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BACKGROUND: Basophils, eosinophils and monocytes may be involved in BCG-induced immune responses and be associated with outcomes of bladder cancer patients receiving intravesical BCG. Our objective was to explore the association of baseline counts of basophils, eosinophils and monocytes with outcomes of patients with high-grade T1 bladder cancer receiving a standard course of intravesical BCG. METHODS: We retrospectively reviewed medical records of patients with primary T1 HG/G3 bladder cancer. After re-TURBT, patients were treated with a 6-week course of intravesical BCG induction followed by intravesical BCG every week for 3 weeks given at 3, 6, 12, 18, 24, 30 and 36 months from initiation of therapy The analysis of potential risk factors for recurrence, muscle invasion and cancer-specific and overall survival was performed using univariable Cox regression models. Those factors that presented, at univariate analysis, an association with the event at a liberal p

In the frame of the project FISR_04543 “CRESCIBLUREEF - Grown in the blue: new technologies for knowledge and conservation of Mediterranean reefs”, we present preliminary data on the ecological and depositional implications of micritic sediments in a coralligenous bioconstruction formed along the Mediterranean shelf in front of the Marzamemi village (Sicily, Italy). The framework of the build- up is mainly built by crustose coralline algae, which in turn create the substrate for a high-diversified epi- and infaunal community. Two types of microcrystalline calcite, tentatively interpreted as allochthonous and autochthonous micrite, strictly related to fine skeletal debris, have been detected. The allochthonous micrite derive from abiotic accumulation of fine sediments in the framework cavities. The autochthonous micrite is deposited in situ through organic-mediated processes. The occurrence of this component allows hypothesizing a possible contribution of non-skeletal carbonate in the strengthening of the primary framework due to its syndepositional cementation.

ObjectivesUlcerative colitis (UC) is a chronic inflammatory disorder of unknown aetiology. Gut virome dysbiosis is fundamental in UC progression, although its role in the early phases of the disease is far from fully understood. Therefore, we sought to investigate the role of a virome-associated protein encoded by theOrthohepadnavirusgenus, the hepatitis B virus X protein (HBx), in UC aetiopathogenesis.DesignHBx positivity of UC patient-derived blood and gut mucosa was assessed by RT-PCR and Sanger sequencing and correlated with clinical characteristics by multivariate analysis. Transcriptomics was performed on HBx-overexpressing endoscopic biopsies from healthy donors.C57BL/6 mice underwent intramucosal injections of liposome-conjugated HBx-encoding plasmids or the control, with or without antibiotic treatment. Multidimensional flow cytometry analysis was performed on colonic samples from HBx-treated and control animals. Transepithelial electrical resistance measurement, proliferation assay, chromatin immunoprecipitation assay with sequencing and RNA-sequencing were performed onin vitromodels of the gut barrier. HBx-silencing experiments were performedin vitroandin vivo.ResultsHBx was detected in about 45% of patients with UC and found to induce colonic inflammation in mice, while its silencing reverted the colitis phenotypein vivo. HBx acted as a transcriptional regulator in epithelial cells, provoking barrier leakage and altering both innate and adaptive mucosal immunityex vivoandin vivo.ConclusionThis study described HBx as a contributor to the UC pathogenesis and provides a new perspective on the virome as a target for tailored treatments.

Mucositis; Radiation toxicities; Simultaneous care Mucositis; Toxicitats per radiació; Atenció simultània Mucositis; Toxicidades por radiación; Atención simultánea Treatment of locally advanced head and neck carcinoma not amenable for surgical resection or resected with high-risk features is usually based on (chemo-)radiation treatment. Oral mucositis represents one of the main side effects of (chemo-)radiation, with an important impact on quality of life and causing approximately 20% of early interruption of treatment, leading to a suboptimal dose administered. Treatment and prevention of oral mucositis have a central role in the therapeutic pathways of head and neck cancer patients but remains quite challenging. Although extensive research is conducted to identify interventions for the management of mucositis, very few interventions had sufficient evidence to generate an international expert consensus. This may be partially explained by confounding factors that could influence the development and assessment of oral mucositis. Little is known about the confounding factors of oral mucositis, which, if not well balanced in an experimental study, could lead to non-solid results. The current paper aims to review the main oral mucositis confounding factors related to head and neck cancer patients. Open access funding provided by Università degli Studi di Brescia within the CRUI-CARE Agreement. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Background: Randomised phase III clinical trials represent a methodological milestone to select effective drugs against metastatic cancers. In this context, and particularly in the efficacy assessment of biologic drugs, the initial metastatic tumour burden is a strong prognostic factor. Methods: A systematic literature review of randomised, phase III, first-line, clinical trials in metastatic breast, colorectal, and lung cancers, published from 2016 to 2021, was performed. Three groups of variables were collected: identity-, method- (including tumour burden assessment) and outcome-related. Results: Seventy trials were selected. A large portion of studies (41.4%) focused on the effects of biologic agents (signal inhibitors and immuno-therapies). A definition of low-burden disease based predominantly on the number of involved organs was reported in 28.6% of studies. No explicit reference to oligo-metastatic disease was found either in inclusion/exclusion criteria or in final descriptive data analyses. Disease extent, heterogeneously defined, was a stratification factor for randomisation in only 25.7% of studies. In two studies, a significant imbalance between arms in patients with low-burden disease was revealed. Conclusions: Attention to initial tumour burden in designing future clinical trials (including the harmonisation of definitions and the reporting of eventual oligo-metastatic disease, complete estimates of tumour volume, and its consideration as a stratification factor) should be increased.

Background: Bacterial resistances to antibiotics is generally considered as the most important cause of H. pylori eradication failure. However, other factors such as the level of gastric acid inhibition could affect the outcome of eradicating regimens. Aim: To evaluate the impact of different degrees of acid inhibition on the efficacy of a triple eradication treatment for H. pylori infection. Secondly, to determine other predictors of unsuccessful eradication. Methods: 323 patients with H. pylori infection were treated with clarithromycin 500mg bid and Tinidazole 500 mg bid plus either omeprazole 20 mg bid or omeprazole 40 mg bid. Endoscopy with gastric biopsies and antimicrobial susceptibility testing were performed in all patients. Eradication was evaluated by means of urea-breath test at least 4 weeks after the therapy. Results: Eradication rates were (ITT and PP) 83.3% and 84.3% in patients receiving omeprazole 40 mg and 81.9% and 84.1% in those receiving omeprazole 80 mg (ns). Culture was successful in 218 patients (68.7%). Resistance to clarithromycin and to metronidazole were found in 30 (13.7%) and 45 patients (20.6%), respectively. Eighteen further patients (8.2%) harboured double-resistant strains. Resistance to antibiotics was comparable across the two treatment groups. In resistant patients the eradication rate was significantly lower than in patients harbouring antibiotic-sensitive strains (62/93, 66.6%, 95% CI 0.56-0.76, vs 107/125, 86%, 95% CI 0.78-0.91; p=0.001). Smoking (OR: 2.68) and antibiotic resistance (OR 2.73) were independent predictors of eradication failure. Oppositely, age, sex, alcohol intake, and omeprazole doses did not predict treatment failure. Conclusions: Omeprazole 20 mg bid achieves the optimal acid inhibition in H. pylori eradication. Increasing antisecretory activity above this level does not significantly enhance cure rates. Smoking and antibiotics-resistance are predictors of eradication failure.

Three major variants of the CARD15 gene confer susceptibility to Crohn's disease (CD). Whether or not these variants correlate with specific clinical features of the disease is under evaluation.We investigated the possible association of CARD15 variants with specific clinical characteristics, including the occurrence of anti-Saccharomyces cerevisiae antibodies (ASCA) and antineutrophil cytoplasmic antibodies (ANCA), in a large cohort of inflammatory bowel disease (IBD) patients and their unaffected relatives.Three hundred and sixteen CD patients (156 with positive family history), 408 ulcerative colitis (UC) patients (206 with positive family history), 588 unaffected relatives, and 205 unrelated healthy controls (HC) were studied. Single nucleotide polymorphisms (SNPs) R702W, G908R, and L1007finsC of the CARD15 gene were investigated and correlated to age at diagnosis, gender, family history, localization, extraintestinal manifestations, previous resective surgery, stenosing/fistulizing pattern, ANCA, and ASCA.Compared to HC, the frequencies of all three variants in CD were significantly increased: 8.7% versus 4.1% for R702W (p0.006), 7.3% versus 2.7% for G908R (p0.002), 9.3% versus 0.7% for L1007finsC (p0.00001). At least one risk allele was found in 38.2% (p0.0001, compared to HC), 13.7% (NS), and 15.1% of CD, UC, and HC, respectively. The L1007finsC risk allele was also significantly increased in unaffected relatives of familial (9.5%; p0.00001), and sporadic CD (9%; p0.00001), compared to HC (0.7%). Sixteen healthy relatives, carriers of two risk alleles, were asymptomatic after 5-8 yr of follow-up. CD carriers of at least one variant were younger (p= 0.03), more likely to have ileal localization (p= 0.0001), stenosing pattern (p= 0.01), previous resective surgery (p= 0.0001), and presence of ASCA (p= 0.0001). No difference in SNPs frequency between familial and sporadic cases of CD was found.In our population, both familial and sporadic CD patients carrying at least one major variant of CARD15 had an aggressive clinical course.

Genetics and immunologic dynamics pushing the evolution of colorectal cancer (CRC) from the primary tumor to the metastases are largely unknown; cancer heterogeneity makes challenging both therapy and mechanistic studies. We selected patients developing CRC with lung-limited metastatic disease as only illness during their life in order to find any relevant genotype–phenotype relationship. Analysis of 523 cancer-relevant genes and of immune cells infiltration in primary and metastatic tissues revealed atypical genomic trajectories (TMB decrease, KRAS and SMAD4 regressive mutations), specific genetic events (ERBB2 point mutations) and scarce T-cell infiltration. These insights provide novel information in oligometastatic CRC biology and new perspectives for cancer monitoring and anti-cancer therapeutic strategies.

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.

Objective: To predict the risk of metastatic lymph nodes and the tumor grading related to oral tongue squamous cell carcinoma (OTSCC) through the combination of clinical data with radiomics metrics by computed tomography, and to develop a supportive approach in the management of the lymphatic cervical areas, with particular attention to the early stages (T1−T2). Between March 2016 and February 2020, patients with histologically confirmed OTSCC, treated by partial glossectomy and ipsilateral laterocervical lymphadenectomy and subjected to computed tomography (CT) before surgery, were identified by two centers: 81 patients (49 female and 32 male) with 58 years as the median age (range 19–86 years). Univariate analysis with non-parametric tests and multivariate analysis with machine learning approaches were used. Clinical, hematological parameters and radiological features extracted by CT were considered individually and in combination. All clinical parameters showed statistically significant differences (p < 0.05) for the Kruskal−Wallis test when discriminating both the tumor grading and the metastatic lymph nodes. DOI, PLR, SII, and SIRI showed an accuracy of 0.70 (ROC analysis) when identifying the tumor grading, while an accuracy ≥ 0.78 was shown by DOI, NLR, PLR, SII, and SIRI when discriminating metastatic lymph nodes. In the context of the analysis of radiomics metrics, the original_glszm_HighGrayLevelZoneEmphasis feature was selected for identifying the tumor grading (accuracy of 0.70), while the wavelet_HHH_glrlm_LowGrayLevelRunEmphasis predictor was selected for determining metastatic lymph nodes (accuracy of 0.96). Remarkable findings were also obtained when classifying patients with a machine learning approach. Radiomics features alone can predict tumor grading with an accuracy of 0.76 using a logistic regression model, while an accuracy of 0.82 can be obtained by running a CART algorithm through a combination of three clinical parameters (SIRI, DOI, and PLR) with a radiomics feature (wavelet_LLL_glszm_SizeZoneNonUniformityNormalized). In the context of predicting metastatic lymph nodes, an accuracy of 0.94 was obtained using 15 radiomics features in a logistic regression model, while both CART and CIDT achieved an asymptotic accuracy value of 1.00 using only one radiomics feature. Radiomics features and clinical parameters have an important role in identifying tumor grading and metastatic lymph nodes. Machine learning approaches can be used as an easy-to-use tool to stratify patients with early-stage OTSCC, based on the identification of metastatic and non-metastatic lymph nodes.

The most frequent form of colorectal cancer is represented by adenocarcinoma being about 98% of tumor histological types. However, other rare histotypes can be found in colon and rectum (adenosquamous, goblet cell adenocarcinoma, lymphoma, medullary carcinoma, melanoma, mesenchymal, neuroendocrine, plasmacytoma, signet ring, squamous tumors). Altogether, these forms account for less than 2% of colorectal tumors. There are no specific diagnostic or therapeutic recommended approaches and most of the information available from literature derives from small and retrospective clinical series. In the present study, we provide a paramount and updated view on clinical and biologic characteristics of rare colorectal tumors.

Background: Percutaneous electrical nerve stimulation (PENS) is a minimally invasive peripheral neuromodulation approach implemented against chronic neuropathic and mixed pain. This bibliometric study aims to quantitatively evaluate the output of PENS for pain treatment in the scientific literature. The main purpose is to stimulate research in the field and bridge potential scientific gaps. Methods: Articles were retrieved from the Web of Science (WOS) database. The search key term was “percutaneous electrical nerve stimulation (All Fields) and pain (All Fields)”. Year of publication, journal metrics (impact factor and quartile, Q), title, document type, topic, and citations were extracted. The join-point regression was implemented to assess differences in time points for the publication output. The software tool VOSviewer (version 1.6.17) was used for the visual analysis. Results: One thousand three hundred and eighteen articles were included in the knowledge visualization process. A linear upward trend for annual new publications was found. Almost two-thirds of the documents were published in top-ranked journals (Q1 and Q2). The topic “efficacy” was prevalent (12.81%). Concerning article type, the search strategy yielded 307 clinical investigations (23.3%). Articles were cited 36,610 times with a mean of 42.4 citations per article. Approximately one-half of the articles were cited less than 23 times in a range of 21 years. The semantic network analysis for keywords found eight clusters. The analysis of collaborative efforts among researchers showed five thematic clusters including 102 authors with a minimum of five documents produced in collaborations. Most partnerships involved the United States, England, and Germany. Conclusions: despite the upward trend in the number of publications on the subject and the publication of articles in top-ranked journals, there is a need to increase scientific collaborations between researchers and institutions from different countries.

Background: This study was conducted to provide an updated estimate of the prognostic power of C-X-C chemokine receptor type 4 (CXCR4) in colorectal cancer (CRC), and analyze modalities of evaluating and reporting its expression. Methods: A systematic review with meta-analysis was performed and described according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Studies were identified through PubMed and Google Scholar. The pooled hazard ratios (HRs) for overall survival (OS) or progression-free survival (PFS) with 95% confidence interval (CI) were estimated with the random-effect model. Results: Sixteen studies were selected covering a period from 2005 to 2020. An immunohistochemical evaluation of CXCR4 was performed in all studies. Only in three studies assessment of mRNA through RT–PCR was correlated with prognosis, in the remaining studies, the authors identified prognostic categories based on immunohistochemical expression. In pooled analyses, significant associations were found between positive or high or strong expression of CXCR4 and T stage ≥3 (P = 0.0001), and positive or high or strong expression of CXCR4 and left side primary tumor localization (P = 0.0186). The pooled HR for OS was 2.09 (95% CI: 1.30–2.88) in favor of high CXCR4 expression, for PFS, it was 1.42 (95% CI: 1.13–1.71) in favor of high CXCR4 expression. Conclusion: High CXCR4 expression is clearly associated with increased risk of death and progression in CRC. However, strong methodologic heterogeneity in CXCR4 assessment hinders direct translation into clinical practice, thus, a consensus to streamline detection and scoring of CXCR4 expression in CRC is indicated.

BackgroundWe previously reported that loss of KRAS mutations (“regressive” mutational trajectories) from primary tumors to metastases associated with the oligo-metastatic status in colorectal cancer (CRC). The present study was undertaken in order to analyze the mutational trajectories of KRAS in a well-characterized cohort of CRC patients who developed poly- or oligo-metastatic disease.Material and MethodsPatients were treated and followed-up according to European Society of Medical Oncology guidelines. Primary CRC FFPE tissue and metastatic circulating-free DNA were extracted using the QIAamp DNA specific kits (Qiagen, Hilden, Germany). Samples were sequenced with the Oncomine Solid Tumour DNA kit (Thermo Fisher Scientific, Waltham, MA, USA). Plasma collection for liquid biopsy was done from 1 to 14 days before starting first-line chemotherapy. Analysis of the prognostic power of KRAS evolutionary trajectories was done with uni- and multivariate analyses.ResultsOne-hundred-fourteen patients were enrolled. Sixty-three patients presented with mutated KRAS (mutKRAS) and 51 with wild-type KRAS (wtKRAS). KRAS mutational concordance was high (70.1%).Two divergent subsets were identified: mutKRAS in primary tumors and wtKRAS in metastatic ones (regressive: mutKRAS → wtKRAS in 8.8% of patients), and vice versa (progressive: wtKRAS → mutKRAS in 21.1% of patients). An association between KRAS regressive trajectory and the oligo-metastatic status (P ConclusionsOur data provide evidence that the evolutionary trajectories of KRAS can have a strong clinical prognostic role and that they can be involved in discriminating between poly-metastatic aggressive vs oligo-metastatic indolent CRC.

Background: The mitochondrial metabolism has been associated with pancreatic ductal adenocarcinoma (PDAC) risk. Recent evidence also suggests the involvement of the genetic variability of the mitochondrial function in several traits involved in PDAC etiology. However, a systematic investigation of the genetic variability of mitochondrial genome (mtSNP) and of all the nuclear genes involved in its functioning (n-mtSNPs) has never been reported. Methods: We conducted a two-phase association study of mtSNPs and n-mtSNPs to assess their effect on PDAC risk. We analyzed 35,297 n-mtSNPs and 101 mtSNPs in up to 55,870 individuals (12,884 PDAC cases and 42,986 controls). In addition, we also conducted a gene-based analysis on 1,588 genes involved in mitochondrial metabolism using Multi-marker Analysis of GenoMic Annotation (MAGMA) software. Results: In the discovery phase, we identified 49 n-mtSNPs and no mtSNPs associated with PDAC risk (P < 0.05). In the second phase, none of the findings were replicated. In the gene-level analysis, we observed that three genes (TERT, SUGCT, and SURF1) involved in the mitochondrial metabolism showed an association below the Bonferroni-corrected threshold of statistical significance (P = 0.05/1588 = 3.1 × 10−5). Conclusions: Even though the mitochondrial metabolism might be involved in PDAC etiology, our results, obtained in a study with one of the largest sample sizes to date, show that neither n-mtSNPs nor mtSNPs are associated with PDAC risk. Impact: This large case–control study does not support a role of the genetic variability of the mitochondrial function in PDAC risk.

The present study was undertaken to analyze prognostic and genetic interactions between type 2 diabetes and metastatic colorectal cancer. Patients’ survival was depicted through the Kaplan–Meier product limit method. Prognostic factors were examined through the Cox proportional‐hazards regression model, and associations between diabetes and clinical‐pathologic variables were evaluated by the χ2 test. In total, 203 metastatic colorectal cancer patients were enrolled. Lymph nodes (P = 0.0004) and distant organs (> 2 distant sites, P = 0.0451) were more frequently involved in diabetic patients compared with those without diabetes. Diabetes had an independent statistically significant negative prognostic value for survival. Highly selected patients with cancer and/or diabetes as their only illness(es) were divided into three groups: (a) seven oligo‐metastatic patients without diabetes, (b) 10 poly‐metastatic patients without diabetes, and (c) 12 poly‐metastatic diabetic patients. These groups of patients were genetically characterized through the Illumina NovaSeq 6000 (San Diego, CA, USA) platform and TruSigt™Oncology 500 kit, focusing on genes involved in diabetes and colorectal cancer. Gene variants associated with diabetes and cancer were more frequent in patients in group 3. We found that type 2 diabetes is a negative prognostic factor for survival in colorectal cancer. Diabetes‐associated gene variants could concur with malignancy, providing a rational basis for innovative models of tumor progression and therapy., Type 2 diabetes (T2D) is a frequent comorbidity among metastatic colorectal cancer patients. Here we show that T2D is a negative prognostic factor and hypothesize that genetic polymorphisms involved in diabetes could concur with malignancy providing new insights for innovative models of tumor progression and therapy in this subset of patients.

BackgroundDuring and after general anaesthesia, opioids are commonly used for pain treatment. Since preclinical studies underlined the potential immunosuppressive activity of these drugs, it was postulated that their perioperative administration could influence cancer outcomes after surgery. Nevertheless, clinical data have been extrapolated mainly from retrospective analyses. Consequently, the precise link between perioperative opioid use and cancer recurrence/metastasis or cancer-related mortality/morbidity is still an unsolved issue.Methods and analysisThis scoping review is planned to follow the Joanna Briggs Institute recommendations. The authors will conduct a literature review through the PRISMA statement using PubMed and EMBASE databases; the Grey literature will be explored using Google Scholar and Conference Proceedings Citation Index (via Web of Science). The search strategy will be limited to articles published in the English language and to human studies. The database searches are planned from the inception to January 2022. Two reviewers will independently screen titles and abstracts, followed by a full-text screening of potentially relevant articles with standardised data extraction. Any disagreement for the inclusion between the two reviewers will be discussed with a third reviewer.Ethics and disseminationThe review aims to map the available literature, focusing on a possible association between perioperative opioid use and cancer outcomes in patients undergoing surgery. The proposed approach will be useful to identify and analyse the knowledge gap in the field and serve as a prerequisite for future research.Scoping review registrationOpen Science Framework https://osf.io/vfhw6/ DOI 10.17605/OSF.IO/VFHW6