Supraorbital Basosquamous Carcinoma Treated with Cemiplimab Followed by Sonidegib: A Case Report and Review of the Literature.

Basal cell carcinoma (BCC) is a skin cancer with low local aggressiveness and a low tendency to metastasize. Basosquamous Carcinoma (BSC) represents an aggressive histological subtype of BCC with intermediate features between Squamous Cell Carcinoma (SCC) and BCC. Cemiplimab is currently approved as first-line therapy in SCC and second-line therapy in BCC patients who have progressed on or are intolerant of a Hedgehog pathway Inhibitor (HHI). Our study describes the case of a 59-year-old man with BSC who was successfully treated with 5 cycles of Cemiplimab as first-line therapy and Sonidegib as second-line therapy. Currently, the efficacy of Cemiplimab against BSC and other histopathological subtypes of BCC has not been fully elucidated, as has the role of sequential or combination therapy with Cemiplimab and HHI in the management of BSC. The aim of this case report is to highlight the need to outline the use of checkpoint inhibitors in BCCs and focus attention on the synergistic role of Cemiplimab and HHIs in such a controversial entity as BSC.

Role of forced expiratory flow at 25-75% as an early marker of small airways impairment in subjects with allergic rhinitis.

A close link exists between allergic rhinitis and asthma. Small airway disease (SAD), defined by a reduction in forced expiratory flow at 25-75% of the pulmonary volume (FEF25-75) and normal spirometry (normal forced expiratory volume at 1 second [FEV1], forced vital capacity [FVC], and FEV1/FVC ratio), may be a marker for early allergic or inflammatory involvement of the small airways in subjects with allergic diseases and no asthma. The aim of this study was to determine if there is a relationship between SAD, the outcome variable, and several allergic predictors in patients without asthma but with allergic rhinitis. A cross-sectional study was performed. Two hundred eleven midshipmen attending the third and fifth course of the Navy Academy of Livorno were screened. Fifty-eight midshipmen showed slight spirometric anomalies. Thus, they were referred to the Navy Hospital of La Spezia for standardized tests: skin-prick test, nasal cytology, spirometry, and methacholine bronchial challenge. A reduced FEF(25-75) was arbitrarily defined as < 80% of predicted. All 58 subjects had a normal FEV1, FVC, and FEV1/FVC ratio. Twenty subjects had a reduced FEF(25-75), consistent with the definition of SAD. A mean value of FEF(25-75) of 70.3 (SD, 8.5) was measured in patients with a reduced FEF, and it was 108.0 (SD, 14.3) in patients with preserved FEF(25-75). All the candidate allergic predictors appeared to be strongly associated with a reduced FEF(25-75). The proportion of subjects with reduced FEF(25-75) appeared to increase with increasing severity of the allergic predictors, and, correspondingly, the mean value of FEF(25-75) appeared to decrease. This study provides evidence that there is a relationship between SAD and allergic parameters such as nasal symptoms and eosinophils.

Role of FEF25-75 as an early marker of bronchial impairment in patients with seasonal allergic rhinitis.

BACKGROUND: Allergic rhinitis may be associated with asthma. Forced expiratory flow between 25 and 75% of vital capacity (FEF2575) is a measure of small airways narrowing. The aim of this study was to evaluate whether patients with seasonal allergic rhinitis (SAR) without symptoms of asthma might, nevertheless, have airways obstruction both in and out of the pollen season. METHODS: Fifty patients (mean age, 23.7+/-4.9 years) with SAR were evaluated both during and outside the pollen season. All of them had moderate-severe grade of nasal obstruction. Total symptom score, rhinomanometry, nasal lavage, nasal scraping, spirometry, and methacholine (MCH) bronchial challenge were assessed in all subjects. RESULTS: Although data on forced vital capacity and response to MCH were similar in and out of the pollen season, all other parameters were markedly different. The major finding of the study was that FEF25-75 was significantly associated with nearly all of the parameters considered, including bronchial hyperreactivity, with Pearson R ranging from 31 to 75% and differences in mean FEF25-75 ranging between 14.5 and 16.5% of predicted. The more significant association was with nasal airflow in the pollen season (R = 82.8%; p < 0.001). A significant association persisted for all parameters while controlling for season. CONCLUSION: This study highlights the link between upper and lower airways and the role of FEF25-75 as an early marker of bronchial impairment in those patients with SAR alone.

Role of FEF25%-75% as a predictor of bronchial hyperreactivity in allergic patients.

BACKGROUND: The small airways may play an important role in the clinical manifestations of asthma. Forced expiratory flow between 25% and 75% (FEF25%-75%) has been proposed as an approximate measure of the caliber of distal airways. Bronchial hyperreactivity (BHR) is a feature of asthma. OBJECTIVE: To evaluate the possible role of FEF25%-75% as a predictor of BHR in allergic patients with asthma and rhinitis. METHODS: A total of 726 patients (mean +/- SD age, 24.7 +/- 6.3 years) were evaluated. Spirometry and methacholine bronchial challenge were evaluated in all the participants. RESULTS: A difference between forced expiratory volume in 1 second and FEF25%-75% greater than 20 or a ratio between these variables greater than 1.24 discriminates between patients with no response to a mild response to methacholine vs patients with a moderate-to-severe response with high sensitivity (P < .001). CONCLUSION: This study highlights the possible role of FEF25%-75% in predicting BHR in allergic individuals with airway disorders.

Decongestion test in patients with allergic rhinitis: functional evaluation of nasal airflow.

BACKGROUND: Rhinomanometry measures nasal airflow that is frequently impaired in allergic rhinitis. Decongestion tests consist of spraying an intranasal vasoconstrictor drug to evaluate the reversibility of nasal airflow limitation. The aim of this study was to evaluate the decongestion test in patients with seasonal allergic rhinitis (SAR) caused by pollen sensitization, perennial allergic rhinitis (PAR) caused by sensitization to perennial allergens only, or mixed allergic rhinitis (MAR) caused by sensitization to both allergens. METHODS: One hundred twenty-three subjects (112 men and 11 women, mean age, 22.9 +/- 5.7 years) were studied; 40 subjects had PAR, 43 subjects had MAR, and 40 subjects had SAR. Total symptom score (including: nasal itching, sneezing, rhinorrhea, and nasal obstruction) was assessed. Rhinomanometry and decongestion tests were performed in all subjects. RESULTS: Nasal symptom severity was superimposable in the three groups (p was not significant). After decongestion tests, an increase of nasal airflow and a decrease of nasal resistance was shown in PAR (p < 0.01), MAR (p < 0.001), and SAR subjects (p < 0.001). The intergroup analysis showed that SAR patients had less reversibility than PAR (p < 0.01). CONCLUSION: This study provides the first evidence of the different response to decongestion tests, taking into consideration the causal allergens.

Association between response to decongestion testing and sensitizations and allergic inflammation.

BACKGROUND: Rhinomanometry is used to measure nasal airflow, which is frequently impaired in allergic rhinitis (AR). Decongestion testing consists of spraying an intranasal vasoconstrictor drug to evaluate recovery of nasal airflow. OBJECTIVE: To evaluate the relationships among type and number of sensitizations, nasal airflow recovery after topical vasoconstrictor drug use, and allergic inflammation. METHODS: A total of 123 patients (112 men and 11 women; mean +/- SD age, 22.9 +/- 5.7 years) were studied: 40 with perennial AR (PAR), 43 with mixed AR (MAR), and 40 with seasonal AR (SAR). Patients with anatomic nasal defects were excluded. Total symptom scores (including nasal itching, sneezing, rhinorrhea, and nasal obstruction), sensitizations, nasal eosinophils, and cytokines (including interleukin 4 [IL-4], IL-5, and interferon-gamma) were evaluated. Electronic rhinomanometry and decongestion testing were performed in all the patients. RESULTS: After administration of a topical nasal vasoconstrictor agent, mean nasal airflow significantly increased from 471 to 580 mL/s (P < .001). In 12 patients (3 with PAR, 3 with MAR, and 6 with SAR), no increase was shown. Changes from baseline were different in the PAR, MAR, and SAR populations (PAR vs MAR, P < .001; PAR vs SAR, P < .001; and MAR vs SAR, P = .25). Type of sensitization (MAR, PAR, or SAR), concentration of eosinophils, and levels of IL-4, IL-5, and interferon-gamma were associated with nasal airflow recovery of at least 120 mL/s. CONCLUSIONS: This study provides the first evidence of a different response to decongestion testing taking into consideration the type of AR.

Nasal airflow recovery after decongestion test is associated with bronchial hyperreactivity in patients with allergic rhinitis.

BACKGROUND: The decongestion test involves spraying an intranasal vasoconstrictor drug to evaluate the recovery of nasal airflow. OBJECTIVE: The aim of this study was to assess the relationship between pulmonary function (assessed by spirometry and methacholine challenge) and nasal airflow recovery after a topical vasoconstrictor had been administered in patients with allergic rhinitis (perennial, seasonal, or mixed allergic rhinitis). METHODS: A total of 150 subjects were studied. The total symptom score, sensitization, and pulmonary function were all assessed. All subjects underwent rhinomanometry and the decongestion test. RESULTS: Univariate analysis revealed that nasal symptoms and spirometric parameters (except FEF(25-75) in subjects with seasonal allergic rhinitis) were not. Only bronchial hyperreactivity, assessed by methacholine challenge, proved to be significantly (and independently) associated with outcome (OR 1.45, P = 0.025). CONCLUSIONS: This study provides the first evidence of an association between a positive response to the decongestion test and bronchial hyperreactivity, assessed by methacholine challenge, in patients with allergic rhinitis.

Desloratadine and levocetirizine improve nasal symptoms, airflow, and allergic inflammation in patients with perennial allergic rhinitis: a pilot study.

BACKGROUND: Nasal obstruction is the main symptom in patients with perennial allergic rhinitis. Some new antihistamines have been demonstrated to be capable of improving this symptom. OBJECTIVE: The aim of this pilot study was to evaluate nasal symptoms, nasal airflow, eosinophils, and IL-4 in patients with perennial allergic rhinitis, before and after treatment with two new antihistamines: desloratadine and levocetirizine. METHODS: Thirty patients with perennial allergic rhinitis were evaluated, 26 males and 4 females (mean age 26+/-7.1 years). All of them received either desloratadine (5 mg/daily) or levocetirizine (5 mg/daily) or placebo for 4 weeks. The study was double-blind, parallel-group, placebo-controlled, and randomized. Total symptom score (including: rhinorrhea, nasal itching, sneezing, and nasal obstruction) was assessed before and after treatment. Rhinomanometry and decongestion test, nasal lavage, and nasal scraping were performed in all subjects before and after treatment. Eosinophils were counted by conventional staining; IL-4 was measured by immunoassay of fluids recovered from nasal lavage. RESULTS: Desloratadine and levocetirizine treatment induced significant symptom relief and significant reduction of IL-4. Both antihistamines significantly affected all parameters in comparison with placebo. CONCLUSIONS: This pilot study demonstrates the effectiveness of antihistaminic treatment in: i) relieving nasal symptoms, including obstruction, ii) improving nasal airflow, iii) exerting decongestant activity, iv) reducing eosinophil infiltration, and v) diminishing IL-4 levels.

Early bronchial airflow impairment in patients with persistent allergic rhinitis and bronchial hyperreactivity.

BACKGROUND: Allergic rhinitis and its impact on asthma (ARIA) document underlines the link between upper and lower airways. Patients suffering from allergic rhinitis frequently (up to 80%) show bronchial hyperreactivity (BHR). OBJECTIVES: This study aimed at evaluating a group of subjects suffering from persistent allergic rhinitis, with BHR but with nasal symptoms only, to investigate the type and intensity of nasal symptoms, nasal and bronchial airflow, and BHR grade during the pollen season. METHODS: One hundred and twenty one polysensitized rhinitics were investigated. Total symptom score (TSS) was assessed in all patients. Rhinomanometry, spirometry and methacholine bronchial challenge were performed in all patients. RESULTS: 65 (53.7%) patients had impaired FEF 25-75 values. TSS correlated with nasal airflow (P<0.001) and BHR grade (P<0.001). Nasal airflow correlated with FEF 25-75 values (P<0.05) and BHR (P<0.001). FEF 25-75 values correlated with FEV(1) levels (P<0.003), BHR grade (P<0.001), and nasal obstruction symptom (P<0.05). Severe BHR correlated with FEV(1) (P<0.05) and FEF 25-75 (P<0.03) values, nasal airflow (P<0.05) and nasal symptoms (P<0.001). CONCLUSIONS: This study evidences that early bronchial impairment is frequently detectable in patients with persistent allergic rhinitis and BHR. Moreover, nasal function is strictly related with bronchial calibre and BHR grade. Therefore, careful evaluation of lower airways should be investigated in all rhinitics as suggested by the ARIA document.

Nasal obstruction is the key symptom in hay fever patients.

BACKGROUND: Allergic rhinitis is characterized by a Th2-dependent inflammation. Nasal obstruction largely depends on allergic inflammation. OBJECTIVE: The aim of this study was to evaluate the possible role of the symptom nasal obstruction in assessing patients with hay fever. METHODS: Fifty patients (mean age, 23.7 +/- 4.9 years) with hay fever were evaluated both during and outside pollen season. All of them had moderate-severe grade of nasal obstruction. Total symptom score (TSS), rhinomanometry, nasal lavage, nasal scraping, spirometry, and methacholine bronchial challenge were performed in all subjects. RESULTS: During the pollen season, patients with severe nasal obstruction showed significantly higher values of TSS, IL-4, IL-5, IL-8, nasal eosinophils and neutrophils, and significantly lower values of nasal airflow, IFNgamma, FEV1, FVC, and FEF 25-75 in comparison with patients with moderate nasal obstruction. Twenty (83%) patients with severe nasal obstruction showed bronchial hyperreactivity (BHR), whereas only 6 (25%) patients with moderate nasal obstruction had BHR. Outside the pollen season overlapping results were observed. CONCLUSIONS: This study provides evidence about the key role played by nasal obstruction in assessing patients with allergic rhinitis.

Induction of interleukin 10 by sublingual immunotherapy for house dust mites: a preliminary report.

BACKGROUND: Subcutaneous specific immunotherapy has been demonstrated to be capable of inducing T-cell regulatory response. Interleukin 10 (IL-10) plays a crucial role in inducing allergen-specific tolerance; however, no previous studies have examined IL-10 production after sublingual immunotherapy (SLIT). OBJECTIVE: To evaluate T-cell proliferation and IL-10 production in patients successfully treated with SLIT for house dust mites (HDMs). METHODS: Peripheral blood mononuclear cells were isolated from patients after at least 3 years of successful HDM SLIT and from matched untreated allergic patients and healthy control subjects. After 3 and 6 days of in vitro stimulation with phytohemagglutinin (PHA), Candida albicans, and Dermatophagoides farinae, proliferation and production of IL-10 were measured. RESULTS: Patients treated with SLIT showed a significant reduction of proliferation induced by C albicans compared with untreated atopic patients (P < .001), but a significant reduction was also demonstrated in healthy controls compared with untreated atopic patients (P < .001). Patients treated with SLIT also showed a significant increase of IL-10 production after Candida and PHA stimuli compared with patients with untreated rhinitis (P < .001 for both). Patients with untreated rhinitis did not produce IL-10. CONCLUSION: This preliminary study confirms reduced T-cell proliferation and preliminarily provides the first evidence, to our knowledge, of peripheral IL-10 production in allergic patients successfully treated with HDM SLIT.

Quality of life and polysensitization in young men with intermittent asthma.

BACKGROUND: Health-related quality of life (HRQoL) represents an important variable in asthma management. To date, to our knowledge, no study has explored the relationship between HRQoL and sensitization in patients with asthma. OBJECTIVE: To evaluate the relationships among HRQoL and sensitization, pulmonary function, and bronchial hyperreactivity in a group of young men with intermittent asthma. METHODS: We studied 185 conscripts with intermittent asthma and bronchial hyperreactivity. The Asthma Quality of Life Questionnaire was used. Skin prick testing, spirometry, and methacholine challenge were performed in all participants. RESULTS: The Asthma Quality of Life Questionnaire median scores were greater than 4, indicating suboptimal HRQoL. Polysensitization was significantly associated with the worst HRQoL, whereas pulmonary function and bronchial hyperreactivity category were not. CONCLUSIONS: This study provides the first evidence that HRQoL is associated with polysensitization in intermittent asthma and underlines the importance of evaluating this issue when managing young patients with slight respiratory symptoms.

Bacillus clausii exerts immuno-modulatory activity in allergic subjects: a pilot study.

UNLABELLED: Bacillus clausii has been demonstrated to exert some immunomodulatory activities and to be safe. Allergic subjetcs show Th2 polarization and defect of T regulatory cells. Aim of the study was to investigate whether Bacillus clausii administration in allergic subjects might modulate cytokine pattern. Ten subjects (mean age 22.3 years) suffering from allergic rhinitis were enrolled. Bacillus clausii spores (Enterogermina: 2 billions spores/vial) were administered at the dosage schedule of 3 vials a day for 4 weeks. Nasal lavage was performed in all subjects before and after the treatment. A panel of cytokines, including IL4, IL10, IFNgamma, and TGFbeta, was measured by immunoassay in the fluid recovered from nasal lavage, before and after the treatment. RESULTS: Bacillus clausii treatment showed a significant decrease of IL4 levels (p=0.004) and a significant increase of IFNgamma (p=0.038), TGFbeta (p=0.039), and IL10 (p=0.009) levels. In conclusion, this study shows that the Bacillus clausii may exert immuno-modulating activity by affecting cytokine pattern in allergic subjects and confirms previous study conducted in allergic children.

Nasal eosinophils display the best correlation with symptoms, pulmonary function and inflammation in allergic rhinitis.

BACKGROUND: The pathogenesis of allergic rhinitis and its link with asthma are well known. Nevertheless, a complete cross-sectional evaluation of the usually available clinical, functional and immunological parameters has never been made. We assessed nasal symptoms and flow, cytology, cytokines, pulmonary function and methacholine positivity in a large number of patients with pure pollinosis. METHODS: Young men presenting at a military hospital for routine follow-up were recruited for the study. They had to suffer from rhinitis alone (without asthma) for at least 2 years and had to have a positive skin prick test to pollens only. During the pollen season, they underwent symptom evaluation, measurement of nasal flow, nasal scraping and lavage (cell count and assay for IL-4, IL-5, IL-8 and IFNgamma), pulmonary function tests and methacholine challenge. RESULTS: Fifty subjects (23.7+/-4.9 years old) were enrolled. All patients had high clinical scores (9.5+/-1.6) and inflammatory cells (eosinophils: 10.5+/-4 and neutrophils 21.3+/-6) and low nasal flow (482+/-111 ml/s). We found that the number of eosinophils in nasal scrapings highly correlated with all the above-mentioned parameters, including nasal flow, cytokines and spirometric values. A significant positive correlation was found between all inflammatory cells and all cytokines. IL-8, IL-4 and neutrophils displayed only a partial correlation with pulmonary parameters (FEV1, FVC and FEF25-75%), at variance wit IL-5 and eosinophils. Methacholine test positivity significantly correlated with the number of eosinophils in the nasal smear. CONCLUSION: Eosinophils in the nasal smear display the best correlation with all the clinical and immunological parameters in allergic rhinitis and also correlate well with methacholine response.

Correlation of nasal inflammation and nasal airflow with forced expiratory volume in 1 second in patients with perennial allergic rhinitis and asthma.

BACKGROUND: Allergic rhinitis and asthma are frequently associated and are characterized by TH2-dependent inflammation. Nasal and bronchial obstruction largely depend on allergic inflammation. OBJECTIVE: To evaluate the relationships among nasal eosinophil counts, interleukin 4 (IL-4) and interferon-gamma (IFN-gamma) levels, nasal airflow, and forced expiratory volume in 1 second (FEV1) in patients with perennial allergic rhinitis and asthma. METHODS: Eight men and 7 women (mean +/- SD age, 24.8 +/- 4.7 years) with perennial allergic rhinitis and asthma were evaluated. All 15 patients had a moderate-to-severe grade of nasal obstruction. Total symptom score, rhinomanometry, nasal lavage, nasal scraping, and spirometry were evaluated in all patients. Eosinophils were counted using conventional staining; IL-4 and IFN-gamma levels were measured by immunoassay in fluids recovered from nasal lavage. RESULTS: Significant positive relationships were demonstrated between eosinophil infiltration and IL-4 levels, nasal airflow and IFN-gamma levels, FEV1 and IFN-gamma levels, and nasal airflow and FEV1 (P < .001 for all). Significant negative relationships were demonstrated between eosinophil infiltration and IFN-gamma levels, IL-4 and IFN-gamma levels, eosinophil infiltration and nasal airflow, IL-4 values and nasal airflow, nasal eosinophil counts and FEV1, and IL-4 values and FEV1 (P < .001 for all). CONCLUSIONS: There is a close association between TH2 cytokines and eosinophil infiltration in the nose. There is also clear evidence concerning the relationships among eosinophil infiltration, IL-4 and IFN-gamma levels, and nasal airflow. Nasal eosinophil, IL-4, and IFN-gamma levels correlate with FEV1. Finally, nasal airflow is related to FEV1. These findings constitute the first evidence of a relationship between TH2-related nasal inflammation and nasal and bronchial airflow in patients with perennial allergic rhinitis and asthma.

Bronchial hyperreactivity and spirometric impairment in patients with seasonal allergic rhinitis.

UNLABELLED: We previously demonstrated in a group of patients with perennial allergic rhinitis alone, impairment of spirometric parameters and high percentage of bronchial hyperreactivity (BHR). Thus, the present study aimed at evaluating a group of subjects suffering from seasonal allergic rhinitis alone to investigate the presence of spirometric impairment and BHR both during and outside the pollen season. METHODS: One-hundred rhinitics sensitized to pollen allergens only were evaluated during and outside the pollen season. Spirometry and methacholine bronchial challenge were performed. RESULTS: Four rhinitics showed impaired values of FEV1 without referred symptoms of asthma during the pollen season. FEF 25-75 values were impaired in 17 rhinitics during the pollen season and in 11 rhinitics outside the pollen season (P<0.05). Fifty-four patients showed positive methacholine bronchial challenge both during and outside the pollen season. PD20/FEV1 methacholine was lower during the pollen season than outside (P<0.05). In BHR positive patients, reduced values of FVC (P<0.05), FEV1 (P<0.05), and FEF 25-75 (P<0.01) were significantly demonstrated in comparison with BHR negative rhinitics. There was a relationship between BHR degree and FEF 25-75 values only during the pollen season (P<0.001). CONCLUSIONS: This study evidences that an impairment of spirometric parameters may be observed also in patients with seasonal allergic rhinitis alone during the pollen season. A high percentage of these patients had BHR. A close relationship between upper and lower airways is confirmed also in the model of pollen allergy. Thus, a careful evaluation of lower airways should be performed also in those patients with seasonal allergic rhinitis alone.

Mizolastine and fexofenadine modulate cytokine pattern after nasal allergen challenge.

Allergen specific nasal challenge (ASNC) is an optimal model to study the pathophysiological mechanisms sustaining allergic inflammation, particularly the cytokine pattern. Antihistamines have been accepted as a highly effective therapy for allergic rhinitis. The aim of this double blind, randomised, placebo controlled study was the evaluation of symptoms and cytokines, during the early phase, after a single dose of mizolastine (10 mg), fexofenadine (120 mg) or placebo, using the model of ASNC. A total of 30 patients with allergic rhinitis underwent nasal challenge 6 hours after treatment. The following parameters were evaluated 30 minutes after ASNC (i.e. early phase): nasal symptoms (rhinorrhea, itching, sneezing, obstruction), and cytokine pattern, including IL1, IL6, and TNFalpha. Mizolastine was associated with early phase reduction of: i) clinical symptoms (p < 0.03), ii) cyotkine levels of IL1 (p = 0.003), IL6 (p < 0.007), and TNF_ (p < 0.003) in comparison with placebo group. Fexofenadine significantly inhibited IL6 (p < 0.004) and TNFalpha (p < 0.004) levels in comparison with placebo. The present findings demonstrate that mizolastine exerts a significant effect on early phase events, reducing symptoms and pro-inflammatory cytokines. Fexofenadine reduces TNFalpha and IL6 levels only. These effects appear to be clinical relevant for mizolastine.