesota (the Factors Affecting Rural Men, or FARM study) were assayed for t(14;18) using polymerase chain reaction amplification; 68 (37%) were t(14;18)-positive. We estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) for various agricultural risk factors and t(14;18)-positive and -negative cases of non-Hodgkin’s lymphoma, based on polytomous logistic regression models fit using the expectation-maximization (EM) algorithm. T(14;18)-positive non-Hodgkin’s lymphoma was associated with farming (OR 1.4, 95% CI = 0.9–2.3), dieldrin (OR 3.7, 95% CI = 1.9–7.0), toxaphene (OR 3.0, 95% CI = 1.5–6.1), lindane (OR 2.3, 95% CI = 1.3–3.9), atrazine (OR 1.7, 95% CI = 1.0–2.8), and fungicides (OR 1.8, 95% CI = 0.9–3.6), in marked contrast to null or negative associations for the same self-reported exposures and t(14;18)-negative non-Hodgkin’s lymphoma. Causal relations between agricultural exposures and t(14;18)-positive non-Hodgkin’s lymphoma are plausible, but associations should be confirmed in a larger study. Results suggest that non-Hodgkin’s lymphoma classification based on the t(14;18) translocation is of value in etiologic research.

Preoperative prediction of pathological tumor volume and stage in clinically localized prostate cancer: Comparison of digital rectal examination, transrectal ultrasonography and magnetic resonance imaging

Accurate preoperative staging is important for proper selection of patients for radical retropubic prostatectomy. Preoperative staging by digital rectal examination, transrectal ultrasound, magnetic resonance imaging (MRI), Gleason grade and prostate specific antigen was compared to pathological stage for 25 patients who underwent radical retropubic prostatectomy. The predictive value for tumor confinement was 36% by rectal examination, 37% by ultrasound and 30% by MRI. The predictive value for extracapsular disease was 100% by rectal examination, 83% by ultrasound and 66% by MRI. Preoperative determinations of tumor volume by any modality did not correlate with pathological tumor volume. Digital rectal examination, ultrasound and MRI clinically understage the disease in most patients but they may be reliable to predict extracapsular disease.

Mutations of the Ki-ras oncogene in endometrial carcinoma

OBJECTIVE The purpose of this study was to assess the extent of involvement of the ras oncogene in endometrial carcinoma. STUDY DESIGN Genomic deoxyribonucleic acid from 30 samples of endometrial carcinoma was examined for point mutations in codons 12, 13, and 61 from the Ha-ras, Ki-ras, and N-ras genes by means of the polymerase chain reaction, slot-blotting, and deoxyribonucleic acid sequencing procedures. RESULTS An apparent somatic mutation of Ki-ras codon 12 in one of 10 paraffin-embedded tumors was confirmed by deoxyribonucleic acid sequence analysis. Two of 20 frozen endometrial carcinoma specimens were also shown to contain a point mutation in Ki-ras codon 12. No correlation between ras mutation and a number of histologic or clinical parameters was observed. CONCLUSIONS These data suggest a potential role for Ki-ras codon 12 mutations in the development of some (10%) endometrial cancers.

Immunohistochemistry of the androgen receptor in human benign and malignant prostate tissue

The role of the androgen receptor in the development and progression of prostatic carcinoma has not been defined. The development of androgen receptor antibodies has provided new opportunities for direct immunohistochemical analysis. We compared the androgen receptor staining characteristics of fresh human prostatic carcinoma with benign prostatic hyperplasia (BPH) using an avidin-biotin complex method. Cancer and BPH obtained from the same radical retropubic prostatectomy specimen in 10 prostate cancer patients (68.5 +/- 7.3 years old standard deviation) and BPH from 10 noncancer patients (71.5 +/- 7.7 years old) were incubated with AR52, a rabbit polyclonal antibody against a synthetic androgen receptor peptide. Nuclei within each section were graded for intensity of androgen receptor staining (0-absent, 1-weak, 2-moderate or 3-strong) and the percentage (0 to 100%) of nuclei sampled staining at each of these intensity levels was determined. A total intensity score (0 to 300) was the summation of the products of each intensity score (0 to 3) and their corresponding percentages. Cancer sections (166 +/- 69) stained less intensely and more heterogeneously than BPH in cancer patients (246 +/- 41, Students t test p < 0.05) and noncancer patients (225 +/- 39, p < 0.05). The decreased intensity and greater heterogeneity of androgen receptor staining in cancer tissue may implicate a quantitative or functional difference in androgen receptor between prostatic carcinoma and BPH.

A case-control study of tobacco use and other non-occupational risk factors for t(14;18) subtypes of non-Hodgkin's lymphoma (United States)

Objective: Non-Hodgkins lymphoma (NHL) encompasses diverse subtypes, and analyzing NHL as a single outcome may mask associations. In a new approach we evaluated associations with subtypes defined by the t(14;18) translocation, reasoning that cases within these subtypes would have more common risk factors than all NHL Combined. Methods: Archival biopsies from cases in a population-based NHL study were assayed for t(14;18) using polymerase chain reaction amplification. Exposures in 68 t(14;18)-positive and 114-negative cases were compared with 1245 controls. The expectation–maximization algorithm was used to fit polytomous regression models based on all available information, including data from 440 unclassified cases. Results: Family history of hemolymphatic cancer was associated with t(14;18)-negative NHL (odds ratio (OR) 2.4, 95% confidence interval (CI) 1.4–3.9), but not t(14;18)-positive NHL. Cigarette smoking was weakly associated with t(14;18)-positive NHL (OR 1.7, CI 0.9–3.3), but ORs decreased as smoking increased. Chewing tobacco was associated with t(14;18)-positive NHL, particularly when used before age 18 (OR 2.5, CI 1.0–6.0, 13 exposed cases). Odds ratios for both case-subtypes were doubled among hair-dye users. Conclusions: Cigarette smoking was not clearly associated with t(14;18)-positive NHL. Family history may be a marker for factors that act specifically through t(14;18)-negative pathogenic mechanisms.

Mature B-cell acute lymphoblastic leukemia with associated translocations (14;18)(q32;q21) and (8;9)(q24;p13): A Burkitt variant?

The translocation t(14;18)(q32;q21) is most commonly associated with follicular lymphoma but has also been described in acute lymphoblastic leukemia (ALL) of B-cell origin. Although these ALL cases have had a pre-pre-B, pre-B, or mature B-cell immunophenotype and L2 or L3 morphology, all have been associated with an abnormality of 8q24. In fact, 91% (10 of 11) have been associated with t(8;22) or t(8;14), marker chromosomes for Burkitt-type ALL. The other case was associated with del(8)(q24). Thus, Burkitt-type ALL may have various immunophenotypes and morphology when associated with t(14;18). We describe a case of mature B-cell ALL associated with t(14;18) and t(8;9)(q24;p13). The morphology was suggestive but not entirely characteristic of the L3 subtype. However, on the basis of the cytogenetic findings and the review of the literature, perhaps this case represents a variant of Burkitt-type ALL, which would be important to recognize for prognostic and therapeutic purposes. We describe our findings and review the literature to heighten awareness of this group of ALLs associated with t(14;18). Additional cases need to be accrued and documented to determine the significance of an associated abnormality of 8q24 in this setting.

Loss of heterozygosity on chromosome 17q11-21 in cancers of women who have both breast and ovarian cancer.

OBJECTIVE Our purpose was to determine the frequency of allele loss in the region of the BRCA1 gene in cancers of women who have both breast and ovarian cancer. STUDY DESIGN Four polymorphic microsatellite markers on chromosome 17q11-21 were examined by the polymerase chain reaction in deoxyribonucleic acid from paraffin blocks of normal tissues, breast cancers, and ovarian cancers in 24 women who had primary cancers in both sites. RESULTS Loss of heterozygosity was seen in one or more markers on chromosome 17q11-21 in 46% of breast cancers and 78% of ovarian cancers. In 38% of cases allele loss was seen in both cancers, and in all these cases the same allele was lost in both cancers. Significantly younger ages at diagnosis of both breast and ovarian cancer were noted among cases with allele loss in both cancers compared with cases in which allele loss was found only in the ovarian cancer (p < 0.05). CONCLUSIONS Because cases in which 17q11-21 allele loss was seen in both cancers had a young age of onset and the same allele was always deleted in both cancers, hereditary alterations in BRCA1 may play a role in this subset. The older age of onset in cases in which allele loss was seen only in the ovarian cancer suggests that the development of these cancers is not related to an inherited defect in BRCA1.

Non-Hodgkin Lymphoma (NHL) subtypes defined by common translocations: utility of fluorescence in situ hybridization (FISH) in a case-control study

We used fluorescence in situ hybridization (FISH) assays to identify t(14;18) translocations in archival paraffin-embedded tumor sections from non-Hodgkin lymphoma (NHL) cases enrolled in a population-based study. t(14;18) was identified in 54% of 152 cases, including 39% of diffuse large cell lymphomas (26 of 66 cases) and 84% of follicular lymphomas (36 of 43 cases). Eighty-seven percent of t(14;18)-positive cases and 57% of t(14;18)-negative cases expressed bcl-2. FISH assays detected twice as many t(14;18)-positive follicular lymphomas as PCR assays. Overall, study findings support the use of FISH assays to detect t(14;18) in archival tumor samples for epidemiologic studies of NHL subtypes.

An Expanded Phase I/II Trial of Cyclophosphamide, Etoposide, and Carboplatin Plus Total Body Irradiation with Autologous Marrow or Stem Cell Support for Patients with Hematologic Malignancies

The major cause for failure of autologous stem cell transplantation for hematologic malignancies is the risk of recurrent disease. As a result, new treatment regimens that include novel agents or combinations of agents and approaches are needed. The current report describes a large Phase I/II, single-center trial that includes 60 patients with a variety of hematologic malignancies. These patients received a fixed dose of carboplatin (1 g/m(2)/d x 72 hours by CI) etoposide (600 mg/m(2)/d x 3 days) and cyclophosphamide (2 g/m(2)/d x 3 days), plus escalating doses of total body irradiation (TBI) (at 1000, 1200, and 1295 cGy) over 3 days. Eleven patients received infusion of autologous marrow, 32 received peripheral blood stem cells, and 17 patients received both. The maximum tolerated dose of this regimen was a radiation dose of 1200 cGy given in 200-cGy fractions BID x 3 days. The dose-limiting toxicity was mucositis, with 97% of patients requiring narcotic analgesia for mouth pain. Overall treatment-related mortality was 6.7%, with 2 of the 4 deaths occurring in a group of 9 patients aged 60 and older. Responses were seen in all patient groups, but the most encouraging outcomes were seen in 12 patients with high-risk or advanced acute myelocytic lymphoma (AML), 7 of whom remain alive and free of disease beyond 5 years. This regimen is intensive and causes considerable mucositis but is otherwise well tolerated and has demonstrated activity in a number of hematologic malignancies, especially AML.