Colorectal cancer chemotherapy: can sex-specific disparities impact on drug toxicities?

PURPOSE: Given the biological differences between females and males, sex-specific evaluations should be carried out to obtain better cancer prevention, diagnosis, and treatment strategies. To this purpose, our aim was to evaluate sex differences for toxicity in a cohort of colorectal cancer (CRC) patients undergoing chemotherapy. METHODS: We performed a retrospective study in 329 CRC patients. Differences between males and females were tested performing the Mann-Whitney U test or the Fisher exact test. Multivariate logistic regression models were computed to evaluate the association between sex and risk of chemotherapy agent-related toxicity. RESULTS: According association sex toxicity, significant differences were observed in the median number of episodes of nausea (p = 0.044), vomit (p = 0.007), heartburn (p = 0.022), thrombocytopenia (p = 0.005), mucositis (p = 0.024). Moreover, statistically significant differences between males and females were observed in the distribution of the highest toxicity grades of nausea (p = 0.024), heartburn (p = 0.016), and thrombocytopenia (p = 0.034). Females have an increased risk of vomit (p = 0.002), alopecia (p = 0.035), heartburn (p = 0.005), mucositis (p = 0.003), and lower risk for thrombocytopenia (p = 0.005). CONCLUSION: According to the association of sex chemotherapy agent-related toxicities, females resulted on average at a significant increased risk of more common adverse events (constipation, dysgeusia, alopecia, heartburn, vomit, asthenia, nausea, pain events, and mucositis). Sex-tailored CRC chemotherapy treatment is necessary to obtain efficacy avoiding toxicity, based on patients' biological and genetic characteristics, a vision that would change CRC setting, a stable disease but still orphan of a real tailored approach.

Asthma in the Real-World: The Relevance of Gender.

BACKGROUND: The possible gender impact on asthma arouses current and outstanding interest, but few studies addressed this issue in the real-world setting. OBJECTIVE: This cross-sectional study tested the hypothesis of a potential difference between asthmatic males and females in a real-life setting, such as a third-level asthma clinic. METHODS: A total of 499 asthmatic outpatients (301 females and 198 males, mean age 58.25 years) were consecutively visited. The visit included history, asthma control, and severity grade, physical examination, lung function, fractional exhaled nitric oxide assessment, and blood sample for biomarkers. RESULTS: There were more females than males (about 3 of 5). Asthmatic females smoked less (p < 0.0001) than males and had higher FEV1 (p = 0.0022) and FVC (p = 0.0004) values than asthmatic males. CONCLUSIONS: Gender difference was associated with smoking and lung function impairment; thus, this issue should be carefully considered in asthmatic patients in daily clinical practice.

A real-world assessment of asthma with chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) includes 2 main phenotypes: CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP). CRS has been reported to be a comorbidity of asthma. OBJECTIVE: This study aimed to investigate the role of CRS in outpatients with asthma visited in real-world setting. METHODS: This cross-sectional study enrolled 499 consecutive outpatients with asthma. Age, sex, body mass index, smoking status, lung function, Asthma Control Test, inflammatory type 2 biomarkers (including fractional exhaled nitric oxide, blood eosinophils, serum total immunoglobulin E, and allergy), treatment step according to the Global Initiative for Asthma, and comorbidities (obstructive sleep apnea syndrome, arterial hypertension, bronchiectasis, diabetes mellitus type 2, and osteoporosis) were evaluated. RESULTS: A total of 179 (35.87%) patients had CRS, in particular 93 (18.64%) had CRSsNP and 86 (17.23%) had CRSwNP. Type 2 inflammation (defined by at least 1 positive biomarker) was present in 81.44% of patients (fractional exhaled nitric oxide > 30 parts per billion in 46.9%, blood eosinophil count > 300 cell/µL in 39.67%, serum total immunoglobulin E >100 IU/mL in 51.54%, and allergy in 53.71%). By multivariate analysis, type 2 inflammation and blood eosinophils greater than 300 cell/µL were the main predictors (odds ratio [OR] 2.54 and 2.26, respectively) of CRS-asthma association. In particular, CRSwNP comorbidity was predicted by type 2 inflammation (OR 3.4) and blood eosinophils greater than 300 cell/µL (OR 3.0). Smoking had conflicting outcome. CONCLUSION: This study confirmed that CRS is a frequent asthma comorbidity because it affects more than one-third of outpatients with asthma. CRSwNP is associated with type 2 inflammation and blood eosinophilia. These outcomes underline that CRSwNP asthma phenotype deserves adequate attention for careful management and optimal identification of the best-tailored therapy.

Biomarker levels in gingival crevicular fluid of generalized aggressive periodontitis patients after non-surgical periodontal treatment.

OBJECTIVES: The aim of this study was to assess the effects of non-surgical periodontal treatment on gingival crevicular fluid (GCF) cytokines in patients with generalized aggressive periodontitis (GAgP), in relation to clinical parameters. MATERIALS AND METHODS: Data were obtained from 16 GAgP patients and 15 periodontally healthy controls. Periodontal parameters and GCF biomarker levels were evaluated at baseline and repeated 3 and 6 months after treatment for GAgP subjects. Moderate and deep pocket sites were analyzed separately. The amount of interleukin (IL)-1ß, IL-9, tumor necrosis factor (TNF)-α, platelet-derived growth factor (PDGF-bb), and vascular endothelial growth factor (VEGF) were measured using a highly specific and sensitive multiplex bead immunoassay. RESULTS: At baseline, cytokine levels in the moderate and deep pocket sites of GAgP patients were higher than those of the healthy control sites. In GAgP group, periodontal treatment led to improvement in all examined clinical parameters and resulted in a statistically significant reduction in the total amounts of IL-1ß, VEGF, and TNF-α, in comparison to baseline, already 3 months after therapy in both moderate and deep pocket sites and of PDGF-bb in deep sites (p < 0.01). At the concentration level, only IL-1ß and VEGF were affected. CONCLUSION: Non-surgical treatment of GAgP provided significant clinical benefits leading to a marked decrease in the GCF levels of some pro-inflammatory and pro-angiogenic cytokines, but not of IL-9 and PDGF-bb. CLINICAL RELEVANCE: Although the periodontal therapy successfully decreased clinical signs of inflammation, the GCF levels of some inflammatory cytokines were still elevated.

Partial Laryngectomy for pT4a Laryngeal Cancer: Outcomes and Limits in Selected Cases.

A large multi-institutional case series of laryngeal cancer (LC) T4a was carried out, including 134 cases treated with open partial horizontal laryngectomies (OPHL) +/- post-operative radiation therapy (PORT). The goal was to understand better whether OPHL can be included among the viable options in selected pT4a LC patients who refuse a standard approach, represented by total laryngectomy (TL) + PORT. All 134 patients underwent OPHL type I (supraglottic), II (supracricoid), or III (supratracheal), according to the European Laryngological Society Classification. Comparing clinical and pathological stages showed pT up-staging in 105 cases (78.4%) and pN up-staging in 19 patients (11.4%). Five-year data on overall survival, disease-specific survival, disease-free survival, freedom from laryngectomy, and laryngo-esophageal dysfunction-free survival (rate of patients surviving without a local recurrence or requiring total laryngectomy and without a feeding tube or a tracheostomy) were, respectively, 82.1%, 89.8%, 75.7%, 89.7%, and 78.3%. Overall, complications were observed in 22 cases (16.4%). Sequelae were observed in 28 patients (20.9%). No patients died during the postoperative period. This large series highlights the good onco-functional results of low-volume pT4a laryngeal tumors, with minimal or absent cartilage destruction, treated with OPHLs. The level of standardization of the indication for OPHL should allow consideration of OPHL as a valid therapeutic option in cases where the patient refuses total laryngectomy or non-surgical protocols with concomitant chemo-radiotherapy.

Reliability of Total Serum IgE Levels to Define Type 2 High and Low Asthma Phenotypes.

Background: High total IgE levels are weak predictors of T2High and have been reported in nonallergic asthma. Therefore, the role of total serum IgE (IgE) in the T2High phenotype is still debated. Objective: This study investigated the reliability of stratifying asthmatics into IgEHigh and IgELow within the T2High and T2Low phenotypes. Methods: This cross-sectional single-center study investigated the association of clinical, functional, and bio-humoral parameters in a large asthmatic population stratified by IgE ≥ 100 kU/L, allergen sensitization, B-EOS ≥ 300/µL, and FENO ≥ 30 ppb. Results: Combining T2 biomarkers and IgE identifies (1) T2Low-IgELow (15.5%); (2) T2Low-IgEHigh (5.1%); (3) T2High-IgELow (33.6%); and T2High-IgEHigh (45.7%). T2Low-IgELow patients have more frequent cardiovascular and metabolic comorbidities, a higher prevalence of emphysema, and higher LAMA use than the two T2High subgroups. Higher exacerbation rates, rhinitis, and anxiety/depression syndrome characterize the T2Low-IgEHigh phenotype vs. the T2Low-IgELow phenotype. Within the T2High, low IgE was associated with female sex, obesity, and anxiety/depression. Conclusions: High IgE in T2Low patients is associated with a peculiar clinical phenotype, similar to T2High in terms of disease severity and nasal comorbidities, while retaining the T2Low features. IgE may represent an additional biomarker for clustering asthma in both T2High and T2Low phenotypes rather than a predictor of T2High asthma "per se".

Voice and communication after open partial horizontal laryngectomies: A cross-sectional outcome study.

OBJECTIVE: The present study evaluates voice and communication after open partial horizontal laryngectomies (OPHLs), according to surgery and patient-related variables. METHODS: Fifty-eight patients were included: 18 type I OPHL, 20 type II OPHL and 20 type III OPHL. Acoustic, aerodynamic, endoscopic, perceptual and self-assessment analyses were carried out. Surgery-related variables and patient-related variables were considered for the analysis. RESULTS: Type I OPHL revealed the best phonatory outcomes. Type II and type III OPHL showed similar and poor results, with a highly deteriorated voice quality. A significant difference in MTP was found for patients who had both arytenoids/cricoarytenoid units preserved. Age and time from surgery showed significant correlations with voice quality after OPHLs. CONCLUSIONS: Voice and communication outcomes after OPHLs are heterogeneous and might be influenced by several factors. Knowing variables with a substantial impact on phonatory outcomes may help clinicians in the preoperative decision-making process and the postoperative rehabilitative program.

Long-Term Safety of Antifibrotic Drugs in IPF: A Real-World Experience.

Pirfenidone and nintedanib are the only two drugs approved for the treatment of idiopathic pulmonary fibrosis (IPF). Both proved to be safe and well-tolerated in clinical trials, but real-world data and direct comparisons are scarce. This real-life study explored the safety profile of pirfenidone and nintedanib with a prolonged follow-up. We retrospectively collected clinical status, adverse events (AEs), and treatment changes from IPF patients who had started an antifibrotic treatment at our centre from December 2011 to December 2020, including 192 patients treated with pirfenidone and 89 with nintedanib. The majority of patients in both groups experienced one or more AEs during the follow-up. A higher proportion of AEs in the nintedanib group were effectively treated with behavioural modifications or additional medications compared with the pirfenidone group (52.5% vs. 40.6%, p = 0.04). Overall, a difference in the impact of AEs due to nintedanib versus pirfenidone resulted in a lower permanent discontinuation of therapy (8.3% vs. 18.3%, p = 0.02), with the latter being associated with a higher risk of drug discontinuation at 48 months after initiation (OR = 2.52, p = 0.03). Our study confirms the safety profile of antifibrotic drugs in IPF but highlights that AEs due to nintedanib are usually easier to manage and lead to fewer cases of permanent discontinuation of therapy.

"Fistula Zero" Project After Total Laryngectomy: The Candiolo Cancer Institute Experience.

OBJECTIVES: Pharyngocutaneous fistula (PCF) is a troublesome complication after total laryngectomy. The "Fistula zero" project aims to reduce the number of PCF by following a detailed protocol based on three fundamental key points. MATERIALS AND METHODS: The Fistula zero project included 77 patients who underwent total laryngectomy in the period from January 2019 to December 2020. The protocol consisted of three main aspects: the systematic placement of a Har-El salivary bypass tube, the continuous horizontal watertight pharyngeal suture using a barbed suture, onlay insetting of a pedicled flap in pre-treated patients. RESULTS: One case of PCF (1.3%) and three small blind fistulas (3.9%) were observed in this series. The mean length of hospitalization was 18 days. CONCLUSION: Pharyngocutaneous fistula (PCF) prolongs hospitalization and delays adjuvant treatments. Thanks to a strict adherence to the protocol, it was possible to reduce PCF rates, avoiding lengthy hospitalization and additional surgical procedures.

Preoperative prognostic factors for functional and clinical outcomes after open partial horizontal laryngectomies.

BACKGROUND: In minority of cases, the clinical recovery of the neolarynx after open partial horizontal laryngectomies (OPHLs) can be challenging, possibly affecting the final functional outcome. METHODS: One hundred and twenty-three patients who underwent OPHLs were selected. A series of clinical preoperative independent variables were considered. All patients were monitored for the following dependent outcome variables: sequelae; need for percutaneous endoscopic gastrostomy positioning; days before tracheal cannula removal and nasogastric tube removal; and length of hospital stay. Univariate and multivariate logistic regression analyses were performed to identify significant associations between preoperative clinical variables and outcomes variables. RESULTS: Multivariate analysis confirmed age, cT classification, body mass index, and smoking habits as significant prognostic factors for worse functional and clinical recovery outcomes. CONCLUSIONS: Knowing what variables are significantly associated with worse clinical and functional outcomes can guide clinicians in defining the best surgical choice not only from an oncological perspective, but also for a better postoperative recovery.

Characterization of T2-Low and T2-High Asthma Phenotypes in Real-Life.

Asthma is a heterogeneous and complex condition characterized by chronic airway inflammation, which may be clinically stratified into three main phenotypes: type 2 (T2) low, T2-high allergic, and T2-high non-allergic asthma. This real-world study investigated whether phenotyping patients with asthma using non-invasive parameters could be feasible to characterize the T2-low and T2-high asthma phenotypes in clinical practice. This cross-sectional observational study involved asthmatic outpatients (n = 503) referring to the Severe Asthma Centre of the San Luigi Gonzaga University Hospital. Participants were stratified according to the patterns of T2 inflammation and atopic sensitization. Among outpatients, 98 (19.5%) patients had T2-low asthma, 127 (25.2%) T2-high non-allergic, and 278 (55.3%) had T2-high allergic phenotype. In comparison to T2-low, allergic patients were younger (OR 0.945, p < 0.001) and thinner (OR 0.913, p < 0.001), had lower smoke exposure (OR 0.975, p < 0.001) and RV/TLC% (OR 0.950, p < 0.001), higher prevalence of asthma severity grade 5 (OR 2.236, p < 0.05), more frequent rhinitis (OR 3.491, p < 0.001) and chronic rhinosinusitis with (OR 2.650, p < 0.001) or without (OR 1.919, p < 0.05) nasal polyps, but less common arterial hypertension (OR 0.331, p < 0.001). T2-high non-allergic patients had intermediate characteristics. Non-invasive phenotyping of asthmatic patients is possible in clinical practice. Identifying characteristics in the three main asthma phenotypes could pave the way for further investigations on useful biomarkers for precision medicine.

Clinical Characterization of the Frequent Exacerbator Phenotype in Asthma.

BACKGROUND: Asthma exacerbation is episodic worsening of respiratory symptoms in conjunction with the deterioration of lung function, which may occur independently from the asthma severity hampering asthmatics' quality of life. This study aimed to characterize the patient phenotype more prone to asthma exacerbation (oral corticosteroid burst ≥2 per year) to allow the proper identification of such patients. METHODS: This real-life, observational, cross-sectional study evaluated 464 asthmatic patients stratified according to the asthma exacerbations experienced in the previous year. Clinical, functional, and blood parameters were retrieved from chart data and were representative of patients in stable conditions. RESULTS: The frequent asthma exacerbator was more commonly female, suffered from chronic rhinosinusitis with nasal polyposis, had reduced lung function and peripheral oxygen saturation, and had increased daily activity limitations. These patients often had severe asthma and more frequently needed hospitalization in their lives. Furthermore, the frequent asthma exacerbator had higher concentrations of serum immunoglobulin E (IgE) and exhaled nitric oxide with cut-off risk values of 107.5 kU/L (OR = 4.1) and 43.35 ppb (OR = 3.8), respectively. CONCLUSIONS: This study illustrates the clinical features of the frequent asthma exacerbator phenotype. Nevertheless, serum IgE and exhaled nitric oxide could allow the identification of this phenotype and the establishment of an appropriate therapeutic approach.

Treatment for T3 to T4a laryngeal cancer by open partial horizontal laryngectomies: Prognostic impact of different pathologic tumor subcategories.

BACKGROUND: The purpose of this retrospective study was to identify subcategories in cT3 to cT4a supraglottic/glottic cancers, describing their different spreading patterns, and local and locoregional recurrence modes. METHODS: Four hundred eighty-nine patients who underwent open partial horizontal laryngectomies (OPHLs) were retrospectively classified as: subcategory I (anterior pT3 with normal arytenoid mobility); subcategory II (posterior pT3 with impaired/absent mobility); subcategory III (anterior pT4 with normal mobility); and subcategory IV (posterior pT4 with impaired/absent mobility). RESULTS: Five-year overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), locoregional, local control, freedom from laryngectomy, and laryngectomy-free survival were significantly better in anterior tumors (subcategories I and III) when compared with the corresponding posterior ones (subcategories II and IV). CONCLUSION: Anterior cT3 tumors are manageable by OPHL, and this approach could also be proposed in the treatment of early anterior cT4aN0. Despite promising results, OPHLs should be considered under investigation in posterior cT3 tumors due to clinical and biological behavior similar to cT4a tumors.

Dietary supplementation of coenzyme Q10 plus multivitamins to hamper the ROS mediated cisplatin ototoxicity in humans: A pilot study.

Oxidative stress exerts major role in the pathogenesis of side effects of many antineoplastic drugs, including ototoxicity of cisplatin. In particular, increased levels of reactive oxygen species (ROS) represent one of the molecular mechanisms underlying the apoptosis of different types of hearing cells. Antioxidants and ROS scavengers may thus represent potential therapeutic options to prevent platinum-associated ototoxicity. The aim of this preliminary case-control study was to explore the efficacy of a dietary antioxidant supplement, in order to hamper the occurrences of ototoxicity in patients undergoing cisplatin chemotherapy. As results, a significant protection against cochlear toxic damage was demonstrated in patients who took the antioxidant supplement, which furthermore prevented the occurrence of hearing disorders and tinnitus. These clinical evidences were corroborated by the oxidative status of patients. After cisplatin chemotherapy, the plasma derivatives of reactive oxygen metabolites (d-ROMs) content rapidly increased in control patients, but it was maintained in those under dietary supplementation, likely because of a higher anti-ROMs potential. Indeed, an increment in rapid anti-ROMs was detected in supplemented patients, though no differences were highlighted in terms of slow anti-ROMs. In conclusion, in this preliminary report we demonstrated the feasibility of a dietary antioxidant supplementation in order to prevent the cisplatin induced hearing damage.

A Simple Protocol to Isolate, Characterize, and Expand Dental Pulp Stem Cells.

Adult stem cells reside in body tissues to preserve organs and whole organism homeostasis. They are acquiring a prominent role in the contemporary medicine. Many protocols to isolate and cultivate adult stem cells have been so far described, though they are often lengthy, laborious, and require very expansive instruments, materials, and reagents. On this basis, we describe a simple, cheap but at the same time functional method to: (1) isolate dental pulp stem cells (DPSC), (2) expand and cultivate DPSC, (3) cryopreserve DPSC, (4) characterize DPSC, and (5) differentiate DPSC into both mesenchymal and non-mesenchymal lineages.

A new simple HPLC method for measuring mitotane and its two principal metabolites Tests in animals and mitotane-treated patients.

A new C18 reversed-phase column and UV HPLC method for the detection of mitotane, its principal metabolites, dichlorodiphenylacetate and dichlrodiphenylethene, and its precursor DDT is described. In this article mitotane, dichlorodiphenylacetate, and dichlrodiphenylethene concentrations in organs of rats fed on a mitotane diet, and the effects of erythromycin and grapefruit juice as cytochrome P450 common inhibitors are presented. Tissue accumulation of mitotane and dichlrodiphenylethene, the acquired ability to eliminate dichlorodiphenylacetate, and inhibition of beta-hydroxylation by both inhibitors are illustrated here. Blood samples from mitotane-treated patients revealed two correlations: plasma mitotane/dichlrodiphenylethene and plasma mitotane/red cell mitotane.

Benefits and drawbacks of open partial horizontal laryngectomies, Part A: Early- to intermediate-stage glottic carcinoma.

BACKGROUND: Laryngeal squamous cell carcinoma (SCC) accounts for 1.9% of cancers worldwide. Most of these are diagnosed in the early stages (T1-T2, and N0). For these, a larynx preserving/conserving option is preferable. Beyond transoral laser microsurgery (TLM), open partial horizontal laryngectomy is a function-sparing surgical technique used to treat laryngeal SCC. METHODS: We retrospectively analyzed the clinical outcomes of 216 patients who underwent open partial horizontal laryngectomy for glottic cT2 laryngeal cancer. RESULTS: Five-year overall survival (OS), disease-specific survival (DFS), locoregional control, local control, laryngeal function preservation, and laryngectomy-free survival rates were 93.1%, 98.0%, 97.1%, 97.5%, 97.8%, and 98.5%, respectively. Disease controls were significantly affected by previous treatment and type of surgery used. CONCLUSION: Although TLM for cT2 laryngeal cancer with unimpaired vocal cord mobility still represents a sound option, open partial horizontal laryngectomy offers higher local control and laryngeal preservation rates for selected patients with impaired mobility of vocal cords combined with involvement of the paraglottic space. © 2015 Wiley Periodicals, Inc. Head Neck 38: E333-E340, 2016.

Oncologic outcomes of supratracheal laryngectomy: Critical analysis.

BACKGROUND: Laryngeal cancer management should pursue function-sparing therapeutic options. Even though demolitive surgery provides better control of disease at intermediate to advanced stages when compared to chemoradiotherapy, it does not preserve laryngeal function. Supratracheal partial laryngectomy has been described as a function-sparing surgical technique for laryngeal cancer with subglottic extension. METHODS: In this retrospective study, we analyzed the clinical outcomes of 115 patients who underwent supratracheal partial laryngectomy. RESULTS: At 5 years, overall survival (OS), disease-free survival (DFS), and locoregional control rates were 78.9%, 68.5%, and 69.6%, respectively; DFS and locoregional control prevalences were greatly affected by pT4a classification (49.0% and 51.4%, respectively); and laryngeal function preservation was maintained in 78.3% of patients despite being affected by pT4a classification (59.3%) and age ≥65 (64.6%). CONCLUSION: For cases with glottic tumors and with subglottic extension, the choice of supratracheal partial laryngectomy versus chemoradiotherapy can be considered to be effective in terms of prognostic and functional results.