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Wendy L Frankel

Publications and source records attributed to Wendy L Frankel.

At least 37 records · Page 2Linked to original sources
PubMed2005

CDX2 is a useful marker of intestinal-type differentiation: a tissue microarray-based study of 629 tumors from various sites.

CONTEXT: CDX2, a critical nuclear transcription factor for intestinal development, is expressed in intestinal epithelium and adenocarcinomas. OBJECTIVES: To determine if CDX2 is a useful marker for intestinal-type differentiation and to correlate tumor histology with CDX2 staining in colorectal adenocarcinomas. DESIGN: Tissue microarrays from 71 colorectal adenocarcinomas, 31 hepatocellular carcinomas, 47 lung adenocarcinomas, 55 squamous cell carcinomas of the lung, 69 neuroendocrine carcinomas of the lung and 43 of the pancreas, 57 pancreatic adenocarcinomas, and 256 endometrial adenocarcinomas were stained with antibody against CDX2. RESULTS: CDX2 staining was positive in 51 (71.8%) of 71 colorectal cancers, including 38 (74.5%) of 51 well- or moderately differentiated tumors and 13 (65.0%) of 20 high-grade tumors. Of the high-grade tumors, 5 (71.4%) of 7 mucinous, 3 (100%) of 3 signet ring cell, and 5 (50.0%) of 10 poorly differentiated tumors were positive. Other tumors showing occasional CDX2 staining included 1 of 30 well- or moderately differentiated neuroendocrine carcinomas of the lung and 2 of 43 from the pancreas, 1 of 47 lung adenocarcinomas, 3 of 57 pancreatic adenocarcinomas, and 15 of 256 endometrial carcinomas. Hepatocellular, poorly differentiated neuroendocrine carcinoma of the lung and squamous cell carcinomas of the lung were not immunoreactive for CDX2. CONCLUSIONS: CDX2 is a useful marker for intestinal-type differentiation, is rarely seen in tumors from the other sites evaluated, and may be useful in determining the site of origin for some metastatic tumors. However, CDX2 is not a sensitive marker for poorly differentiated colorectal carcinoma.

Adenocarcinoma↗
PubMed2004

Evidence for tissue-directed immune responses: analysis of CD4- and CD8-dependent alloimmunity.

BACKGROUND: Transplant rejection has generally been considered a CD4 T-cell-dependent immune process. CD4-independent, CD8 T-cell rejection pathways have recently gained attention because of their relative resistance to immunosuppression. In the current study, the role of the allograft tissue in activation of these distinct pathways was examined by comparing host-immune responses with allogeneic pancreatic islets or hepatocytes transplanted across the same genetic disparity. METHODS: To compare activation of CD4-dependent versus CD8-dependent alloimmunity, islets or hepatocytes retrieved from FVB/N (H-2) mice were transplanted into CD8 or CD4 T-cell-reconstituted severe combined immunodeficiency mice, CD4 or CD8 knockout (KO) mice, and anti-CD4 monoclonal antibody (mAb) or anti-CD8 mAb treated C57BL/6 mice (all H-2). The ability to immunomodulate CD4-dependent allograft rejection (in CD8 KO mice) was examined in the context of several mechanistically distinct immunotherapeutic strategies, including anti-CD4 mAb, donor-specific transfusion and anti-CD154 mAb, and anti-lymphocyte function-associated antigen-1 mAb. RESULTS: The studies demonstrate that, whereas hepatocytes evoke alloreactive CD4-dependent and (CD4-independent) CD8 T-cell immune responses, allogeneic islets only activate CD4-dependent immune pathways. CD4-dependent host-immune responses initiated by pancreatic islet allografts were readily suppressed by a variety of short-term immunotherapies, whereas hepatocyte-initiated CD4-dependent alloimmune responses were not. CONCLUSIONS: These results demonstrate that immune characteristics of the specific allograft tissue uniquely influence the pattern of host immune responses such that the propensity to activate CD4- or CD8-dependent alloimmune responses can be distinguished. Furthermore, CD4-dependent immune responses activated by different tissues from the same donor strain are distinguished by their susceptibility to specific immunotherapy.

Animals↗
PubMed2004

Role of cancer-associated stromal fibroblasts in metastatic colon cancer to the liver and their expression profiles.

The cancer microenvironment and interaction between cancer and stromal cells play critical roles in tumor development and progression. The molecular features of cancer stroma are less well understood than those of cancer cells. Cancer-associated stromal fibroblasts are the predominant component of stroma associated with colon cancer and its functions remain unclear. Fibroblast cell cultures were established from metastatic colon cancer in liver, liver away from the metastatic lesions, and skin from three patients with metastatic colorectal cancer. We generated expression profiles of cancer-associated fibroblasts using oligochip arrays and compared them to those of uninvolved fibroblasts. The conditioned media from the cancer-associated fibroblast cultures enhanced proliferation of colon cancer cell line HCT116 to a greater extent than cultures from uninvolved fibroblasts. In microarray expression analysis, cancer-associated fibroblasts clustered tightly into one group and skin fibroblasts into another. Approximately 170 of 22,000 genes were up-regulated in cancer-associated fibroblasts (fold change > 2, P < 0.05) as compared to skin fibroblasts, including many genes encoding cell adhesion molecules, growth factors, and COX2. By immunohistochemistry in-vivo, we confirmed COX2 and TGFB2 expression in cancer-associated fibroblasts in metastatic colon cancer. The distinct molecular expression profiles of cancer-associated fibroblasts in colon cancer metastasis support the notion that these fibroblasts form a favorable microenvironment for cancer cells.

Cell Line, Tumor↗
PubMed2004

Mismatch repair gene PMS2: disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation.

The MutLalpha heterodimer formed by mismatch repair (MMR) proteins MLH1 and PMS2 is a major component of the MMR complex, yet mutations in the PMS2 gene are rare in the etiology of hereditary nonpolyposis colorectal cancer. Evidence from five published cases suggested that contrary to the Knudson principle, PMS2 mutations cause hereditary nonpolyposis colorectal cancer or Turcot syndrome only when they are biallelic in the germline or abnormally expressed. As candidates for PMS2 mutations, we selected seven patients whose colon tumors stained negative for PMS2 and positive for MLH1 by immunohistochemistry. After conversion to haploidy, truncating germline mutations of PMS2 were found in two patients (2192delTAACT and deletion of exon 8). These mutations abrogated PMS2 protein in germline cells by Western analysis. In two additional patients, PMS2 protein from one allele also was abrogated. Novel or previously described missense variants of PMS2 were detected, but their pathogenicity is undetermined. We detected and characterized a new transcript, PMS2CL, showing 98% sequence identity with exons 9 and 11-15 of PMS2 and emanating from a locus close to PMS2 in chromosome 7p. Its predicted protein product was not detected. Thus, in addition to several previously described PMS2-related genes resembling the 5' end of PMS2, at least one related gene resembles the 3' end of PMS2. In conclusion, both detectable and presently undefined germline mutations are deleterious and produce susceptibility to cancer by the two-hit mechanism. Paralogous genes interfere with mutation detection, resulting in underdiagnosis of PMS2 mutations. Mutation detection in PMS2 requires haploid DNA.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Hepatocellular adenomatosis is a rare entity that may mimic other hepatocellular lesions.

A 14-year-old girl presented to her pediatrician with right lower quadrant pain that progressed to right upper quadrant pain with radiation to her back. Her past medical history included mitral valve prolapse, and she had no history of oral contraceptive use. Abdominal computed tomography revealed a liver mass and multiple smaller areas of low attenuation, too small to characterize. The clinical and radiographic features were suggestive of hepatocellular adenoma, and she underwent a left hepatic lobectomy. The liver contained one 4.2 cm nodule and multiple (10 to 20) smaller nodules that were well-demarcated from the adjacent liver parenchyma. All lesions were histologically hepatocellular adenomas and, therefore, she was diagnosed with hepatocellular adenomatosis. This case is unique because of the small number of cases of hepatocellular adenomatosis diagnosed in teenagers, and little long-term follow-up.

Adenoma, Liver Cell↗
PubMed2004

Hepatoid adenocarcinoma of the stomach.

A 54-year-old man presented to his doctor with hematemesis and was found at endoscopy to have an ulcerated lesion in his stomach. A computed tomography scan was performed and revealed a mass in the fundus of the stomach. Multiple other lesions were identified in the liver, lungs, retroperitoneal space, and mesentery. Gross examination showed two separate gastric lesions containing nests and single cells with mucin intermixed with sheets of tumor cells with abundant eosinophilic cytoplasm invading throughout the wall of the stomach. Immunohistochemical studies were performed and the cells were positive for hepatocyte, MOC 31, cytokeratin A1/A3, and CK 7, and were negative for CK 20, alpha-fetoprotein, and thyroid transcription factor. The histologic features together with the immunohistochemical findings were diagnostic of a hepatoid adenocarcinoma of the stomach. Hepatoid adenocarcinoma is a rare tumor associated with a very poor prognosis. Immunohistochemical studies may help to identify the characteristic features of hepatoid differentiation and prevent mistaking this tumor for other types of carcinoma.

Adenocarcinoma↗
PubMed2004

Ciliated hepatic foregut cyst: a rare but increasingly reported liver cyst.

We report a case of a ciliated hepatic foregut cyst (CHFC) in the left lobe of the liver in a 42-year-old woman. To date, only 60 cases of these respiratory epithelial lined hepatic cysts have been reported since first described by Friedrich in 1857. CHFC are believed to be congenitally derived from the embryonic foregut and are considered benign lesions that are most often unilocular. Recently, however, there has been documented malignant transformation in these cysts. The majority of patients with a CHFC are asymptomatic and the cyst is usually an incidental finding during abdominal imaging studies or during surgical exploration. Interestingly, 85% of the total number of cases of CHFC have been reported within the last two decades. This recent rise in case reports is likely explained by greater detection because of the dramatic rise in the use of abdominal imaging. In our case, however, ultrasound failed to demonstrate any lesion within the liver and on computed tomography the cyst was more consistent with a soft tissue mass. Therefore, pathologic evaluation was necessary for the correct diagnosis of this liver lesion and to exclude malignancy.

Adult↗
PubMed2004

Microvascular density does not correlate with histopathology and outcome in neuroendocrine tumors of the pancreas.

Microvascular density (MVD), a marker for tumor angiogenesis, has been demonstrated to have prognostic significance in various malignancies. Previous studies have demonstrated that MVD is an independent prognostic factor in pancreatic adenocarcinoma and that longer survival is associated with hypovascular tumors. The prognostic importance of MVD in pancreatic neuroendocrine tumor (NET) has not been documented. We evaluated MVD in pancreatic NET and correlated it with clinicopathologic features and patient outcome to determine whether MVD is a useful prognostic indicator for these patients. Twenty-five pancreatic NETs from our archival files resected between 1981 and 2000 were identified. The mean MVD was determined for each tumor from the 3 most vascularized 200 x fields. Clinical follow-up ranged from 1 to 19 years, with a mean of 4.9 years. At last follow-up, 6 patients were dead of disease, 10 patients were alive without disease, 4 patients were alive with disease, and 5 patients were alive with disease status unknown. Mean MVD ranged from 43 to 527 microvessels per 200 x field. MVD did not correlate with tumor size, the examined histologic parameters, or patient outcome. MVD in pancreatic NET does not correlate with the clinicohistologic features evaluated in this study or with the patient outcome and is not a useful prognostic indicator in these patients. These results suggest that factors other than the simple number of microvessels are important in determining pancreatic NET behavior. However, most tumors were highly vascular, and additional studies may be helpful to clarify further the role of vascularity and assess the utility of antiangiogenic agents in the treatment of pancreatic NET.

Female↗
PubMed2004

Immunohistochemical analysis of biliary tract lesions.

The distinction among inflammatory, benign, and malignant lesions of the biliary tract can at times be difficult. Several methods have been used, including immunohistochemistry (IHC), with variable success. We evaluated a panel of IHC stains to determine their utility in discriminating between bile duct lesions. Formalin-fixed, paraffin-embedded 4-microm sections from 12 inflammatory lesions, 10 bile duct adenomas, and 13 bile duct carcinomas were immunostained using a modified avidin-biotin-complex technique after epitope enhancement using antibodies for p53, Ki-67, and bcl-2. For p53 and bcl-2, greater than 1% of cells staining positive was interpreted as positive. The proliferation index was calculated by determining the number of Ki-67-positive cells in a 1000 cell count. In the inflammatory group, 0 of 12 reacted with anti-p53, 2 of 12 were positive with anti-bcl-2, and the proliferation index with was 22.9% +/- 3.9%. Two of 10 bile duct adenomas showed reactivity with anti-bcl-2, and none were decorated with anti-p53 or Ki-67. In the carcinoma group, 6 of 13 were positive with anti-p53, 9 of 12 were positive with anti-bcl-2, and the proliferation index was 35.3% +/- 5.5%. The proliferation rates differed significantly between groups (P < 0.05). The presence of bcl-2 and p53 immunoreactivity coupled with a high proliferative rate in a biliary tract lesion suggests a malignant process. A panel using these antibodies may be useful in difficult cases.

Adenoma, Bile Duct↗
PubMed2004

Role for activating transcription factor 3 in stress-induced beta-cell apoptosis.

Activating transcription factor 3 (ATF3) is a stress-inducible gene and encodes a member of the ATF/CREB family of transcription factors. However, the physiological significance of ATF3 induction by stress signals is not clear. In this report, we describe several lines of evidence supporting a role of ATF3 in stress-induced beta-cell apoptosis. First, ATF3 is induced in beta cells by signals relevant to beta-cell destruction: proinflammatory cytokines, nitric oxide, and high concentrations of glucose and palmitate. Second, induction of ATF3 is mediated in part by the NF-kappaB and Jun N-terminal kinase/stress-activated protein kinase signaling pathways, two stress-induced pathways implicated in both type 1 and type 2 diabetes. Third, transgenic mice expressing ATF3 in beta cells develop abnormal islets and defects secondary to beta-cell deficiency. Fourth, ATF3 knockout islets are partially protected from cytokine- or nitric oxide-induced apoptosis. Fifth, ATF3 is expressed in the islets of patients with type 1 or type 2 diabetes, and in the islets of nonobese diabetic mice that have developed insulitis or diabetes. Taken together, our results suggest ATF3 to be a novel regulator of stress-induced beta-cell apoptosis.

Activating Transcription Factor 3↗
PubMed2004

Splenic rupture: a rare presentation of pancreatic carcinoma.

CONTEXT: Splenic rupture secondary to solid malignancy is an infrequent complication that usually occurs late in the progression of a previously diagnosed cancer. In rare instances, splenic rupture precipitates the discovery of an unsuspected pancreatic carcinoma. We report 2 cases of adenocarcinoma of the pancreas in which the patients presented with splenic rupture. OBJECTIVES: To review the clinicopathologic features of splenic rupture due to pancreatic carcinoma and to increase awareness of malignancy as a possible etiology for atraumatic splenic rupture. DESIGN: We reviewed the clinical and pathologic data from 2 patients. A literature search was conducted to identify previous reports of splenic rupture associated with pancreatic cancer. We summarized the characteristics of the earlier cases and compared them with those of our patients. RESULTS: We found only 4 previous reports of splenic rupture preceding the diagnosis of pancreatic cancer. In 3 of these cases, the pancreatic carcinoma grossly invaded the spleen at the time of resection. In contrast, malignancy was not suspected as the etiology of the rupture in our patients until histologic examination of the resected spleen revealed carcinoma. CONCLUSION: Splenic rupture is an unusual presentation of cancer of the pancreas, and to our knowledge only 4 cases have been reported previously in the literature. Although an underlying malignancy is relatively rare, spleens resected for atraumatic rupture should be carefully examined for possible neoplastic etiologies.

Female↗
PubMed2003

Cystic schwannoma of the pancreas.

Intrapancreatic schwannoma is a rare neoplasm. We report a case of a 46-year-old man with a cystic schwannoma in the head of the pancreas. This tumor, based on clinical manifestations and radiologic features, was initially suspected to be a cystic mucinous tumor of the pancreas or a pseudocyst. Histologically, the tumor was a typical schwannoma with cyst formation caused by degenerative changes. Immunostaining showed the tumor cells to be strongly and diffusely positive for S-100 protein, vimentin, and CD56, and negative for cytokeratin AE1/AE3, desmin, smooth muscle myosin specific, CD34, and CD117, which support the diagnosis of schwannoma. Cystic schwannoma is a rare neoplasm occurring in the pancreas and should be considered in the differential diagnoses for patients presenting with pancreatic cystic lesions.

Biomarkers, Tumor↗
PubMed2003

Targeting LFA-1 synergizes with CD40/CD40L blockade for suppression of both CD4-dependent and CD8-dependent rejection.

Allogeneic hepatocytes elicit CD4-dependent and (CD4-independent) CD8+ T-cell-initiated graft rejection. The (CD4-independent) CD8+ T-cell pathway is resistant to immunosuppressive strategies that readily and indefinitely suppress CD4+ T-cell-dependent rejection responses. Consequently, successful immunoregulation of hepatocyte-initiated immune responses requires a strategy which regulates both CD4-dependent and CD8-dependent rejection responses. Interference with CD40/CD40 ligand (CD40L) costimulation only transiently suppresses CD4- and CD8-dependent hepatocyte rejection. Interference with CD28/B7 costimulation transiently suppresses CD4-dependent hepatocyte rejection, but is ineffective for suppression of CD8-dependent hepatocyte rejection. To date, hepatocyte survival > 60 days post-transplant has not been achieved by any immunotherapeutic strategy. In the current study, we evaluated a novel immunosuppressive strategy which targets both LFA-1 and CD40L-mediated signals. Targeting LFA-1 suppressed (CD4-independent) CD8+ T-cell-initiated hepatocyte rejection such that allogeneic hepatocyte survival > 60 days was achieved in 70% of CD4 KO mice. Targeting both LFA-1-mediated signals and CD40/CD40L costimulation resulted in synergistic effects, such that hepatocellular survival > 60 days was achieved in 100% of C57BL/6 mice (which have both CD4- and CD8-dependent T-cell pathways available).

Animals↗
PubMed2003

Neuroendocrine carcinomas of the pancreas with 'Rhabdoid' features.

Neuroendocrine carcinomas of the pancreas are rare neoplasms whose morphologic features generally mirror those seen in neuroendocrine tumors in other organs. Rarely, however, they may display unusual morphologic appearances that can introduce difficulties for diagnosis. We report four cases of primary neuroendocrine carcinomas of the pancreas (islet cell tumors) that were characterized by prominent "rhabdoid" features of the tumor cells. The lesions occurred in two men and two women 37-79 years of age who presented with symptoms of biliary obstruction and epigastric pain; one patient had recurrent gastric ulcers and an elevated gastrin level. The tumors were located in the head and tail of the pancreas and measured 2.5-4.5 cm in greatest diameter. Histologic examination revealed sheets of monotonous tumor cells with uniform round nuclei showing dispersed chromatin and containing abundant densely eosinophilic cytoplasmic inclusions that displaced the nuclei toward the periphery. In all cases, the rhabdoid elements appeared to merge with areas showing a more conventional neuroendocrine morphology. Immunohistochemical studies in all cases showed strong cytoplasmic positivity of the rhabdoid tumor cells for chromogranin, synaptophysin, and cytokeratin. Recognition of this unusual morphologic appearance is of importance to avoid mistaking these lesions for other types of malignant neoplasm.

Adenocarcinoma↗
PubMed2003

The utility of estrogen receptor and progesterone receptor immunohistochemistry in the distinction of metastatic breast carcinoma from other tumors in the liver.

CONTEXT: The distinction of metastatic breast adenocarcinoma (MBA) to the liver from hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), and metastatic adenocarcinoma from other sites may require the use of immunohistochemistry. The use of antibodies directed against estrogen receptor (ER) and progesterone receptor (PR) has been suggested to help make this distinction. OBJECTIVE: To examine the utility of ER and PR immunohistochemistry in the distinction of MBA from HCC, CC, and other metastatic adenocarcinomas in the liver. METHODS: Ninety-two previously characterized hepatic neoplasms were identified, including HCC (n = 14), CC (n = 16), and metastatic tumors from breast (n = 17), colorectal (n = 14), pancreatic (n = 15), and esophageal/gastric (n = 16) origins. For all cases of metastatic tumor, the primary tumor was reviewed to verify the diagnosis. All tumors were graded as well, moderately, or poorly differentiated. Estrogen receptor and PR immunohistochemical staining was performed on all cases and evaluated by 2 pathologists. RESULTS: Immunoreactivity for ER was identified only in MBA, with 6 (35%) of 17 cases positive. Positive immunoreactivity for PR was not restricted to MBA, but was seen in HCC, CC, esophageal/gastric, and pancreatic metastases. Positive immunostaining with PR was nearly as frequent in poorly differentiated carcinomas of nonbreast origin (3/16 cases, 19%) as in poorly differentiated breast carcinomas (2/8 cases, 25%). CONCLUSION: Progesterone receptor exhibited poor specificity and sensitivity for the distinction of MBA from HCC, CC, and other metastatic adenocarcinomas. Estrogen receptor exhibited poor sensitivity for MBA, although the specificity was good. The finding that PR positivity was present with a similar frequency in poorly differentiated tumors of breast and nonbreast origin limits the usefulness of this marker. Therefore, ER and PR staining have limited utility in the distinction of MBA from HCC, CC, and other metastatic adenocarcinomas in the liver.

Adenocarcinoma↗