Lisa A. Cerilli

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.

A Practical Approach to Testicular Biopsy Interpretation for Male Infertility

CONTEXT The combination of testicular biopsy and clinical evaluation for male infertility is becoming progressively more important because new technologies allow men previously considered infertile to father children. Although most general pathologists are experienced with normal, neoplastic, and cryptorchid testicular specimens, the testicular biopsy for infertility requires understanding of a different set of diagnostic categories not otherwise commonly encountered. OBJECTIVE To highlight a standardized nomenclature for germ cell abnormalities allowing for effective communication with the urologist and maximal clinical benefit from the biopsy. DATA SOURCES Previously published consensus statements, review articles, peer-reviewed research publications, and abstracts. CONCLUSIONS A practical approach to evaluating testicular biopsies for fertility and the clinical implications for each abnormality are herein outlined.

Mesothelin and GPR30 Staining Among a Spectrum of Pancreatic Epithelial Neoplasms

Introduction: Our study attempts to characterize mesothelin and GPR30 / estrogen receptor (ER) staining in pancreatic pathology. Materials and Methods: Immunohistochemical staining for mesothelin, GPR30, and ER was performed on a variety of pancreatic lesions. Results: 24 of 42 (57%) adenocarcinomas stained for mesothelin, while 0 of 16 non-carcinomas (0%) stained (p = 0.0000784). 35 of 39 (90%) adenocarcinomas stained for GPR30, while only 4 of 15 (27%) non-carcinomas stained (p = 0.0000036). Apart from stromal staining in one case of mucinous cystic neoplasm, no cases stained for ER. 27 of 37 (73%) adenocarcinoma fine needle aspirates were positive for mesothelin. Discussion: GPR30 is more sensitive, but less specific than mesothelin for pancreatic adenocarcinoma. Mesothelin is detected in most adenocarcinoma fine needle aspirates. ER is rarely detected in pancreatic lesions.

Expression of the p16(INK4a) gene product in premalignant and malignant epithelial lesions of the gallbladder

The sequence of molecular changes leading to neoplastic transformation in the gallbladder remains elusive. The aim of this study is to characterize the spectrum of nuclear p16 protein product immunohistochemical expression in tissue microarray cores taken from resected gallbladders, comprising histologically normal gallbladder epithelia (n = 29), dyplastic epithelia (n = 19), reactive atypia (n = 7), and gallbladder adenocarcinoma (n = 23). Nuclear staining for p16 was evaluated for intensity (range, 0-3) and distribution (range, 0-3), and a summary staining score (range, 0-6) was obtained. Pairwise comparisons were significant for increased p16 protein expression in dysplastic epithelium (6/19, 31.6%) and invasive carcinoma (9/23, 39.1%) when compared to normal epithelium (0/29, 0%) (P = .003 and P = .0006, respectively). A quantitative increase of nuclear expression of p16 in reactive atypia (1/7, 14%) when compared to normal was also statistically significant (P = .049). Our data demonstrate that nuclear p16 expression is absent in normal gallbladder epithelium and is a frequent event in high-grade dysplasia of the gallbladder and gallbladder adenocarcinoma.

Histiocytic Lymphadenopathy Secondary to Metallosis Following Hip Replacement

Using metal alloys, high-grade plastics, and polymeric materials, surgeons can replace a dysfunctional joint with a long-lasting prosthesis. The “stem” portions of most hip implants are composed of titaniumor cobalt/chromium-based alloys; cobalt/chromium-based alloys or ceramic materials (aluminum oxide or zirconium oxide) are used in the “ball” portion. The acetabular socket is synthesized from metal, ultrahigh molecular weight polyethylene, or a combination of these materials. Over time, these composite materials may undergo significant wear, resulting in debris material and osteolysis (eg, removal of bits of bone around the implant, with a host inflammatory response). The pelvic nodes draining these areas are subject to develop a distinctive form of histiocytic lymphadenopathy. The recipient nodes become enlarged and effaced by sheets of histiocytes with abundant pale granular gray-blue cytoplasm (Figure 1). Black needles and flakes are present in the histiocytes, which represent cobalt-chromium debris fragments (Figure 2). Other debris fragments result from the metals from the prosthesis and are birefringent under polarized light (Figure 3). This form of lymphadenopathy is unusual but easily recognizable if one is familiar with its appearance.

C-kit-positive gastric metastasis of lobular carcinoma of the breast masquerading as gastrointestinal stromal tumor

A 61-year-old woman with no significant past history underwent gastric biopsies demonstrating a strongly c-kit-positive epithelioid malignancy, initially thought to represent gastrointestinal stromal tumor (GIST). Subsequent clinical and immunohistochemical evaluation proved the neoplasm to represent metastatic lobular carcinoma. This case illustrates that although c-kit is highly specific and sensitive for GIST, its expression may occur in a variety of other neoplasms, some of which morphologically resemble GIST and may present in the gastrointestinal tract as metastases. Therefore, a review of other c-kit-positive lesions is also highlighted.

Benign Intraneural Epithelium in the Breast

53-year-old woman noticed a small nodule in the left lateral breast near the axillary region. Results of a mammogram were normal. The nodule was removed and consisted of a 0.4 3 0.2 3 0.2-cm piece of fat. It contained several small intraductal papillomas with superimposed hyperplasia of ordinary type. Epithelial elements within a nearby small nerve were identified (arrow). The lack of cytologic atypia and an architectural identity to the hyperplastic component of the papilloma led us to believe this was benign epithelium. The patient received no further therapy and is well 5 months later. Perineural involvement by benign breast disease is limited to one report of 2 patients 1 and a review of 1000 consecutive breast lesions coded as sclerosing adenosis. 2 The

Small Cell Carcinoma: Arising in Lynch Syndrome: A Previously Undocumented Occurrence

Lynch syndrome is a genetic cancer predisposition syndrome caused by an inherited defect in 1 of 4 DNA mismatch repair genes (mutL homolog 1, mutS homolog 2, mutS homolog 6, and postmeiotic segregation 2). Despite the theoretically increased risk in all tissues, Lynch syndrome exhibits tissue specificity, with a particular tendency among affected individuals to develop colorectal and endometrial cancer at a young age. A number of other malignancies, including those derived from the ovary, stomach, small bowel, and urothelium, have also been linked to this syndrome. A growing body of evidence exists to support an association between mismatch repair mutations and a growing spectrum of hereditary nonpolyposis colon cancer-associated neoplasms. In this article, a previously undocumented mismatch repair-related malignancy in a patient with Lynch syndrome is reported.