Search Results (4)

Background: The incidence of patients showing neck metastasis and no obvious primary tumor at the initial diagnostic evaluation or neck cancer of unknown primary (NCUP) is rising. It is estimated that a relevant part of these tumors arises in the tonsillar crypts or base of the tongue and are p16+-related. However, today, the detection rate of the primary tumor is suboptimal. Identifying the primary tumor and its biomolecular characterization is essential since it influences the treatment administered, possibly reducing radiation fields and providing de-escalation to primary surgical management. However, p16 IHC (immunohistochemistry) might not be sufficient to diagnose HPV-related OPSCC. The other subset of patients discussed are the HPV-positive patients who have a history of tobacco exposure and/or p53 mutations. Possible factors that could negatively influence the outcomes of these patients are investigated and discussed below. So, this paper aims to analyze the diagnostic, bio-molecular, clinico-radiological, morphological, prognostic and therapeutical aspects of p16-positive OPSCC, highlighting the possible bias that can occur during the diagnostic and prognostic process. Methods: A narrative review was conducted to investigate the biases in the diagnostic and therapeutic process of two groups of patients: those who are p16-positive but HPV-negative patients, and those who are p16-positive and HPV-positive with exposure to traditional risk factors and/or p53 mutations. The keywords used for the literature research included the following: NCUP, OPSCC, p16IHC, HPV testing, p16 positive HPV negative OPSCC, p16 positive HPV positive OPSCC, tonsillectomy, tobacco exposure, p53 mutations, cystic neck metastasis, extranodal extension (ENE), radiotherapy, de-escalation and neck neck dissection. Results: HPV-positive OPSCC has specific clinico-radiological features. Bilateral tonsillectomy should be considered for the identification of the primary tumor. P16 IHC alone is not sufficient for diagnosing HPV-related OPSCC; additional detection methods are required. The role of tobacco exposure and p53 mutations should be investigated especially in cases of HPV-positive tumors. Extranodal extension (ENE) must be taken into consideration in the prognostic staging of HPV-positive tumors. Surgical primary treatment involving neck dissection (ND) and bilateral tonsillectomy followed by adjuvant radiation may represent the most appropriate approach for N3 cases. Diagnosis, prognosis and therapeutical implications must be addressed considering clinical, biomolecular and morphological aspects. At least today, the numerous biases that are still present influencing the diagnostic and prognostic process do not permit considering de-escalation protocols. Conclusions: A precise and accurate diagnosis is required in order to adequately stage and manage p16+ OPSCC, particularly with neck metastasis. The role of tobacco exposure and/or p53 mutations must be considered not only in p16+ OPSCC but especially in HPV-positive OPSCC. Until a more accurate diagnosis is possible, ENE should be considered even in p16+HPV+ OPSCC. Primary surgery with unilateral ND and bilateral tonsillectomy might be the treatment of choice given the numerous diagnostic and prognostic pitfalls. Therefore, it is inappropriate and risky to propose de-escalation protocols in routine clinical practice due to the risk of undertreatment. Full article

Microsatellites (or short-tandem repeats (STRs)) are widely used in anthropology and evolutionary studies. Their extensive polymorphism and rapid evolution make them the ideal genetic marker for dating events, such as the age of a gene or a population. This usage requires the estimation of mutation rates, which are usually estimated by counting the observed Mendelian incompatibilities in one-generation familial configurations (typically parent(s)–child duos or trios). Underestimations are inevitable when using this approach, due to the occurrence of mutational events that do not lead to incompatibilities with the parental genotypes (‘hidden’ or ‘covert’ mutations). It is known that the likelihood that one mutation event leads to a Mendelian incompatibility depends on the mode of genetic transmission considered, the type of familial configuration (duos or trios) considered, and the genotype(s) of the progenitor(s). In this work, we show how the magnitude of the underestimation of autosomal microsatellite mutation rates varies with the populations’ allele frequency distribution spectrum. The Mendelian incompatibilities approach (MIA) was applied to simulated parent(s)/offspring duos and trios in different populational scenarios. The results showed that the magnitude and type of biases depend on the population allele frequency distribution, whatever the type of familial data considered, and are greater when duos, instead of trios, are used to obtain the estimates. The implications for molecular anthropology are discussed and a simple framework is presented to correct the naïf estimates, along with an informatics tool for the correction of incompatibility rates obtained through the MIA. Full article

Tumor mutational burden (TMB) is a promising predictive biomarker for cancer immunotherapy. Patients with a high TMB have better responses to immune checkpoint inhibitors. Currently, the gold standard for determining TMB is whole-exome sequencing (WES). However, high cost, long turnaround time, infrastructure requirements, and bioinformatics demands have prevented WES from being implemented in routine clinical practice. Panel-sequencing-based estimates of TMB have gradually replaced WES TMB; however, panel design biases could lead to overestimation of TMB. To stratify TMB-high patients better without sequencing all genes and avoid overestimating TMB, we focused on DNA damage repair (DDR) genes, in which dysfunction may increase somatic mutation rates. We extensively explored the association between the mutation status of DDR genes and TMB in different cancer types. By analyzing the mutation data from The Cancer Genome Atlas, which includes information for 33 different cancer types, we observed no single DDR gene/pathway in which mutation status was significantly associated with high TMB across all 33 cancer types. Therefore, a computational algorithm was proposed to identify a cancer-specific gene set as a surrogate for stratifying patients with high TMB in each cancer. We applied our algorithm to skin cutaneous melanoma and lung adenocarcinoma, demonstrating that the mutation status of the identified cancer-specific DDR gene sets, which included only 9 and 14 genes, respectively, was significantly associated with TMB. The cancer-specific DDR gene set can be used as a cost-effective approach to stratify patients with high TMB in clinical practice. Full article

The ability of human immunodeficiency virus (HIV) to avoid recognition by humoral and cellular immunity (viral escape) is well-documented, but the strength of the immune response needed to cause such a viral escape remains poorly quantified. Several previous studies observed a more rapid escape of HIV from CD8 T cell responses in the acute phase of infection compared to chronic infection. The rate of HIV escape was estimated with the help of simple mathematical models, and results were interpreted to suggest that CD8 T cell responses causing escape in acute HIV infection may be more efficient at killing virus-infected cells than responses that cause escape in chronic infection, or alternatively, that early escapes occur in epitopes mutations in which there is minimal fitness cost to the virus. However, these conclusions were challenged on several grounds, including linkage and interference of multiple escape mutations due to a low population size and because of potential issues associated with modifying the data to estimate escape rates. Here we use a sampling method which does not require data modification to show that previous results on the decline of the viral escape rate with time since infection remain unchanged. However, using this method we also show that estimates of the escape rate are highly sensitive to the time interval between measurements, with longer intervals biasing estimates of the escape rate downwards. Our results thus suggest that data modifications for early and late escapes were not the primary reason for the observed decline in the escape rate with time since infection. However, longer sampling periods for escapes in chronic infection strongly influence estimates of the escape rate. More frequent sampling of viral sequences in chronic infection may improve our understanding of factors influencing the rate of HIV escape from CD8 T cell responses. Full article