Birt-Hogg-Dubé syndrome, a genodermatosis that increases risk for renal carcinoma

Over the past decade cancer-causing genes have been identified for the most common histologic types of renal cancer, specifically clear cell, papillary type 1 and papillary type 2. Genes predisposing to the more rare chromophobe renal carcinoma and renal oncocytoma were unknown until the recent discovery of a novel gene, BHD, on chromosome 17p that was found to be mutated in the germline of affected family members with the Birt-Hogg-Dubé (BHD) syndrome. These patients develop the hallmark BHD skin lesions (fibrofolliculomas), lung cysts and spontaneous pneumothorax. Importantly, BHD patients have an increased risk for developing a variety of renal neoplasia, most commonly chromophobe and oncocytic hybrid tumors. This review will describe the phenotypic manifestations of BHD including the histologic features of BHD-associated renal tumors, the identification of this novel renal cancer-predisposing gene, the BHD mutation spectrum found in BHD patients, and will discuss the potential role of BHD as a tumor suppressor gene.     

miR-146a suppresses the sensitivity to interferon-α in hepatocellular carcinoma cells

Previous studies have demonstrated expression of Toll-like receptors (TLRs) in the surface epithelium of normal ovaries (OSE) and in epithelial ovarian tumors. Most notably, OSE-derived cancers express TLR4, which activates the nuclear factor-kappa B (NF-κB) signaling cascade as a mediator of inflammatory response. Currently, there is considerable interest in elucidating the role of TLR-mediated signaling in cancers. Nevertheless, the expression of TLRs in granulosa cell tumors (GCTs) of the ovary, and the extent to which GCT expression of TLRs may influence cell-signaling pathways and/or modulate the efficacy of chemotherapeutics, has yet to be determined. In the present study, human GCT lines (COV434 and KGN) were utilized to evaluate expression of functional TLR4. TLR4 is expressed in GCT cell lines and ligation of TLR4 with bacterial lipopolysaccharide (LPS) led to IκB degradation and activation of NF-κB. NF-κB activation was confirmed by nuclear localization of NF-κB p65 following treatment with LPS and the naturally occurring ligand, HSP60. Notably, immunoneutralization of TLR4 blocked nuclear localization, and inhibition of NF-κB signaling attenuated LPS-induced TNFα plus increased doubling time in both cell lines. Contradictory to reports using human OSE cell lines, inhibition of NF-κB signaling failed to sensitize GCT lines to TRAIL or cisplatin. In summary, findings herein are the first to demonstrate a functional TLR-signaling pathway specifically in GCTs, and indicate that in contrast to OSE-derived cancers, inhibition of NF-κB does not sensitize GCTs to TRAIL or cisplatin.     

miR-146a suppresses the sensitivity to interferon-α in hepatocellular carcinoma cells

Background

Interferon-based (IFN-based) therapy is effective in the treatment of advanced hepatocellular carcinoma (HCC). However, the issue of resistance to this therapy remains to be solved. The aim of this study was to identify microRNAs (miRNAs) that govern the sensitivity to IFN-α in HCC cells.

Methods

miRNA microarray analysis using IFN-α-resistant clones of PLC/PRF/5 (PLC-Rs) and their parental cells (PLC-P) was conducted. Changes in the anti-cancer effects of IFN-α were studied after gain-of-function and loss-of-function of the candidate miRNA.

Results

miR-146a expression was significantly higher in PLC-Rs than in PLC-P. miR-146a decreased the sensitivity to IFN-α through the suppression of apoptosis. Further experiments showed that miR-146a-related resistance to IFN-α was mediated through SMAD4.

Conclusions

The results indicated that miR-146a regulated the sensitivity of HCC cells to the cytotoxic effects of IFN-α through SMAD4, suggesting that this miRNA could be suitable for prediction of the clinical response and potential therapeutic target in HCC patients on IFN-based therapy.     

Hypoxia-induced Factor-1α in endometrial carcinoma: a mini-review of current evidence

Despite the well-established role of hypoxia in cancer biology, the literature on its effects on endometrial cancer is scarce; it mainly refers to experimental settings rather than patient-derived results. Herein, an overview of the hypoxia inducible factor 1α (HIF-1α) biology, focusing on endometrial cancer, is presented. The molecular mechanisms possibly involved in endometrial cancer progression are presented, followed by a systematic approach to the current literature on immunohistochemistry evaluation of HIF-1α expression in endometrial carcinoma. Since no consensus has been made regarding HIF-1α evaluation, the evidence of possible involvement of HIF-1α in endometrial carcinoma prognosis is weak. After a consensus has been made, properly powered studies may be able to clarify whether HIF-1α can act as a prognosticator in endometrial carcinoma.     

Anterior sacral meningocele infected with Fusobacterium in a patient with recently diagnosed colorectal carcinoma – a case report

Background

Anterior sacral meningoceles are rare, and usually occur with other malformations of the posterior lower spine. While these are more frequently reported in pediatric cohorts, we report a case in an elderly woman.

Case presentation

We report on a 71 year-old woman with a recently diagnosed colorectal adenocarcinoma who presented with a severe bacterial meningitis. The cerebrospinal fluid cell count revealed a pleocytosis of 80,000 cells/μl and a severe disturbance of the blood-brain-barrier. Fusobacterium nucleatum was cultured as the causing pathogen. A lumbar MRI showed, in addition to contrast-enhancing meninges as sign of inflammation, a presacral mass. In the next step, the mass was diagnosed as an anterior sacral meningocele connected to the gut. An adequate antibiotic was used to treat the leptomeningitis. The connection between gut and meningocele was closed surgically and the patient recovered well and underwent further treatment of her colorectal adenocarcinoma.

Conclusion

We report on a case of meningitis with an anterior sacral meningocele that was connected to the gut in a patient with a infiltrative colorectal adenocarcinoma. Anatomic variants have to be considered as rare causes of meningitis with typical intestinal germs.

     

Breast metastasis from squamous cell carcinoma of the oropharynx: a case report

Background

Breast metastases from extramammary tumors are extremely rare, the most common primary tumors being contralateral breast carcinoma, followed by lung, gynecological, gastrointestinal, melanoma, and hematological cancers. Only a few cases deriving from head and neck squamous cell carcinoma have been reported in the literature to date.

Case presentation

We report a case of a 47-year-old Caucasian woman who presented to our hospital with a solitary breast lesion in the right upper external quadrant associated with multiple bone and visceral metastases. Two years before, she had undergone radical resection of a squamous cell carcinoma of the oropharynx (stage pT2, pN1), which was followed by adjuvant radiotherapy. Breast ultrasound showed a hypoechogenic tumor lesion of 4 cm in the right upper external quadrant that was associated with multiple axillary and infra-/supraclavicular adenopathies. A positron emission tomographic scan documented multiple visceral and bone metastases with a single hypermetabolic lesion of the right breast. The results of histology and immunohistochemistry were consistent with a metastasis from a squamous cell carcinoma. The patient died of acute respiratory insufficiency 1 month after her breast metastasis diagnosis and before starting any systemic antitumoral treatment.

Conclusions

Although breast metastases are extremely rare, they should be considered in any patient with a history of cancer and confirmed by histology and immunohistochemistry because they are very difficult to distinguish from other primary breast tumors based only on clinical and radiological features. There are no standardized treatment guidelines for breast metastasis management. Surgery and radiotherapy can play a role in symptom palliation, but they do not have any relevant impact on survival, the prognosis being poor, with an estimated overall survival less than 1 year from diagnosis.

     

Gallium-67 scintigraphy and non-small-cell bronchogenic carcinoma: a quantitative in-vivo predictive assay?

Gallium-67 scintigraphy has been of limited use in detecting lung cancers and micrometastases. To study its potential for determining the aggressiveness of a cancer, we reviewed the charts of 44 patients with non-small-cell bronchogenic carcinoma who had not been receiving treatment when 67Ga scintigraphy was performed. The mean length of survival for the 18 patients with low or little uptake of the tracer, corrected for tumour size, was 19.7 months, and for the 26 with high uptake 9.4 months (p less than 0.01). Such in-vivo predictive assays may be a rational goal for tumour scintigraphy.     

Verrucous carcinoma of the head and neck – not a human papillomavirus-related tumour?

Association between verrucous carcinoma (VC) of the head and neck and human papillomaviruses (HPV) is highly controversial. Previous prevalence studies focused mostly on α‐PV, while little is known about other PV genera. Our aim was to investigate the prevalence of a broad spectrum of HPV in VC of the head and neck using sensitive and specific molecular assays. Formalin‐fixed, paraffin‐embedded samples of 30 VC and 30 location‐matched normal tissue samples were analysed, by using six different polymerase chain reaction‐based methods targeting DNA of at least 87 HPV types from α‐PV, β‐PV, γ‐PV and μ‐PV genera, and immunohistochemistry against p16 protein. α‐PV, γ‐PV and μ‐PV were not detected. β‐PV DNA was detected in 5/30 VC (16.7%) and in 18/30 normal tissue samples (60.0%): HPV‐19, ‐24 and ‐36 were identified in VC, and HPV‐5, ‐9, ‐12, ‐23, ‐24, ‐38, ‐47, ‐49 and ‐96 in normal tissue, whereas HPV type was not determined in 2/5 cases of VC and in 6/18 normal tissue samples. p16 expression was detected in a subset of samples and was higher in VC than in normal tissue. However, the reaction was predominantly cytoplasmic and only occasionally nuclear, and the extent of staining did not exceed 75%. Our results indicate that α‐PV, γ‐PV and μ‐PV are not associated with aetiopathogenesis of VC of the head and neck. β‐PV DNA in a subset of VC and normal tissue might reflect incidental colonization, but its potential biological significance needs further investigation.     

Small interfering RNA–mediated gene suppression as a therapeutic intervention in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the lethal and difficult-to-cure cancers worldwide. Owing to the late diagnosis and drug resistance of malignant hepatocytes, treatment of this cancer by conventional chemotherapy agents is challenging, and researchers are seeking new alternative treatment options to overcome therapy resistance in this neoplasm. RNA interference (RNAi) is a potent and specific approach in targeting gene expression and has emerged as a novel therapeutic tool for many diseases, including cancers. Small interfering RNA (siRNA) is a type of RNAi that is produced intracellularly from exogenous synthetic oligonucleotides and can selectively knock down target gene expression in a sequence-specific manner. Various factors play roles in the initiation and progression of HCC and provide multiple candidate targets for siRNA intervention. In addition, due to the liver's unique architecture and availability of some hepatic siRNA delivery methods, this organ has received much more attention as a target tissue for such oligonucleotide action. Recent advances in designing nanoparticle systems for the in vivo delivery of siRNAs have markedly enhanced the potency of siRNA-mediated gene silencing under clinical development for HCC therapy. The utility of siRNAs as anti-HCC agents is the subject of the current review. siRNA-based gene therapies could be one of the main feasible approaches for HCC therapy in the future.     

Fine needle aspiration biopsy of anaplastic thyroid carcinoma developing from a Hürthle cell tumor: a case report

BACKGROUND: Anaplastic thyroid carcinoma is a highly malignant tumor in elderly people with a long history of multinodular goiter and is usually associated with a rapidly fatal clinical evolution. The tumor often develops as a result of anaplastic transformation of a slowly growing papillary carcinoma or follicular neoplasm. CASE: An 85-year-old woman had a multinodular goiter and had been asymptomatic, with a normal white blood cell count and chest radiograph three months prior to her hospital admission for the treatment. The tumor presented with low grade fever, leukocytosis, multiple metastatic lung nodules and enlargement of the intrathoracic thyroid in a period of three months, causing compression of the esophagus and trachea. Despite a total thyroidectomy, the tumor recurred within one month and caused dysphagia and death. CONCLUSION: FNAB permitted the diagnosis of an anaplastic thyroid carcinoma arising from an intrathoracic Hürthle cell tumor.     

Enhanced radioimmunotherapeutic efficacy of a monoclonal antibody cocktail against SMMC—7721 human hepatocellular carcinoma

The improved tumoricidal effect of the radioantibody mixture (“cocktail”)has been reported recently for the treatment of colon tumor.In the present study,we demonstrated the enhanced radioimmunotherapeutic efficacy of a monoclonal antibody (MAb) cocktail against human hepatocellular carcinoma.Therapeutic efficacy was determined by measuring the change in tumor size over a period,determining the percentage of growth inhibition of each treatment at various times after radioantibody therapy.Radioimmunotherapy of SMMC-7721 human hepatoma xenografts in athymic unde mice with combination of ^131Ilabeled Hepama-1 and ^131 I-labeled 9403 mouse MAbs was more effective than using either Hepeam-1 or 9403 MAb alone The MAb cocktail could target a greater number of hepatoma cells and increase the magnitude of hepatoma cell uptake of radioantibodies.The in vitro results explain the enhanced effect of the MAb cocktail in in vivo model system.     

miR-181a–Twist1 pathway in the chemoresistance of tongue squamous cell carcinoma

Although many researches have been undertaken to disclose the mechanisms of chemoresistance, the mechanisms remain unclear. The aim of this study is to elucidate the role of miR-181a–Twist1 pathway in the chemoresistance of tongue squamous cell carcinoma (TSCC). We found that cisplatin-induced chemoresistance in TSCC cell lines underwent EMT (epithelial–mesenchymal transition) and was accompanied by enhancing metastatic potential (migration and invasion in vitro), miR-181a downregulation and Twist1 upregulation. Functional analyses indicated that miR-181a reversed chemoresistance, inhibited EMT and metastatic potential in TSCC cells. Twist1 was confirmed as a direct miR-181a target gene by luciferase reporter gene assays. Twist1 knockdown by siRNA led to a reversal of the chemoresistance, inhibited EMT and metastatic potential in TSCC cells. Our study demonstrates that miR-181a–Twist1 pathway may play an important role in the development of cisplatin-chemoresistance, with EMT and an increase the metastatic potential of TSCC cells.     

Roles of fascin in human carcinoma motility and signaling: prospects for a novel biomarker?

Fascin is a globular actin cross-linking protein that has a major function in forming parallel actin bundles in cell protrusions that are key specialisations of the plasma membrane for environmental guidance and cell migration. Fascin is widely expressed in mesenchymal tissues and the nervous system and is low or absent in adult epithelia. Recent data from a number of laboratories have highlighted that fascin is up-regulated in many human carcinomas and, in individual tissues, correlates with the clinical aggressiveness of tumours and poor patient survival. In cell culture, over-expression or depletion of fascin modulates cell migration and alters cytoskeletal organisation. The identification of biomarkers to provide more effective early diagnosis of potentially aggressive tumours, or identify tumours susceptible to targeted therapies, is an important goal in clinical research. Here, we discuss the evidence that fascin is upregulated in carcinomas, its contributions to carcinoma cell behaviour and its potential as a candidate novel biomarker or therapeutic target.