Therese Bocklage

The XRCC1 399 glutamine allele is a risk factor for adenocarcinoma of the lung

Defects in the repair and maintenance of DNA increase risk for cancer. X-ray cross-complementing group 1 protein (XRCC1) is involved with the repair of DNA single-strand breaks. A nucleotide substitution of guanine to adenine leading to a non-conservative amino acid change was identified in the XRCC1 gene at codon 399 (Arg/Gln). This change is associated with higher levels of aflatoxin B1-adducts and glycophorin A somatic mutations. A case-control study was conducted to test the hypothesis that the 399Gln allele is positively associated with risk for adenocarcinoma of the lung. XRCC1 genotypes were assessed at codon 399 in 172 cases of lung adenocarcinoma and 143 cancer-free controls. Two ethnic populations were represented, non-Hispanic White and Hispanic. The distribution of XRCC1 genotypes differed between cases and controls. Among cases, 47.7% were Arg/Arg, 35.5% were Arg/Gln, and 16.9% were Gln/Gln. Among controls, XRCC1 allele frequencies were 45.5% for Arg/Arg, 44.8% for Arg/Gln, and 9.8% for Gln/Gln. Logistic regression analysis was used to assess the association between lung adenocarcinoma and the G/G genotype relative to the A/A or A/G genotypes. In non-Hispanic White participants, the lung cancer risk associated with the G/G genotype increased significantly after adjustment for age (OR=2.81; 95% CI, 1.2-7.9; P=0.03) and increased further after adjustment for smoking (OR=3.25; 95% CI, 1.2-10.7; P=0.03). Among all groups, a significant association was found between the G/G homozygote and lung cancer (OR=2.45; 95% CI, 1.1-5.8; P=0.03) after adjustment for age, ethnicity, and smoking. This study links a functional polymorphism in the critical repair gene XRCC1 to risk for adenocarcinoma of the lung.

Predicting gene promoter methylation in non-small-cell lung cancer by evaluating sputum and serum

The use of 5-methylcytosine demethylating agents in conjunction with inhibitors of histone deacetylation may offer a new therapeutic strategy for lung cancer. Monitoring the efficacy of gene demethylating treatment directly within the tumour may be difficult due to tumour location. This study determined the positive and negative predictive values of sputum and serum for detecting gene methylation in primary lung cancer. A panel of eight genes was evaluated by comparing methylation detected in the primary tumour biopsy to serum and sputum obtained from 72 patients with Stage III lung cancer. The prevalence for methylation of the eight genes in sputum (21–43%) approximated to that seen in tumours, but was 0.7–4.3-fold greater than detected in serum. Sputum was superior to serum in classifying the methylation status of genes in the tumour biopsy. The positive predictive value of the top four genes (p16, DAPK, PAX5 β, and GATA5) was 44–72% with a negative predictive value for these genes ⩾70%. The highest specificity was seen for the p16 gene, and this was associated with a odds ratio of six for methylation in the tumour when this gene was methylated in sputum. In contrast, for serum, the individual sensitivity for all genes was 6–27%. Evaluating the combined effect of methylation of at least one of the four most significant genes in sputum increased the positive predictive value to 86%. These studies demonstrate that sputum can be used effectively as a surrogate for tumour tissue to predict the methylation status of advanced lung cancer where biopsy is not feasible.

Phase IB study of the combination of docetaxel, gemcitabine, and bevacizumab in patients with advanced or recurrent soft tissue sarcoma: the Axtell regimen.

BACKGROUND To assess the response of patients with soft tissue sarcoma (STS) to the combination of docetaxel, bevacizumab, and gemcitabine. Vascular endothelial growth factor (VEGF)-A levels and expression of VEGF-A and VEGF receptors 1 and 2 were evaluated. PATIENTS AND METHODS Thirty-eight chemotherapy-naive patients with STS were enrolled. A dose-finding study for gemcitabine from 1000, 1250, then 1500 mg/m(2) was done in nine patients (three cohorts), followed by an expansion cohort of 27 patients. Dose of docetaxel was 50 mg/m(2), bevacizumab was 5 mg/kg, and gemcitabine was 1500 mg/m(2), every 2 weeks. Serum VEGF-A was measured by enzyme-linked immunosorbent assay and tissue VEGF-A and its receptors by immunohistochemistry. RESULTS The median follow-up was 36 months. The overall response rate observed was 31.4%, with 5 complete and 6 partial responses, and 18 stable diseases lasting for a median of 6 months. There was no significant hematologic toxicity. The adverse events with the highest grade were attributed to bevacizumab. There was no correlation of VEGF pathway biomarkers with outcome. CONCLUSIONS The combination of gemcitabine, docetaxel, and bevacizumab is safe and effective in patients with STS. The most concerning adverse events were consequences of bevacizumab administration. The benefit of bevacizumab in this patient population remains unclear.BACKGROUND To assess the response of patients with soft tissue sarcoma (STS) to the combination of docetaxel, bevacizumab, and gemcitabine. Vascular endothelial growth factor (VEGF)-A levels and expression of VEGF-A and VEGF receptors 1 and 2 were evaluated. PATIENTS AND METHODS Thirty-eight chemotherapy-naive patients with STS were enrolled. A dose-finding study for gemcitabine from 1000, 1250, then 1500 mg/m2 was done in nine patients (three cohorts), followed by an expansion cohort of 27 patients. Dose of docetaxel was 50 mg/m2, bevacizumab was 5 mg/kg, and gemcitabine was 1500 mg/m2, every 2 weeks. Serum VEGF-A was measured by enzyme-linked immunosorbent assay and tissue VEGF-A and its receptors by immunohistochemistry. RESULTS The median follow-up was 36 months. The overall response rate observed was 31.4%, with 5 complete and 6 partial responses, and 18 stable diseases lasting for a median of 6 months. There was no significant hematologic toxicity. The adverse events with the highest grade were attributed to bevacizumab. There was no correlation of VEGF pathway biomarkers with outcome. CONCLUSIONS The combination of gemcitabine, docetaxel, and bevacizumab is safe and effective in patients with STS. The most concerning adverse events were consequences of bevacizumab administration. The benefit of bevacizumab in this patient population remains unclear.

Collagen and biphasic calcium phosphate bone graft in large osseous defects.

The cavity left by the removal of tumors represents a challenge for the orthopedic oncologic surgeon. This article takes a critical look at the use of a synthetic bone graft to fill the residual space. A combination of hydroxyapatite, tricalcium phosphate, and bovine collagen was used for intramedullary tumors. Thirty patients were followed for an average of 23 months. The majority (93%) returned to full activity with only 6 (20%) complications. Study results showed collagen and biphasic calcium phosphate ceramic bone graft makes an effective substrate for filling intramedullary cavities remaining after tumor excision.

Solitary Fibrous Tumor of the Orbit With a t(9;22)(q31;p13)

Solitary fibrous tumors are well-described neoplasms found predominantly in the subpleural region but also in many other body sites. They generally behave in a benign fashion, although a few cases that exhibit a malignant course have been reported. Genetic information on solitary fibrous tumors is sparse. This case illustrates a previously unreported finding of a tumor-specific t(9;22)(q31;p13) in a solitary fibrous tumor of the orbit of a 58-year-old man.

Estrogen and progesterone receptor status and outcome in epithelial ovarian cancers and low malignant potential tumors

OBJECTIVE Receptors for estrogen (ER) and progesterone (PR) are prognostic indicators for a variety of endocrine tumors including breast and endometrial. This study was conducted to determine if ER and PR expression patterns are predictive of outcome in patients with epithelial ovarian cancer (EOC) or ovarian low malignant potential (LMP) tumors. METHODS ER and PR protein levels were assessed by immunohistochemistry in 45 LMP and 89 EOC samples. Patterns of ER/PR expression (individually and combinations of ER-/PR-, ER+/PR-, ER-/PR+, and ER+/PR+) were correlated with standard prognostic factors of overall survival (OS) in this patient population. RESULTS For patients with EOC, the 5-year OS per ER-/PR+, ER+/PR-, ER+/PR+, and ER-/PR- expression was 83%, 79%, 61%, and 48%, respectively, and these differences were statistically significant. In multivariate analyses, ER/PR expression patterns were found to be independent predictors of OS, as were the classical prognostic factors of grade, stage, debulking, and chemotherapy response to treatment. In patients with mucinous LMP tumors, ER and PR were absent. Because no LMP patients died of disease during the studied period, no correlation analysis with OS could be performed. CONCLUSIONS Patterns of ER/PR expression provide prognostic information in EOC. Additional studies evaluating hormonal inhibition may help personalize the therapy of patients with ovarian cancer.

In vivo light scattering for the detection of cancerous and precancerous lesions of the cervix

A noninvasive optical diagnostic system for detection of cancerous and precancerous lesions of the cervix was evaluated in vivo. The optical system included a fiber-optic probe designed to measure polarized and unpolarized light transport properties of a small volume of tissue. An algorithm for diagnosing tissue based on the optical measurements was developed that used four optical properties, three of which were related to light scattering properties and the fourth of which was related to hemoglobin concentration. A sensitivity of ~77% and specificities in the mid 60% range were obtained for separating high grade squamous intraepithelial lesions and cancer from other pathologies and normal tissue. The use of different cross-validation methods in algorithm development is analyzed, and the relative difficulties of diagnosing certain pathologies are assessed. Furthermore, the robustness of the optical system for use by different doctors and to changes in fiber-optic probe are also assessed, and potential improvements in the optical system are discussed.

Aspiration Cytology Features of the Warthin Tumor–Like Variant of Papillary Thyroid Carcinoma

BACKGROUND Warthinklike tumor of thyroid is a recently described variant of papillary thyroid carcinoma characterized histologically by a papillary architecture, oxyphilic tumor cells and extensive, chronic inflammation. CASES Fine needle aspiration was performed on solitary thyroid nodules in two females aged 19 and 35 years. Both patients complained of neck lumps, and the older one noted several months of fatigue and weight gain. The specimens were cytologically similar and were characterized by two distinct sets of features, one suggesting the tall cell or oxyphilic variant of papillary thyroid carcinoma and the other suggesting chronic lymphocytic (Hashimotos) thyroiditis. Neoplastic follicular cell nuclei were divided into those with grooves, pseudoinclusions and hyperlobation consistent with papillary thyroid carcinoma, while other tumor nuclei exhibited a uniform, round contour; hypergranular chromatin; and relatively prominent nucleoli reminiscent of Hürthle cells. Chronic inflammation was abundant and intimately associated with neoplastic cell groups. CONCLUSION Warthinlike tumor of the thyroid possesses cytoplasmic and nuclear features with overlap with several other thyroid lesions. Although a definitive diagnosis at aspiration biopsy may be very difficult, the lesions are recognizably neoplastic and identifiable as probable or definite papillary thyroid carcinoma.

Two Cases of Sarcoma Arising in Giant Cell Tumor of Bone Treated with Denosumab.

Giant cell tumor (GCT) of bone is a generally benign, but often locally aggressive, neoplasm of bone, with a propensity for recurrence. Sarcomatous transformation is rare and typically occurs with a history of recurrences and radiation treatment. Denosumab, an inhibitor of the RANK ligand involved in bone resorption in GCT, is increasingly used in treatment of recurrent or unresectable giant cell tumor of bone. We report two cases of sarcomatous transformation of GCT to osteosarcoma in patients receiving denosumab. One was a 59-year-old male with a 12-year history of GCT and multiple recurrences taking denosumab for 2.5 years. The second case was in a 56-year-old male with a seven-year history of GCT taking denosumab for six months. Review of the literature shows one case report of malignant transformation of GCT in a patient being treated with denosumab. As the use of denosumab for treatment of GCT will likely increase, larger, controlled studies are needed to ascertain whether denosumab may play a role in malignant transformation of giant cell tumor of bone.

Fine-needle aspiration biopsy of large-cell undifferentiated carcinoma of the salivary glands: Presentation of two cases, literature review, and differential cytodiagnosis of high-grade salivary gland malignancies

Primary undifferentiated carcinoma of the salivary glands is a rare, high‐grade neoplasm which accounts for a very small number (1–5.5%) of malignant salivary gland tumors. The large‐cell variant (LCU) is less well‐characterized than the small‐cell form. We report on the fine‐needle aspiration (FNA) biopsy findings of 2 cases of LCU, one arising in the parotid gland, and the other in a buccal mucosa accessory salivary gland. The 2 cases were similar in composition: isolated and loosely cohesive large cells with abundant cytoplasm, and variably pleomorphic nuclei with prominent nucleoli. One case also featured multinucleated tumor giant cells and macrophage polykaryons; the latter has not previously been described in FNA biopsies of LCU. There was no evidence of squamous, myoepithelial, or widespread mucinous differentiation by morphological, cytochemical, or immunohistochemical analyses (focal rare mucin production was identified on special stains in one case). The differential diagnosis is lengthy and consists of other high‐grade primary salivary gland malignancies as well as metastatic lesions, including melanoma. The pattern of immunohistochemical reactivity (positive keratin, negative S‐100, and HMB‐45 antigens), and lack of conspicuous mucin production or significant lymphoid infiltrate, were useful in establishing the correct diagnosis. Diagn. Cytopathol. 1998;19:44–50.