1,721,337 research outputs found
Biomarkers for the identification of recurrence in human epidermal growth factor receptor 2-positive breast cancer patients
No full textPurpose of review
This review discusses the mechanisms of anti-human epidermal growth factor receptor 2 (HER2) resistance in breast cancer patients, detailing possible predictive biomarkers of therapy benefit that could implement novel therapeutic strategies.
Recent findings
Despite a remarkable improvement in survival over the past two decades, up to 30% of early-stage HER2þ breast cancer patients exhibit de-novo or acquired resistance to targeted therapy, underlying the need of developing predictive biomarkers.
Summary
The role of HER family receptor redundancy, p95HER2 expression, and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin downstream pathway activation in counteracting the inhibitory effects of anti-HER2 targeted therapy has been addressed. We also discuss the possible inconsistencies in the definition of HER2 positivity according to American Society of Clinical Oncology/College of American Pathologists guidelines or molecular intrinsic subtypes, and address the role played by tumor heterogeneity and evolutionary clonal selection on therapy selective pressure. Finally, the interplay between adaptive immunity and anti-HER2 targeted therapy is extensively discussed, focusing on its putative predictive and prognostic role
Over-using chemotherapy in the adjuvant setting
No full textAvoidance of unnecessary or ineffective treatment should be one of the main goals in adjuvant breast
oncology today. Unfortunately, both patients and doctors hunt for tiny statistical differences in survival
curves. This search could not only lead to an oncological approach of unlimited addition that we will not
be able to afford, but would also end inevitably in indeterminate overtreatment with substantial risks of
unexpected toxic effects eating away whatever progress we might make. “Do not harm” remains the
main principle in medicine. To be able to follow this rule, we need to better understand the biology of
breast cancer. The mistake of “one treatment fits all” can only be changed when we critically review trial
designs of adjuvant breast oncology. The risk of overtreatment is there and selection of precisely defined
cohorts for phase 3 trials is necessary, despite pressure of scientific ambition, pragmatism, and demands
of industry. The “add on” clinical trial design model accepts the inability to confirm that standard therapy
is still necessary if a positive result from the addition of the new therapy is obtained. The same model can
be applied to “extended” adjuvant treatments in breast cancer subtypes. Addition of “miraculin” to the
standard of care should generate a new standard. Such trials that show a modest benefit on average at a
population level take us a step away from refining care for the individual, and might support the use of
multiple and costly interventions with potential short and long term side effects. It is essential to escalate
treatment when necessary and to de-escalate when un-necessary
Monoclonal proliferation of germinal center cells (incipient follicular lymphoma) in an axillary lymph node of a melanoma patient
No full textA monoclonal proliferation of germinal center cells within a lymph node follicle was incidentally discovered during the staging surgical procedures in a patient with Clark III–level cutaneous melanoma. In one of the 19 axillary lymph nodes examined, we identified a single morphologically atypical lymphoid follicle, predominantly composed of medium-sized cells and immunoreactive for B-cell antigens and for the markers of germinal center origin CD10 and bcl-6. A monoclonal rearrangement of the immunoglobulins heavy chains (IgH) was documented by polymerase chain reaction after laser capture microdissection. The cells of the aberrant follicle expressed the bcl-2 protein at higher levels than the surrounding T lymphocytes in the absence of bcl-2 gene rearrangement. We propose for this lesion the designation of incipient follicular lymphoma. The present findings also confirm the previously reported association between melanoma and lymphoproliferative disorders
Prognostic significance of P27 and cyclin D1 co-expression in laryngeal squamous cell carcinoma : possible target for novel therapeutic strategies Journal of Chemotherapy
No full textTumour cells are characterised by uncontrolled growth due to alterations in the genes that play a key role in cell repair systems and apoptosis: pro-mitotic oncogenes such as cyclin D1, and tumour suppressor genes such asp27. Recent studies have demonstrated that these genes are involved in different epithelial neoplasms and that their expression is generally associated with prognosis. The aim of this immunohistochemical study was to analyse the clinical relevance of cyclin D1/p27 co-expression in a homogeneous series of 132 laryngeal squamous cell carcinomas. Multivariate analysis showed that cyclin D1 and p27 were the only statistically significant predictors of disease-free and overall survival. In relation to the simultaneous expression of p27 protein and cyclin D1, the patients with a cyclin D1+/p27-phenotype had the poorest disease-free and overall survival rates. On the basis of these immunohistochemical results, it was possible to select a subgroup of patients with a high risk of recurrence and poor prognosis to undergo more extended surgical treatment and/or combination antitumoral therapeutic procedures
Pathology Tissue-quantitative Mass Spectrometry Analysis to Profile Histone Post-translational Modification Patterns in Patient Samples
Full text linkHistone post-translational modifications (hPTMs) generate a complex combinatorial code that has been implicated with various pathologies, including cancer. Dissecting such a code in physiological and diseased states may be exploited for epigenetic biomarker discovery, but hPTM analysis in clinical samples has been hindered by technical limitations. Here, we developed a method (PAThology tissue analysis of Histones by Mass Spectrometry - PAT-H-MS) that allows to perform a comprehensive, unbiased and quantitative MS-analysis of hPTM patterns on formalin-fixed paraffin-embedded (FFPE) samples. In pairwise comparisons, histone extracted from formalin-fixed paraffin-embedded tissues showed patterns similar to fresh frozen samples for 24 differentially modified peptides from histone H3. In addition, when coupled with a histone-focused version of the super-SILAC approach, this method allows the accurate quantification of modification changes among breast cancer patient samples. As an initial application of the PAThology tissue analysis of Histones by Mass Spectrometry method, we analyzed breast cancer samples, revealing significant changes in histone H3 methylation patterns among Luminal A-like and Triple Negative disease subtypes. These results pave the way for retrospective epigenetic studies that combine the power of MS-based hPTM analysis with the extensive clinical information associated with formalin-fixed paraffin-embedded archives
Lack of Bcl10 gene mutations in laryngeal squamous cell carcinoma
No full textThe Bcl10 gene encodes a protein probably involved in some apoptotic regulatory pathways. Bcl10 mutations lead to the translation of truncated proteins that show gain-of-function transforming activity; it has been suggested that Bcl10 may represent a major target gene for inactivation in many human cancers. To define the frequency of Bcl10 mutations in laryngeal squamous cell carcinoma and their possible association with tumour progression, we investigated a large panel of tumours representative of all grades and stages of malignancy. To detect pathogenic mutations in exons 1, 2 and 3 of the Bcl10 gene, we performed a silver-staining polymerase chain reaction - single-strand conformation polymorphism (PCR-SSCP) analysis followed by direct DNA sequencing. We revealed the presence of SSCP variants in 18 out of 91 laryngeal tumours. Direct DNA sequencing showed previously described polymorphisms but no pathogenic mutations. We have strong evidence that the Bcl10 gene is not involved in laryngeal carcinogenesis
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