Obesity and microvascular invasion in hepatocellular carcinoma.

BACKGROUND: We hypothesized that hepatocellular carcinoma (HCC) patients with higher Body Mass Index (BMI) might have more microvascular invasion (MVI) in their tumors. METHODS: Records from 138 consecutive patients who underwent surgery at Columbia University Medical Center from January 1, 2002 to January 9, 2008 were evaluated. RESULTS: 40 patients (29%) had MVI, including 14% with BMI <25, 31% with BMI = 25-30, and 40% with BMI >30 (p = .05). However, only maximum alpha-fetoprotein was significantly associated with overall mortality in a Cox model. CONCLUSIONS: MVI was associated with obesity. A better understanding of the mechanism of this association may lead to interventions for the treatment and prevention of HCC.

Filamin C Truncation Mutations Are Associated With Arrhythmogenic Dilated Cardiomyopathy and Changes in the Cell-Cell Adhesion Structures.

OBJECTIVES: The purpose of this study was to assess the phenotype of Filamin C (FLNC) truncating variants in dilated cardiomyopathy (DCM) and understand the mechanism leading to an arrhythmogenic phenotype. BACKGROUND: Mutations in FLNC are known to lead to skeletal myopathies, which may have an associated cardiac component. Recently, the clinical spectrum of FLNC mutations has been recognized to include a cardiac-restricted presentation in the absence of skeletal muscle involvement. METHODS: A population of 319 U.S. and European DCM cardiomyopathy families was evaluated using whole-exome and targeted next-generation sequencing. FLNC truncation probands were identified and evaluated by clinical examination, histology, transmission electron microscopy, and immunohistochemistry. RESULTS: A total of 13 individuals in 7 families (2.2%) were found to harbor 6 different FLNC truncation variants (2 stopgain, 1 frameshift, and 3 splicing). Of the 13 FLNC truncation carriers, 11 (85%) had either ventricular arrhythmias or sudden cardiac death, and 5 (38%) presented with evidence of right ventricular dilation. Pathology analysis of 2 explanted hearts from affected FLNC truncation carriers showed interstitial fibrosis in the right ventricle and epicardial fibrofatty infiltration in the left ventricle. Ultrastructural findings included occasional disarray of Z-discs within the sarcomere. Immunohistochemistry showed normal plakoglobin signal at cell-cell junctions, but decreased signals for desmoplakin and synapse-associated protein 97 in the myocardium and buccal mucosa. CONCLUSIONS: We found FLNC truncating variants, present in 2.2% of DCM families, to be associated with a cardiac-restricted arrhythmogenic DCM phenotype characterized by a high risk of life-threatening ventricular arrhythmias and a pathological cellular phenotype partially overlapping with arrhythmogenic right ventricular cardiomyopathy.

Anaplastic Pancreatic Carcinoma Arising Within a Mucinous Cystic Neoplasm of the Pancreas: A Case Report and a Brief Review of the Literature.

Background: Anaplastic pancreatic carcinomas (APCs) are among the least frequently encountered pancreatic malignancies, ranging from 0.5% to 7% of all nonendocrine pancreatic malignancies. Furthermore, few cases of APCs have been described arising within a pancreatic mucinous cystic neoplasm (MCN). Case Presentation: A 36-year-old female presented with left upper quadrant pain and a 10 × 8 cm complex cystic mass in the pancreatic tail. Fine needle aspiration of the cyst showed papillary clusters of cells with mild cytological atypia, cyst fluid carcinoembryonic antigen >4000 ng/mL, and amylase of 25 U/L. After an open distal pancreatectomy and splenectomy, the specimen revealed an MCN with multifocal microscopic foci of invasive well-differentiated adenocarcinoma. After additional sampling, foci of undifferentiated malignancy-morphologically resembling sarcomas but with immunohistochemical staining consistent with anaplastic carcinoma-were identified. The patient had an uneventful recovery and is currently undergoing a regimen of gemcitabine-based adjuvant chemotherapy; she remains disease-free at 5 months after initial diagnosis. Conclusions: In this study, we describe a rare case of APC originating from a large pancreatic MCN lesion. This case underlines the importance of scrupulous pathological evaluation of the entire MCN epithelium and adds to the limited world literature of APC originating from pancreatic MCN lesions.

The novel ATM inhibitor (AZ31) enhances antitumor activity in patient derived xenografts that are resistant to irinotecan monotherapy.

Irinotecan, a standard of care therapy for CRC, elicits cytotoxic effects by generating double strand breaks resulting in DNA damage. The activation of the ATM pathway plays a fundamental role in regulating the cellular response and repair to DNA damage. The objective of this preclinical study was to determine whether ATM inhibition would enhance sensitivity to irinotecan treatment. Treatment effects of AZ31, irinotecan or AZ31 + irinotecan were investigated in CRC cell lines and CRC patient derived xenografts. Activation of ATM and downstream targets p-RAD50 and p-H2AX were evaluated by immunohistochemistry. Combinational effects were demonstrated in 4 out of 8 CRC explants. Interestingly, each of the combinational sensitive CRC PDX models were shown to be more resistant to irinotecan single agent therapy. Treatment with irinotecan significantly elevated the ATM pathway evident by an increase in the activation of H2AX and RAD50. Combinational therapy reduced the activation of H2AX and RAD50 when compared to irinotecan alone in the combination sensitive CRC098. AZ31 + irinotecan was effective at reducing tumor growth in tumors that exhibited resistance to irinotecan in our CRC PDX model. These findings support further investigation of this combinational therapy for the treatment of CRC patients.

Pax8: a marker for carcinoma of Müllerian origin in serous effusions.

PAX8 is a nuclear transcription factor with limited expression in normal and neoplastic tissues in a cell lineage-dependent manner. PAX8 has been detected in embryonic Müllerian ducts, human fallopian tubes, and ovarian carcinomas. However, little is known about its expression in other areas of the female genital tract. In this study, we used immunohistochemistry (IHC) to examine PAX8 expression in the normal uterine corpus and cervix, malignant tumors arising from these sites, and malignant effusions. We reported here that PAX8 was also detected in endometrial epithelial cells and endocervical glands, with a lower expression level in the latter, but not in the stromal cells of these areas. All endometrial carcinomas (N = 52) were positive for PAX8, whereas endocervical adenocarcinomas (N = 5) and uterine leiomyosarcomas (N = 3) were negative for PAX8. PAX8 was detected in 70% (22/31) and 68.8% (11/16) of metastatic carcinomas of the ovary and endometrium in serous effusions, respectively. No PAX8 was detected in carcinomas of nongynecologic origin or noncarcinomas (N = 71) in serous effusions except in one renal-cell carcinoma and one carcinoma of unknown primary in a woman. In addition, papillary serous carcinomas of the peritoneum (N = 10) were diffusely positive for PAX8, implying a Müllerian origin similar to malignant tumors in the female genital tract. Our findings suggest that PAX8 is an additional IHC marker for carcinomas of Müllerian origin hence we recommend including PAX8 for evaluation of malignant serous effusions in women, especially when tumors of Müllerian origin are in the differential diagnosis.

Development of HPV vaccines for HPV-associated head and neck squamous cell carcinoma.

High-risk genotypes of the human papillomavirus (HPV), particularly HPV type 16, are found in a distinct subset of head and neck squamous cell carcinomas (HNSCC). Thus, these HPV-associated HNSCC may be prevented or treated by vaccines designed to induce appropriate HPV virus-specific immune responses. Infection by HPV may be prevented by neutralizing antibodies specific for the viral capsid proteins. In clinical trials, vaccines comprised of HPV virus-like particles (VLPs) have shown great promise as prophylactic HPV vaccines. However, given that capsid proteins are not expressed at detectable levels by infected basal keratinocytes, vaccines with therapeutic potential must target other non-structural viral antigens. Two HPV oncogenic proteins, E6 and E7, are important in the induction and maintenance of cellular transformation and are co-expressed in the majority of HPV-containing carcinomas. Therefore, therapeutic vaccines targeting these proteins may have potential to control HPV-associated malignancies. Various candidate therapeutic HPV vaccines are currently being tested whereby E6 and/or E7 is administered in live vectors, in peptides or protein, in nucleic acid form, as components of chimeric VLPs, or in cell-based vaccines. Encouraging results from experimental vaccination systems in animal models have led to several prophylactic and therapeutic vaccine clinical trials. Should they fulfill their promise, these vaccines may prevent HPV infection or control its potentially life-threatening consequences in humans.