Mia Perez

Early diagnostic value of survivin and its alternative splice variants in breast cancer.

BackgroundThe inhibitor of apoptosis (IAP) protein Survivin and its splice variants are differentially expressed in breast cancer tissues. Our previous work showed Survivin is released from tumor cells via small membrane-bound vesicles called exosomes. We, therefore, hypothesize that analysis of serum exosomal Survivin and its splice variants may provide a novel biomarker for early diagnosis of breast cancer.MethodsWe collected sera from forty breast cancer patients and ten control patients who were disease free for 5 years after treatment. In addition, twenty-three paired breast cancer tumor tissues from those same 40 patients were analyzed for splice variants. Serum levels of Survivin were analyzed using ELISA and exosomes were isolated from this serum using the commercially available ExoQuick kit, with subsequent Western blots and immunohistochemistry performed.ResultsSurvivin levels were significantly higher in all the breast cancer samples compared to controls (pu2009<u20090.05) with exosome amounts significantly higher in cancer patient sera compared to controls (pu2009<u20090.01). While Survivin and Survivin-∆Ex3 splice variant expression and localization was identical in serum exosomes, differential expression of Survivin-2B protein existed in the exosomes. Similarly, Survivin and Survivin-∆Ex3 proteins were the predominant forms detected in all of the breast cancer tissues evaluated in this study, whereas a more variable expression of Survivin-2B level was found at different cancer stages.ConclusionIn this study we show for the first time that like Survivin, the Survivin splice variants are also exosomally packaged in the breast cancer patients’ sera, mimicking the survivin splice variant pattern that we also report in breast cancer tissues. Differential expression of exosomal-Survivin, particularly Survivin-2B, may serve as a diagnostic and/or prognostic marker, a “liquid biopsy” if you will, in early breast cancer patients. Furthermore, a more thorough understanding of the role of this prominent antiapoptotic pathway could lead to the development of potential therapeutics for breast cancer patients.

Congenital Granular Cell Epulis

Congenital granular cell epulis is a rarely reported lesion of unknown histogenesis with a strong predilection for the maxillary alveolar ridge of newborn girls. Microscopically, it demonstrates nests of polygonal cells with granular cytoplasm, a prominent capillary network, and attenuated overlying squamous epithelium. The lesion lacks immunoreactivity for S-100, laminin, chromogranin, and most other markers except neuron-specific enolase and vimentin. Through careful observation of its unique clinical, histopathologic, and immunohistochemical features, this lesion can be distinguished from the more common adult granular cell tumor as well as other differential diagnoses.

Outpatient Intravenous Interleukin-2 with Famotidine Has Activity in Metastatic Melanoma

UNLABELLEDnDaily short intravenous interleukin-2 (IL-2) infusions have been developed to decrease toxicity while maintaining the anticancer activity of this agent against melanoma. Such IL-2 schedules have previously been shown to promote lymphokine-activated killer cell (LAK) activity. Famotidine may increase LAK activity by increasing IL-2 internalization by the IL-2 receptor on lymphocytes. Twenty-one patients with metastatic melanoma were treated with IL-2 18 million IU/m² intravenously (i.v.) over 15-30 minutes and famotidine 20 mg i.v. daily for 3 days for 6 consecutive weeks on an outpatient basis. Cycles were repeated every 8 weeks.nnnPATIENT CHARACTERISTICSn13 males/8 females, median age, 51 (range: 26-79), and median Eastern Cooperative Oncology Group performance status, 1; common metastatic sites: lymph nodes (16), lungs (14), subcutaneous (8), liver (7), and bone (7). Prior systemic therapy: chemotherapy (7); IL-2 (7); and interferon (5). Most common toxicities were myalgia/arthralgia, rigors, nausea/emesis, and mild elevation of liver function tests. No patients required hospitalization for toxicity of therapy. One patient (5%) has had a complete response (ongoing at 29+ months), while 4 other patients (19%) had partial responses (total response rate: 24%; 95% confidence interval: 9%-48%). Responses occurred in lung, spleen, bones, lymph nodes, and subcutaneous sites. Median response duration=20+ months. Outpatient intravenous IL-2 and famotidine has activity in melanoma.

Early diagnostic value of survivin and its alternative splice variants in breast cancers.

35 Background: The inhibitor of apoptosis (IAP) protein Survivin and its splice variants are differentially expressed in breast cancer tissues and have recently been shown to be released from tumor cells via small membrane-bound vesicles called exosomes. Tumor-derived exosomes play multiple roles in tumor growth and metastasis and may produce these functions by impacting immune escape, tumor invasion and angiogenesis. We, therefore, hypothesize that analysis of exosomal Survivin and its splice variants may provide a novel biomarker for early diagnosis of breast cancer in addition to current recommended methods.nnnMETHODSnTwenty paired breast cancer patients sera and tumor tissue, and ten normal control sera were used for analysis. ELISA was performed to quantitate serum levels of Survivin. Exosomes were isolated from the sera using Exoquick. RT-PCR, western blots with densitometry, and immunohistochemistry followed by confocal microscopy were then performed.nnnRESULTSnFor each breast cancer patient serum, Survivin levels were significantly higher compared to control (p<0.05). While Survivin and the DEx3 splice variant expression and localization were similar, differential expression of Survivin and the 2B splice variant protein and mRNA existed in the exosomes and tissue samples. Survivin and -DEx3 proteins were the predominant forms detected in 100% (20/20) of the breast cancer tissues evaluated, whereas a more variable expression of Survivin-2B, with enhanced levels found in areas of necrosis. We also for the first time here show the exosomal localization of Survivin and its splice variants DEx3 and 2B in sera from breast cancer patients.nnnCONCLUSIONSnThe result of the proposed project supports our hypothesis that differential expression of exosomal-Survivin and its alternative splice variants may serve as a diagnostic marker in breast cancer patients. For future direction, we plan to study the prognostic value of exosomal-Survivin and its splice variants on a large panel of primary breast cancers within a setting of well-followed clinical outcomes.

Diffuse Hepatic Epithelioid Hemangioendothelioma Developed in a Patient with Hepatitis C Cirrhosis

Hepatic epithelioid hemangioendothelioma (HEHE) is an infrequent vascular tumor of endothelial origin that primarily occurs in women in the mid-fifth decade of life without underlying chronic liver disease or cirrhosis. Liver transplant should be the first-line of therapy in patients with large or diffuse unresectable tumors even in the presence of metastatic disease due to the favorable long-term outcome. We report the case of a 48-year-old female who complained of abdominal pain and weight loss. She has a history of cirrhosis secondary to chronic hepatitis C (HCV) and was treated with interferon and ribavirin with sustained virological response. Her work-up revealed multiple confluent infiltrating bilobar liver masses diagnosed as HEHE. She underwent a successful liver transplant without evidence of recurrent HCV infection. She developed cervical spine (C4-C6) HEHE metastases 4 years after transplant. She underwent surgical resection and local radiotherapy after resection with good clinical response. To the best of our knowledge, this is the first report of HEHE that developed in a patient with HCV cirrhosis successfully treated with antiviral therapy before transplant and liver transplant with good allograft function without evidence of recurrent liver tumor or HCV infection but developed metastases to the cervical spine 4 years after transplant.

Hemangioendothelioma with a Prominent Lymphoid Infiltrate Mimicking Follicular Dendritic Cell Tumor: Report of a Case

Abstract: Hemangioendothelioma is a vascular tumor with several different morphologic patterns that can include a component of ovoid or spindled cells, but generally lacks an inflammatory component. The combined morphologic and immunohistochemical features are generally sufficient to accurately diagnose this tumor and its many variants. We present a challenging lymphocyte-rich soft tissue lesion that was not recognized to be an unusual hemangioendothelioma until after several recurrences in the arm of a 63 year-old male, which was originally diagnosed as a follicular dendritic cell tumor instead. Local recurrence developed 3 and 11 years later with resections. The most recent tumor consisted predominantly of epithelioid spindled cells with moderate amounts of bubbly pale to eosinophilic cytoplasm with rare discrete cytoplasmic vacuoles, admixed with a prominent lymphoid infiltrate and occasional erythrocytes. The tumor cells were positive for keratin and vascular markers (CD31, CD34, and Factor VIII), but negative for follicular dendritic cell markers (CD21, CD23, CD35). Slides from the two previous excisions were re-analyzed, and showed the same morphologic and immunohistochemical features as the latest recurrence. The diagnosis was revised to recurrent lymphocyte-rich hemangioendothelioma. The patient is free of tumor at 7 years follow-up. This represents an unusual and potentially confusing pattern of hemangioendothelioma that is not previously well described in the literature. Vascular tumors should be included in the differential diagnosis of suspected dendritic cell tumors, even if a lymphocyte-rich infiltrate is present. Vascular as well as dendritic cell markers should be included in the immunohistochemical panel employed in their evaluation.

Recognizing the distinct cytomorphologic features of solid pseudopapillary neoplasm of the pancreas

Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare low-grade malignant tumor with an indolent clinical course and a favorable prognosis that is most commonly seen in young women of reproductive age. We present a case of SPN in a middle-aged man, diagnosed on a limited cytology specimen. Interestingly, this tumor has unique cytomorphologic findings in fine needle aspiration cytology smears, which help distinguish it from other pancreatic lesions. The presence of fibrovascular cores lined by loosely cohesive monomorphic neoplastic cells is a reliable cytomorphologic feature on aspiration cytology. Recognition of this characteristic finding is crucial for the diagnosis of this entity, especially when it presents in unexpected patient populations or when faced with scant cytology specimens. This report focuses on the distinguishing characteristics of SPN and how they compare and contrast with other pancreatic lesions that are in the differential diagnosis of SPN.

Linking obesity-induced leptin-signaling pathways to common endocrine-related cancers in women

Obesity is related to many major diseases and cancers. Women have higher rates of obesity and obesity is linked to commonly occurring cancers in women. However, there is a lack of knowledge of the unique mechanism(s) involved in each type of cancer. The objective of this review is to highlight the need for novel experimental approaches and a better understanding of the common and unique pathways to resolve controversies regarding the role of obesity in cancer. In women, there is a link between hormones and obesity-associated genes in cancer development. Leptin is an obesity-associated gene that has been studied extensively in cancers; however, whether the defect is in the leptin gene or in its signaling pathways remains unclear. Both leptin and its receptor have been positively correlated with cancer progression in some endocrine-related cancers in women. This review offers an up-to-date and cohesive review of both upstream and downstream pathways of leptin signaling in cancer and a comprehensive picture of cancer pathogenesis in light of current evidence of leptin effects in several major types of cancer. This work is intended to aid in the design of better therapeutic strategies for obese/overweight women with cancer.

Pathologic significance of a novel oncoprotein in thyroid cancer progression

The incidence of thyroid cancer is increasing worldwide, and there is an emerging need to develop accurate tools for diagnosis. Fine needle aspiration biopsy has greatly improved evaluation of thyroid nodules, but challenges with indeterminate lesions remain in up to 25% of biopsies. Novel tissue biomarkers may assist in improved nodule characterization. Microcalcifications occurring in thyroid cancers suggest proteins involved in bone formation may play a role in thyroid carcinogenesis. We evaluated the expression of the known osteogenic protein, Enigma, in thyroid cancer as a candidate oncoprotein and role in carcinogenesis based on association with other known oncoproteins such as bone morphogenetic protein‐1 (BMP‐1).