A Troubling Diagnosis of Verrucous Squamous Cell Carcinoma (“the Bad Kind” of Keratosis) and the Need of Clinical and Pathological Correlations: A Review of the Literature with a Case Report

Verrucous carcinoma (also known as Ackerman tumor) is an uncommon exophytic low-grade well-differentiated variant of squamous cell carcinoma. This neoplasm typically involves the oral cavity, larynx, genitalia, skin, and esophagus. It is well known for its locally aggressiveness and for its clinically slow-growing behaviour with minimal metastatic potential. Verrucous carcinoma of oral cavity is so closely aligned with the use of snuff and chewing tobacco that it has been called the “snuff dipper's cancer”. Recent studies have proved the role of HPV. The typical clinical presentation of oral verrucous carcinoma has long been known, as its remarkably innocuous appearance and biological behaviour. In this work, we report a review of the scientific literature and describe a troublesome case of oral verrucous cancer

Report of a case of discoid lupus erythematosus localised to the oral cavity: immunofluorescence findings.

Discoid Lupus Erythematosus (DLE) is a chronic disease with a typical cutaneous involvement. This pathology rarely involves mucosa: oral cavity is interested in 20% of DLE patients. We describe a case of oral DLE in a 50-year-old woman with an anamnesis for autoimmune disorders. This study shows the helpful role of immunofluorescence in the diagnosis of autoimmune diseases. The first diagnostic step was the clinical observation of the oral mucosa: the lesion area was erythematous, athrophic and hyperkeratotic. The patient then underwent laboratory examination. We utilized human epithelial cells (Hep-2010) for Indirect Immuno-Fluorescence (IIF). Moreover, the biopsy site for Direct Immuno-Fluorescence (DIF) and histopathological analysis was the untreated oral lesion. IIF detected an increase of Anti-Nuclear Antibody (ANA) and positivity for SSA-RO. By DIF, we observed IgG/IgA/fibrinogen along basal layer. Multiple biopsies reported signs of chronic basal damage. Steroid systemic therapy induced a considerable lesion regression. We suggest the use of immunofluorescence with the integration of further data to improve diagnosis of rare diseases and to establish a suitable therapy

Cytosolic phosphorylated EGFR is predictive of recurrence in early stage penile cancer patients: A retropective study

Background: Penile cancer (PC) is a rare tumor, and therapeutic options are limited for this disease, with an overall 5-year overall survival around 65-70%. Adjuvant therapy is not recommended for patients with N0-1 disease, despite up to 60% of these patients will die within 5 years from diagnosis. Methods: Medical records of all patients who underwent radical surgery at University Federico II of Naples and at National Tumor Institute "Pascale" of Naples for early squamous cell carcinoma of the penis from January, 2000 to December, 2011 were retrieved. Paraffin wax embedded tissue specimens were retrieved from the pathology archives of the participating Institutions for all patients. Expression of p-EGFR, EGFR and positivity to HPV were evaluated along with other histological variables of interest. Demographic data of eligible patients were retrieved along with clinical characteristics such as type of surgical operation, time of follow up, time of recurrence, overall survival. A multivariable model was constructed using a forward stepwise selection procedure. Results: Thirty eligible patients were identified. All patients were positive for EGFR by immunohistochemistry, while 13 and 16 were respectively positive for nuclear and cytosolic p-EGFR. No EGFR amplification was detected by FISH. Eight patients were positive for high-risk HPV by ISH. On univariable analysis, corpora cavernosa infiltration (OR 7.8; 95% CI = 0,8 to 75,6; P = 0,039) and positivity for cytosolic p-EGFR (OR 7.6; 95% CI = 1.49 to 50; P = 0.009) were predictive for recurrence, while only positivity for cytosolic p-EGFR (HR = 9.0; 95% CI 1.0-100; P = 0,0116) was prognostic for poor survival. Conclusion: It is of primary importance to identify patients with N0-1 disease who are at increased risk of recurrence, as they do not normally receive any adjuvant therapy. Expression of p-EGFR was found in this series to be strongly related to increase risk of recurrence and shorter overall survival. This finding is consistent with the role of p-EGFR in other solid malignancies. Integration of p-EGFR with classic prognostic factors and other histology markers should be pursued to establish optimal adjuvant therapy for N0-1 PC patients

Targeting oncogenic Src homology 2 domain-containing phosphatase 2 (SHP2) by inhibiting its protein-protein interactions

We developed a new class of inhibitors of protein-protein interactions of the SHP2 phosphatase, which is pivotal in cell signaling and represents a central target in the therapy of cancer and rare diseases. Currently available SHP2 inhibitors target the catalytic site or an allosteric pocket but lack specificity or are ineffective for disease-associated SHP2 mutants. Considering that pathogenic lesions cause signaling hyperactivation due to increased levels of SHP2 association with cognate proteins, we developed peptide-based molecules with nanomolar affinity for the N-terminal Src homology domain of SHP2, good selectivity, stability to degradation, and an affinity for pathogenic variants of SHP2 that is 2-20 times higher than for the wild-type protein. The best peptide reverted the effects of a pathogenic variant (D61G) in zebrafish embryos. Our results provide a novel route for SHP2-targeted therapies and a tool for investigating the role of protein-protein interactions in the function of SHP2

Survivin promoter -31G/C polymorphism in oral cancer cell lines.

Survivin (SVV) is a protein that belongs to the inhibitor of apoptosis proteins (IAP) family and is involved in the G2/M phase progression of the cell cycle as a spindle-associated molecule. The biological features of this protein are well documented and its activity appears to be involved in mitochondria-dependent and -independent antiapoptotic pathways. Overexpression of SVV at the transcriptional and translational level has been associated with cancer, a multifactorial disorder in which the occurrence of a -31G to C polymorphism in the promoter region may significantly contribute to the development of this pathology. To verify this hypothesis, the occurrence of a single nucleotide polymorphism (SNP) in cis-acting cell cycle-dependent elements (CDEs) and in cell cycle homology regions (CHRs) of the survivin TATA-less promoter was investigated. A total of 23 oral squamous cell carcinoma (OSCC) cell lines and normal epithelium-derived normal human epidermal keratinocyte (NHEK) cell lines were analyzed by RFLP and direct DNA sequencing of their promoter region. Furthermore, survivin expression at the transcriptional and translational levels was evaluated in these cells by RT-PCR and Western blotting, respectively. The findings indicate that the presence of a G or C allele is not directly correlated to survivin expression, at the mRNA or at the protein level, at least in the OSCC lines analyzed in this study

Reliability of forced internal rotation and active internal rotation to assess lateral instability of the biceps pulley

PURPOSE: the aim of this study was to investigate the relationship between positive painful forced internal rotation (FIR) and lateral pulley instability in the presence of a pre-diagnosed posterosuperior cuff tear. The same investigation was conducted for painful active internal rotation (AIR). METHODS: a multicenter prospective study was conducted in a series of patients scheduled to undergo arthroscopic posterosuperior cuff repair. Pain was assessed using a visual analog scale (VAS) and the Disabilities of the Arm, Shoulder and Hand questionnaire (DASH) was administered. The VAS score at rest, DASH score, and presence/absence of pain on FIR and AIR were recorded and their relationships with lesions of the lateral pulley, cuff tear patterns and shape of lesions were analyzed. RESULTS: the study population consisted of 115 patients (mean age: 55.1 years) recruited from 12 centers. The dominant arm was affected in 72 cases (62.6%). The average anteroposterior extension of the lesion was 1.61 cm. The mean preoperative VAS and DASH scores were 6.1 and 41.8, respectively. FIR and AIR were positive in 94 (81.7%) and 85 (73.9%) cases, respectively. The lateral pulley was compromised in 50 cases (43.4%). Cuff tears were partial articular in 35 patients (30.4%), complete in 61 (53%), and partial bursal in 19 (16.5%). No statistical correlation between positive FIR or AIR and lateral pulley lesions was detected. Positive FIR and AIR were statistically associated with complete lesions. Negative FIR was associated with the presence of partial articular tears. CONCLUSIONS: painful FIR in the presence of a postero-superior cuff tear does not indicate lateral pulley instability. When a cuff tear is suspected, positive FIR and AIR are suggestive of full-thickness tear patterns while a negative FIR suggests a partial articular lesion. LEVEL OF EVIDENCE: level I, validating cohort study with good reference standards

Aberrant function of the C-terminal tail of HIST1H1E Aacelerates cellular senescence and causes premature aging

Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging

Rational Extension of the Ribosome Biogenesis Pathway Using Network-Guided Genetics

Gene networks are an efficient route for associating candidate genes with biological processes. Here, networks are used to discover more than 15 new genes for ribosomal subunit maturation, rRNA processing, and ribosomal export from the nucleus