Head and neck carcinoma (HNC) are diseases arising from several tracts of the aerodigestive ways. Most HNC are squamous cell carcinoma (SCCHN). Immunotherapy is a treatment strategy aimed to ...reinforce the immune system. Several types of immunotherapy are available in the clinical scenario. Checkpoint inhibitors were developed later in SCCHN; nivolumab and pembrolizumab have reached the clinical approval, having both drugs demonstrated to significantly improve the overall survival, if compared with the standard of treatment (according to the results of the CheckMate 141 and KEYNOTE-040 trials). Nevertheless, immunotherapy may fail because of the genetics of SCCHN. In fact, two genetically different types of SCCHN have been discovered, one virus-related (HPV) and the other mutagens-related. They seem to show in clinical trials very different responses to immunotherapy. Given the existence of a number of factors predictive of response to immunotherapy in SCCHN, a future clinical approach may be to characterize the genetic and immunologic feature of SCCHN and to perform a well-tailored immunotherapy. This review will summarize the main immunotherapy strategies available in SCCHN, discussing their real efficacy, highlighting also the ways to improve them.
The coronavirus disease-2019 (COVID-19) is a highly transmissible viral illness caused by SARS-CoV-2, which has been defined by the World Health Organization as a pandemic, considering its remarkable ...transmission speed worldwide. SARS-CoV-2 interacts with angiotensin-converting enzyme 2 and TMPRSS2, which is a serine protease both expressed in lungs, the gastro-intestinal tract, and cardiac myocytes. Patients with COVID-19 experienced adverse cardiac events (hypertension, venous thromboembolism, arrhythmia, myocardial injury, fulminant myocarditis), and patients with previous cardiovascular disease have a higher risk of death. Cancer patients are extremely vulnerable with a high risk of viral infection and more negative prognosis than healthy people, and the magnitude of effects depends on the type of cancer, recent chemotherapy, radiotherapy, or surgery and other concomitant comorbidities (diabetes, cardiovascular diseases, metabolic syndrome). Patients with active cancer or those treated with cardiotoxic therapies may have heart damages exacerbated by SARS-CoV-2 infection than non-cancer patients. We highlight the cardiovascular side effects of COVID-19 focusing on the main outcomes in cancer patients in updated perspective and retrospective studies. We focus on the main cardio-metabolic risk factors in non-cancer and cancer patients and provide recommendations aimed to reduce cardiovascular events, morbidity, and mortality.
Recent studies have underlined HMGA protein's key role in the onset of testicular germ cell tumors, where HMGA1 is differently expressed with respect to the state of differentiation, suggesting its ...fine regulation as master regulator in testicular tumorigenesis. Several studies have highlighted that the
transcript is strictly regulated by a set of inhibitory microRNAs. Thus, the aim of this study is to test whether HMGA1 overexpression in human seminomas may be induced by the deregulation of miR-26a and Let-7a-two
-targeting microRNAs.
mRNA and Let-7a and miR-26a levels were measured in a seminoma dataset available in the Cancer Genome Atlas database and confirmed in a subset of seminomas by qRT-PCR and western blot. A TCam-2 seminoma cell line was then transfected with Let-7a and miR-26a and tested for proliferation and motility abilities.
an inverse correlation was found between the expression of miR-26a and Let-7a and
expression levels in seminomas samples, suggesting a critical role of these microRNAs in
levels regulation. Accordingly, functional studies showed that miR-26a and Let-7a inhibited the proliferation, migration and invasion capabilities of the human seminoma derived cell line TCam-2.
these data strongly support that the upregulation of HMGA1 levels occurring in seminoma is-at least in part-due to the downregulation of
-targeting microRNAs.
Cetuximab plus chemotherapy is a first-line treatment option in metastatic KRAS and NRAS wild-type colorectal cancer (CRC) patients. No data are currently available on continuing anti-epidermal ...growth factor receptor (EGFR) therapy beyond progression.
We did this open-label, 1:1 randomized phase II trial at 25 hospitals in Italy to evaluate the efficacy of cetuximab plus 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) as second-line treatment of KRAS exon 2 wild-type metastatic CRC patients treated in first line with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) plus cetuximab. Patients received FOLFOX plus cetuximab (arm A) or FOLFOX (arm B). Primary end point was progression-free survival (PFS). Tumour tissues were assessed by next-generation sequencing (NGS). This report is the final analysis.
Between 1 February 2010 and 28 September 2014, 153 patients were randomized (74 in arm A and 79 in arm B). Median PFS was 6.4 95% confidence interval (CI) 4.7–8.0 versus 4.5 months (95% CI 3.3–5.7); hazard ratio (HR), 0.81; 95% CI 0.58–1.12; P = 0.19, respectively. NGS was performed in 117/153 (76.5%) cases; 66/117 patients (34 in arm A and 32 in arm B) had KRAS, NRAS, BRAF and PIK3CA wild-type tumours. For these patients, PFS was longer in the FOLFOX plus cetuximab arm median 6.9 (95% CI 5.5–8.2) versus 5.3 months (95% CI 3.7–6.9); HR, 0.56 (95% CI 0.33–0.94); P = 0.025. There was a trend in better overall survival: median 23.7 (95% CI 19.4–28.0) versus 19.8 months (95% CI 14.9–24.7); HR, 0.57 (95% CI 0.32–1.02); P = 0.056.
Continuing cetuximab treatment in combination with chemotherapy is of potential therapeutic efficacy in molecularly selected patients and should be validated in randomized phase III trials.
Recurrent somatic mutations in the promoter region of telomerase reverse transcriptase (TERT) gene and in the exon 3 of CTNNB1 gene have been recognized as common events in hepatocellular carcinoma ...(HCC) with variable frequencies depending on etiology and geographical region. We have analyzed TERT promoter and CTNNB1 gene mutations in 122 cases of hepatitis B (HBV) and hepatitis C (HCV) related HCCs, in 7 cases of cholangiocarcinoma (CC) and hepatocholangiocarcinoma (HCC-CC) as well as in autologous cirrhotic tissues. Overall, 50.4% and 26% of HCC as well as 14.3% and none of CC and HCC-CC were mutated in TERT promoter and in CTNNB1 exon 3, respectively. TERT and CTNNB1 mutations were found more frequently in HCV related (53.6% and 26.4%, respectively) than HBV related (41.7% and 16.7%, respectively) HCCs and coexisted in 57.6% of CTNNB1 mutated tumors. Mutations in TERT and CTNNB1 were not associated with the functional promoter polymorphism rs2853669. No mutations were detected in the 129 non-HCC cirrhotic tissues. In conclusion, mutations in TERT promoter and in CTNNB1 gene represent specific cancer signatures in the pathogenesis of viral related HCC and could be promising early biomarkers as well as targets for tailored therapies.
Background:
Despite great technical advances in imaging, such as multidetector computed tomography and magnetic resonance imaging (MRI), diagnosing pancreatic solid lesions correctly remains ...challenging, due to overlapping imaging features with benign lesions. We wanted to evaluate functional MRI to differentiate pancreatic tumors, peritumoral inflammatory tissue, and normal pancreatic parenchyma by means of dynamic contrast-enhanced MRI (DCE-MRI)-, diffusion kurtosis imaging (DKI)-, and intravoxel incoherent motion model (IVIM) diffusion-weighted imaging (DWI)-derived parameters.
Methods:
We retrospectively analyzed 24 patients, each with histopathological diagnosis of pancreatic tumor, and 24 patients without pancreatic lesions. Functional MRI was acquired using a 1.5 MR scanner. Peritumoral inflammatory tissue was assessed by drawing regions of interest on the tumor contours. DCE-MRI, IVIM and DKI parameters were extracted. Nonparametric tests and receiver operating characteristic (ROC) curves were calculated.
Results:
There were statistically significant differences in median values among the three groups observed by Kruskal–Wallis test for the DKI mean diffusivity (MD), IVIM perfusion fraction (fp) and IVIM tissue pure diffusivity (Dt). MD had the best results to discriminate normal pancreas plus peritumoral inflammatory tissue versus pancreatic tumor, to separate normal pancreatic parenchyma versus pancreatic tumor and to differentiate peritumoral inflammatory tissue versus pancreatic tumor, respectively, with an accuracy of 84%, 78%, 83% and area under ROC curve (AUC) of 0.85, 0.82, 0.89. The findings were statistically significant compared with those of other parameters (p value < 0.05 using McNemar’s test). Instead, to discriminate normal pancreas versus peritumoral inflammatory tissue or pancreatic tumor and to differentiate normal pancreatic parenchyma versus peritumoral inflammatory tissue, there were no statistically significant differences between parameters’ accuracy (p > 0.05 at McNemar’s test).
Conclusions:
Diffusion parameters, mainly MD by DKI, could be helpful for the differentiation of normal pancreatic parenchyma, perilesional inflammation, and pancreatic tumor.
Aberrant activation of PI3K/AKT signalling represents one of the most common molecular alterations in lung cancer, though the relative contribution of the single components of the cascade to the ...NSCLC development is still poorly defined. In this manuscript we have investigated the relationship between expression and genetic alterations of the components of the PI3K/AKT pathway KRAS, the catalytic subunit of PI3K (p110α), PTEN, AKT1 and AKT2 and the activation of AKT in 107 surgically resected NSCLCs and have analyzed the existing relationships with clinico-pathologic features. Expression analysis was performed by immunohistochemistry on Tissue Micro Arrays (TMA); mutation analysis was performed by DNA sequencing; copy number variation was determined by FISH. We report that activation of PI3K/AKT pathway in Italian NSCLC patients is associated with high grade (G3-G4 compared with G1-G2; n = 83; p<0.05) and more advanced disease (TNM stage III vs. stages I and II; n = 26; p<0.05). In addition, we found that PTEN loss (41/104, 39%) and the overexpression of p110α (27/92, 29%) represent the most frequent aberration observed in NSCLCs. Less frequent molecular lesions comprised the overexpression of AKT2 (18/83, 22%) or AKT1 (17/96, 18%), and KRAS mutation (7/63, 11%). Our results indicate that, among all genes, only p110α overexpression was significantly associated to AKT activation in NSCLCs (p = 0.02). Manipulation of p110α expression in lung cancer cells carrying an active PI3K allele (NCI-H460) efficiently reduced proliferation of NSCLC cells in vitro and tumour growth in vivo. Finally, RNA profiling of lung epithelial cells (BEAS-2B) expressing a mutant allele of PIK3 (E545K) identified a network of transcription factors such as MYC, FOS and HMGA1, not previously recognised to be associated with aberrant PI3K signalling in lung cancer.
Triple-negative breast cancer (TNBC) has a significant clinical relevance of being associated with a shorter median time to relapse and death and does not respond to endocrine therapy or other ...available targeted agents. Increased aggressiveness of this tumor, as well as resistance to standard drug therapies, may be associated with the presence of stem cell populations within the tumor. Several stemness markers have been described for the various histological subtypes of breast cancer, such as CD44, CD24, CD133, ALDH1, and ABCG2. The role of these markers in breast cancer is not clear yet and above all there are conflicting opinions about their real prognostic value. To investigate the role of CSCs markers in TNBC cancerogenesis and tumor progression, we selected 160 TNBCs samples on which we detected protein expression of CD44, CD24, CD133, ALDH1, and ABCG2 by immunohistochemistry. Our results highlighted a real prognostic role only for CD44 in TNBCs. All other CSCs markers do not appear to be related to the survival of TNBC patients. In conclusion, despite the fact that the presence of the cancer stem cells in the tumor provides important information on its potential aggressiveness, today their detection by immunohistochemistry is not sufficient to confirm their role in carcinogenesis, because specific markers probably are not yet identified.
Hashimoto's thyroiditis (HT) seems to have favourable prognostic impact on papillary thyroid cancer (PTC), but data were obtained analysing all disease stages. Given that HT-related microenvironment ...involves solely the thyroid, we aimed to assess the relationship between HT, as detected through pathological assessment, and outcome in intrathyroidal PTC. This was a multicentre, retrospective, observational study including 301 PTC with no evidence of extrathyroidal disease. Primary study endpoint was the rate of clinical remission. Auxiliary endpoint was recurrence-free survival (RFS). HT was detected in 42.5% of the cohort and was associated to female gender, smaller tumour size, lower rate of aggressive PTC variants and less frequent post-surgery radio-iodine administration. HT showed relationship with significantly higher rate of clinical remission (
< 0.001, OR 4, 95% CI 1.78-8.94). PTCs with concomitant HT had significantly longer RFS, as compared with non-HT tumours (
= 0.004). After adjustment for other parameters affecting disease outcome at univariate analysis (age at diagnosis, histology, tumour size and multifocality), prognostic effect of HT remained significant (
= 0.006, OR 3.28, 95% CI 1.39-7.72). To verify whether HT could optimise the identification of PTCs with unfavourable outcome, we assessed the accuracy of 'non-HT status' as negative prognostic marker, demonstrating poor capability of identifying patients not maintaining clinical remission until final follow-up (probability of no clinical remission in PTCs without HT: 21.05%, 95% CI 15.20-27.93). In conclusion, our data show that HT represents an independent prognostic parameter in intrathyroidal PTC, but cannot improve prognostic specificity.
Malignant melanoma accounts for about 1% of all skin cancers, but it causes most of the skin cancer-related deaths. Circulating tumor DNA (ctDNA) testing is emerging as a relevant tool for the ...diagnosis and monitoring of cancer. The availability of highly sensitive techniques, including next generation sequencing (NGS)-based panels, has increased the fields of application of ctDNA testing. While ctDNA-based tests for the early detection of melanoma are not available yet, perioperative ctDNA analysis in patients with surgically resectable melanoma offers relevant prognostic information: i) the detection of ctDNA before surgery correlates with the extent and the aggressiveness of the disease; ii) ctDNA testing after surgery/adjuvant therapy identifies minimal residual disease; iii) testing ctDNA during the follow-up can detect a tumor recurrence, anticipating clinical/radiological progression. In patients with advanced melanoma, several studies have demonstrated that the analysis of ctDNA can better depict tumor heterogeneity and provides relevant prognostic information. In addition, ctDNA testing during treatment allows assessing the response to systemic therapy and identifying resistance mechanisms. Although validation in prospective clinical trials is needed for most of these approaches, ctDNA testing opens up new scenarios in the management of melanoma patients that could lead to improvements in the diagnosis and therapy of this disease.
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