Neo-adjuvant chemo-radiation of rectal cancer with Volumetric Modulated Arc Therapy: summary of technical and dosimetric features and early clinical experience

<p>Abstract</p> <p>Background</p> <p>To report about initial technical and clinical experience in preoperative radiation treatment of rectal cancer with volumetric modulated arcs with the RapidArc^®(RA) technology.</p> <p>Methods</p> <p>Twenty-five consecutive patients (pts) were treated with RA. All showed locally advanced rectal adenocarcinoma with stage T2-T4, N0-1. Dose prescription was 44 Gy in 22 fractions (or 45 Gy in 25 fractions). Delivery was performed with single arc with a 6 MV photon beam. Twenty patients were treated preoperatively, five did not receive surgery. Twenty-three patients received concomitant chemotherapy with oral capecitabine. A comparison with a cohort of twenty patients with similar characteristics treated with conformal therapy (3DC) is presented as well.</p> <p>Results</p> <p>From a dosimetric point of view, RA improved conformality of doses (CI_95%= 1.1 vs. 1.4 for RA and 3DC), presented similar target coverage with lower maximum doses, significant sparing of femurs and significant reduction of integral and mean dose to healthy tissue. From the clinical point of view, surgical reports resulted in a down-staging in 41% of cases. Acute toxicity was limited to Grade 1-2 diarrhoea in 40% and Grade 3 in 8% of RA pts, 45% and 5% of 3DC pts, compatible with known effects of concomitant chemotherapy. RA treatments were performed with an average of 2.0 vs. 3.4 min of 3DC.</p> <p>Conclusion</p> <p>RA proved to be a safe, qualitatively advantageous treatment modality for rectal cancer, showing some improved results in dosimetric aspects.</p

Early clinical experience of radiotherapy of prostate cancer with volumetric modulated arc therapy

<p>Abstract</p> <p>Background</p> <p>To report about initial clinical experience in radiation treatment of carcinoma of prostate with volumetric modulated arcs with the RapidArc (RA) technology.</p> <p>Methods</p> <p>Forty-five patients with a median age of 72 ± 3, affected by prostate carcinoma (T1c: 22 patients, T2a-b: 17 patients, T3a-b: 6 patients. N0: 43 patients, N1-Nx: 2 patients, all M0), with initial PSA of 10.0 ± 3.0 ng/mL, were treated with RapidArc in a feasibility study. All patients were treated with single arc using 6MV photons. Dose prescription ranged between 76 (7 patients) and 78 Gy (38 patients) in 2Gy/fraction. Plan quality was assessed by means of Dose Volume Histogram (DVH) analysis. Technical parameters of arcs and pre-treatment quality assurance results (Gamma Agreement Index, GAI) are reported to describe delivery features. Early toxicity was scored (according to the Common Terminology Criteria of Adverse Effects scale, CTCAE, scale) at the end of treatment together with biochemical outcome (PSA).</p> <p>Results</p> <p>From DVH data, target coverage was fulfilling planning objectives: V_95%was in average higher than 98% and V_107%~0.0% (D_2%~104.0% in average). Homogeneity D_5%-D_95%ranged between 6.2 ± 1.0% to 6.7 ± 1.3%. For rectum, all planning objectives were largely met (e.g. V_70Gy= 10.7 ± 5.5% against an objective of < 25%) similarly for bladder (e.g. D_2%= 79.4 ± 1.2Gy against an objective of 80.0Gy). Maximum dose to femurs was D_2%= 36.7 ± 5.4Gy against an objective of 47Gy. Monitor Units resulted: MU/Gy = 239 ± 37. Average beam on time was 1.24 ± 0.0 minutes. Pre-treatment GAI resulted in 98.1 ± 1.1%. Clinical data were recorded as PSA at 6 weeks after RT, with median values of 0.4 ± 0.4 ng/mL. Concerning acute toxicity, no patient showed grade 2-3 rectal toxicity; 5/42 (12%) patients experienced grade 2 dysuria; 18/41 (44%) patients preserved complete or partial erectile function.</p> <p>Conclusion</p> <p>RapidArc proved to be a safe, qualitative and advantageous treatment modality for prostate cancer.</p

The Impact of Locoregional Treatment on Response to Nivolumab in Advanced Platinum Refractory Head and Neck Cancer: The Need Trial

Background: Previous locoregional treatment could affect the response to nivolumab in platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). The aim of this study is to evaluate the impact of the clinicopathological characteristics and previous treatment in predicting early progression to nivolumab in a real-world population. Methods: This is an observational, multicenter retrospective/prospective study including patients (pts) with platinum refractory R/M HNSCC who received nivolumab 240 mg every 2 weeks from October 2018 to October 2019. We analyzed the association between previous treatment, clinicopathological characteristics, and early progression (within 3 months). Results: Data from 61 pts were reviewed. Median age was 67 years (30–82). Forty-two pts (69%) received previous locoregional treatment. Early progression to nivolumab occurred in 36 pts (59%), while clinical benefit (stable disease and partial response) was achieved in 25 pts (41%). Early progression to nivolumab was significantly associated to previous locoregional treatment both at univariate and multivariate analysis (p = 0.005 and p = 0.048, respectively). Conclusion: nivolumab in R/M HNSCC is burdened with a high early progression rate. Previous wide neck dissection and high dose radiotherapy may compromise the efficacy of nivolumab, distorting the anatomy of the local lymphatic system and hindering the priming of immune response

Inhibition by yeast killer toxin-like antibodies of oral Streptococci adhesion to tooth surfaces in an ex vivo model.

BACKGROUND: Monoclonal (KTmAb) and recombinant (KTscFv) anti-idiotypic antibodies, representing the internal image of a yeast killer toxin, proved to be microbicidal in vitro against important eukaryotic and prokaryotic pathogens such as Candida albicans, Pneumocystis carinii, Mycobacterium tuberculosis, Staphylococcus aureus, S. haemolyticus, Enterococcus faecalis, E. faecium, and Streptococcus pneumoniae, including multidrug-resistant strains. KTmAb and KTscFv exerted a strong therapeutic effect in well-established animal models of candidiasis and pneumocystosis. Streptococcus mutans is the most important etiologic agent of dental caries that might result from the metabolic end products of dental plaque. Effective strategies to reduce the disease potential of dental plaque have considered the possibility of using antibiotics or antibodies against oral streptococci in general and S. mutans in particular. In this study, the activity of KTmAb and KTscFv against S. mutans and the inhibition and reduction by KTmAb of dental colonization by S. mutans and other oral streptococci in an ex vivo model of human teeth were investigated. MATERIALS AND METHODS: KTscFv and KTmAb were used in a conventional colony forming unit (CFU) assay against a serotype C strain of S. mutans, and other oral streptococci (S. intermedius, S. mitis, S. oralis, S. salivarius). An ex vivo model of human teeth submerged in saliva was used to establish KTmAb potential of inhibiting or reducing the adhesion to dental surfaces by S. mutans and other oral streptococci. RESULTS: KTmAb and KTscFv kill in vitro S. mutans and other oral streptococci. KTmAb inhibit colonization of dental surfaces by S. mutans and oral streptococci in the ex vivo model. CONCLUSIONS: Killer antibodies with antibiotic activity or their engineered derivatives may have a potential in the prevention of dental caries in vivo

Histopathological and Molecular Study of Pacific Oyster Tissues Provides Insights into V. aestuarianus Infection Related to Oyster Mortality

Consumer preference for healthy and sustainable food products has been steadily increasing in recent years. Bivalve mollusks satisfy these characteristics and have captured ever-increasing market shares. However, the expansion of molluscan culture in worldwide and global trade have favored the spread of pathogens around the world. Combined with environmental changes and intensive production systems this has contributed to the occurrence of mass mortality episodes, thus posing a threat to the production of different species, including the Pacific oyster Crassotrea gigas. In the San Teodoro lagoon, one of the most devoted lagoons to extensive Pacific oyster aquaculture in Sardinia, a mortality outbreak was observed with an estimated 80% final loss of animal production. A study combining cultural, biomolecular and histopathological methods was conducted: (1) to investigate the presence of different Vibrio species and OsHV-1 in selected oyster tissues (digestive gland, gills, and mantle); (2) to quantify Vibrio aestuarianus and to evaluate the severity of hemocyte infiltration in infected tissues; (3) to produce post-amplification data and evaluating ToxR gene as a target for phylogenetic analyses. Results provide new insights into V. aestuarianus infection related to oyster mortality outbreaks and pave the way to the development of tools for oyster management

Integrated Genomics Identifies miR-181/TFAM Pathway as a Critical Driver of Drug Resistance in Melanoma

MicroRNAs (miRNAs) are attractive therapeutic targets and promising candidates as molecular biomarkers for various therapy-resistant tumors. However, the association between miRNAs and drug resistance in melanoma remains to be elucidated. We used an integrative genomic analysis to comprehensively study the miRNA expression profiles of drug-resistant melanoma patients and cell lines. MicroRNA-181a and -181b (miR181a/b) were identified as the most significantly down-regulated miRNAs in resistant melanoma patients and cell lines. Re-establishment of miR-181a/b expression reverses the resistance of melanoma cells to the BRAF inhibitor dabrafenib. Introduction of miR-181 mimics markedly decreases the expression of TFAM in A375 melanoma cells resistant to BRAF inhibitors. Furthermore, melanoma growth was inhibited in A375 and M14 resistant melanoma cells transfected with miR-181a/b mimics, while miR-181a/b depletion enhanced resistance in sensitive cell lines. Collectively, our study demonstrated that miR-181a/b could reverse the resistance to BRAF inhibitors in dabrafenib resistant melanoma cell lines. In addition, miR-181a and -181b are strongly down-regulated in tumor samples from patients before and after the development of resistance to targeted therapies. Finally, melanoma tissues with high miR-181a and -181b expression presented favorable outcomes in terms of Progression Free Survival, suggesting that miR-181 is a clinically relevant candidate for therapeutic development or biomarker-based therapy selection

Clinicopathologic correlates and prognostic relevance of the immune checkpoint CD73 (NT5E) in resected biliary cancers (BC)

Background: CD73, an ecto-5’-nucleotidase (NT5E), creates an immunosuppressive tumour-promoting microenvironment by converting ATP to adenosine. The expression of CD73 has been linked to poorer patients (pts) outcome across several cancer types and the targeted inhibition of this immunoinhibitory protein has been recently advanced to clinical development. However, the clinicopathologic role of CD73 as well as its potential implications are largely unexplored in BC. Methods: The expression of CD73 was assessed by immunohistochemistry on both tumour (tCD73) and stromal tissue (sCD73) of a clinically-annotated cohort of radically-resected BC and scored for staining intensity as follows: +1, +2 and +3. RNAseq was performed on RNA isolated from surgical specimens. Differences between groups were evaluated using the Chi-square test. Survival functions were estimated by the Kaplan-Meier method and comparisons were made using the log-rank test. The Cox proportional hazards model was used to assess the impact of covariates on survival outcomes. Results: CD73 immunohistochimichal expression was evaluated on resected specimens of 70 BC pts. 43 pts (61%) were tCD73-positive, while 44 pts (62%) were sCD73-positive. Among the former group, the intensity score was 1+ in 19 pts (44%), 2+ in 16 pts (37%), 3+ in 10 pts (23%), while in the latter group was 1+ in 22 pts (50%), 2+ in 10 pts (22%) and 3+ in 12 pts (27%). CD73 positivity was associated with older age (&gt; 70 years, p = 0.01), gallbladder subsite (p = 0.03), and nodal involvement (p = 0.04). Patients with tCD73-positive BC experienced a significantly shorter relapse-free survival (8,4 vs 39,4 months; p = 0.016) and overall survival (60,7 vs 13,7 months; p = 0.017). Notably, high tCD73 expressors (score 3+) displayed the poorest prognosis (12,03 months; p = 0.023). When evaluated on univariate and multivariate analysis, tCD73 positivity was an independent prognostic factor for both relapse-free survival (p = 0.038) and overall survival (p = 0.023), together with ECOG PS and pTNM stage. Whole-transcriptome sequencing is ongoing to correlate CD73 expression with cancer-related pathways. Conclusions: In this study, we provided a clinicopathologic characterization of CD73 expression in resected BC, demonstrating that tCD73 is an independent negative prognostic biomarker in this disease. Although these findings are in need of a validation in larger dataset, they foster novel combination of anti-CD73 agents with conventional therapy in the poorer-prognosis subset of CD73-positive BC