Radiation‐induced nausea and vomiting in head and neck cancer: Is it something worth considering in the intensity modulated radiotherapy era? “A narrative review”

Radiation therapy is one of the cornerstones in the treatment of head and neck squamous cell carcinomas (HNSCC), alone or in combination with chemotherapy or surgery. Technological advances which occurred over the last few decades have increased the efficacy of radiotherapy (RT), particularly, intensity‐modulated RT (IMRT). IMRT can deliver treatments on complex tumoral targets with dose escalation while sparing organs at risk; anyway IMRT deposits dose in unpredictable patterns outside of the target volume with the purpose of improving conformality. Radiation‐induced nausea and vomiting (RINV) is a frequent albeit neglected side effect of RT that can lead to delays in treatment with serious consequences on cure rates. According to several guidelines (MASCC 2016, NCCN 2018), RT for HNSCC has traditionally been regarded as a low emetic risk treatment. Nevertheless, several works suggest that IMRT could increase RINV. Further studies are needed to define the exact incidence and the detailed pathophysiology of RINV in patients with HNSCC treated with state of art IMRT techniques, with and without concurrent chemotherapy.     

Potential role of serum mesothelin in predicting survival of patients with malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor survival rates. Therefore, it is essential to have effective biological markers predicting the course of the disease and prognosis. The aim of the present study was to highlight the prognostic significance of serum soluble mesothelin-related protein (Se-SMRP) in patients with MPM at diagnosis. Se-SMRP was determined in 60 patients using an ELISA commercial kit. Se-SMRP levels were subdivided into three tertile-based categories and in each category overall survival (OS) indexes were determined using the Kaplan-Meier and Cox regression analyses. The association between Se-SMRP levels and OS was also assessed by restricted cubic spline (RCS) analysis. No notable differences in the Kaplan-Meier probabilities were identified across the Se-SMRP categories (<0.66 nM, 0.66–1.46 nM, >1.46 nM) although an upward trend in death rate ratios (RR) was pointed out by comparing the higher (RR=1.95) and intermediate (RR=1.86) categories with the lower category (RR=1.00). In addition, such an increasing tendency, particularly when the biomarker exceeded 1.0 nM, was confirmed by an RCS function of Se-SMPR levels fitted to survival data using the Cox regression equation. The present study provided evidence in favor of a prognostic value of Se-SMRP in patients with MPM.     

Trop‐2 cleavage by ADAM10 is an activator switch for cancer growth and metastasis

Trop-2 is a transmembrane signal transducer that can induce cancer growth. Using antibody targeting and N-terminal Edman degradation, we show here that Trop-2 undergoes cleavage in the first thyroglobulin domain loop of its extracellular region, between residues R87 and T88. Molecular modeling indicated that this cleavage induces a profound rearrangement of the Trop-2 structure, which suggested a deep impact on its biological function. No Trop-2 cleavage was detected in normal human tissues, whereas most tumors showed Trop-2 cleavage, including skin, ovary, colon, and breast cancers. Coimmunoprecipitation and mass spectrometry analysis revealed that ADAM10 physically interacts with Trop-2. Immunofluorescence/confocal time-lapse microscopy revealed that the two molecules broadly colocalize at the cell membrane. We show that ADAM10 inhibitors, siRNAs and shRNAs abolish the processing of Trop-2, which indicates that ADAM10 is an effector protease. Proteolysis of Trop-2 at R87-T88 triggered cancer cell growth both in vitro and in vivo. A corresponding role was shown for metastatic spreading of colon cancer, as the R87A-T88A Trop-2 mutant abolished xenotransplant metastatic dissemination. Activatory proteolysis of Trop-2 was recapitulated in primary human breast cancers. Together with the prognostic impact of Trop-2 and ADAM10 on cancers of the skin, ovary, colon, lung, and pancreas, these data indicate a driving role of this activatory cleavage of Trop-2 on malignant progression of tumors.     

Interferon‐γ, Interleukins‐6 and ‐4, and Factor XIII‐A as Indirect Markers of the Classical and Alternative Macrophage Activation Pathways in Chronic Periodontitis

Background: Macrophages account for 5% to 30% of the inflammatory infiltrate in periodontitis and are activated by the classic and alternative pathways. These pathways are identified by indirect markers, among which interferon (IFN)‐γ and interleukin‐6 (IL)‐6 of the classic pathway and IL‐4 of the alternative pathway have been studied widely. Recently, factor XIII‐A (FXIII‐A) was reported to be a good marker of alternative pathway activation. The aim of this study is to determine the macrophage activation pathways involved in chronic periodontitis (CP) by the detection of the indirect markers IFN‐γ, IL‐6, FXIII‐A, and IL‐4. Methods: Biopsies were taken from patients with CP (n = 10) and healthy individuals (n = 10) for analysis of IFN‐γ, IL‐6, IL‐4, and FXIII‐A by Western blot (WB), immunohistochemistry (IHC), and enzyme‐linked immunosorbent assay (ELISA). The same biopsies of healthy and diseased gingival tissue were used, and the expressions of these markers were compared between healthy individuals and those with CP. Results: The presence of macrophages was detected by CD68+ immunohistochemistry and their IFN‐γ, IL‐6, IL‐4, and FXIII‐A markers by WB, IHC, and ELISA in all samples of healthy and diseased tissue. IL‐6, IL‐4, and FXIII‐A were significantly higher in patients with CP, whereas FXIII‐A was higher in healthy individuals. Conclusion: The presence of IFN‐γ, IL‐6, IL‐4, and FXIII‐A in healthy individuals and in patients with CP suggests that macrophages may be activated by both classic and alternative pathways in health and in periodontal disease.     

Epidemiology of migraine

One-year migraine prevalence rates in the general population for Western countries vary from 4% to 9% in men and from 11% to 25% in women. Non-Western countries report lower figures. Incidence rates for people under 30 years of age vary from 1.5 to 6 per 1000 person-years in men and from 3 to 24 per 1000 person-years in women. Data on the prevalence of migraine in general, on the gender ratio and on the variations in prevalence in the different age ranges are fairly comparable and can be regarded as very close to reality. On the contrary, data on the incidence of migraine, on the prevalence of different migraine subtypes, such as migraine with aura and the so-called migrainous disorder, and on the frequency of migraine attacks show a striking discordance that somewhat undermines their reliability. The main critical points in prevalence and incidence studies are migraine definition and the methodological approaches used for case screening. Even if International Headache Society (IHS) classification is certainly an improvement over previous tools used in epidemiological studies, the diagnostic criteria for migraine without aura are quite scanty and not easily remembered by subjects belonging to the general population, and those for migraine with aura appear not only difficult to translate for use in a questionnaire or an interview, but also too loose. In particular, the lack of any low-end limit for aura duration may cause an overestimation of migraine with aura prevalence.     

Selective Cumulative Inhibition of Platelet Thromboxane Production by Low-dose Aspirin in Healthy Subjects

Acetylation of platelet cyclooxygenase by oral aspirin is dose dependent and cumulative with repeated administration. However, no single dose of aspirin has been found to be completely selective of platelet thromboxane (TX) synthesis inhibition in man. We determined the dose dependence, cumulative nature and selectivity of aspirin effects on platelet TXB₂ and renal prostaglandin (PG) and prostacyclin (PGI₂) production. We measured, by radioimmunoassay, serum TXB₂ levels after whole blood clotting and urinary excretion of PGE₂, PGF_2α, and 6-keto-PGF_1α, before and after single or repeated oral aspirin doses given to 46 healthy subjects. Single doses of 6-100 mg aspirin resulted in a linear (r = 0.92, P < 0.01) inhibition of platelet TXB₂ production, ranging from 12 to 95% after 24 h. A daily dose of 0.45 mg/kg given for 7 d produced a cumulative and virtually complete inhibition of platelet TXB₂ production, without significantly reducing the urinary excretion of PGE₂, PGF_2α, and 6-keto-PGF_1α in both healthy men and women. The platelet inhibitory effect of this regimen was maintained unaltered throughout 1 mo of therapy, with no evidence of cumulative inhibition of renal PG-synthesis. Moreover, furosemide-induced renal PGI₂ synthesis and renin release were unaffected by chronic low-dose aspirin. Following cessation of aspirin therapy, platelet TXB₂ production returned toward control values at a similar rate as after a single higher dose.