Long-Term Effectiveness of Anti-IL4R Therapy Following Suboptimal Response to Anti-IL5/5R Therapy in Severe Eosinophilic Asthma.

BACKGROUND: Dupilumab is an anti-IL4R monoclonal antibody (mAb) with proven efficacy in severe eosinophilic asthma (SEA). A suboptimal response to anti-IL5/5R mAbs is seen in some patients with ongoing evidence of T2 inflammation. OBJECTIVE: To understand whether targeting IL-13 pathways with dupilumab in these patients may lead to better clinical outcomes. METHODS: We performed a retrospective analysis of the extended clinical effectiveness of dupilumab up to 2 years of treatment in patients with SEA who had not responded adequately to anti-IL5/5R biologics. Ability to achieve clinical remission and change in the remission domains of exacerbation rate (AER), maintenance oral corticosteroid dose (mOCS), lung function (FEV1) and asthma control (ACQ6) were recorded. RESULTS: Thirty-seven patients (mean age 41, 70% female) were included in the analysis. The mean (SD) AER fell by almost 90% from 3.16(1.28) at dupilumab initiation to 0.35(0.72) after 1 year. The median (IQR) mOCS dose (n=20) fell from 10(5-25) mg to 0 (0-5) mg at 1 year, with 14/20 (70%) able to stop prednisolone altogether. Clinical remission was achieved in 16/37 (43%). Patients who achieved remission had a higher pre-IL5/5R FeNO level (85ppb [39-198] vs 75ppb [42-96], p=0.03). CONCLUSION: Significant improvements in clinical outcomes are possible following a switch to dupilumab in patients experiencing a suboptimal response to anti-IL5/5R therapies. A higher FeNO in poor responders to anti-IL5/5R who achieve remission with dupilumab is suggestive of an IL-13 driven sub-phenotype of T2-high asthma in which the eosinophil appears unlikely to play a key role in the disease pathogenesis.

Long-Term Effectiveness of Benralizumab in Eosinophilic Granulomatosis With Polyangiitis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystemic disease characterized by eosinophilic tissue inflammation. Benralizumab, an anti-IL-5 receptor (anti-IL-5R) monoclonal antibody, induces rapid depletion of eosinophils; its longer-term effect in EGPA is unknown. OBJECTIVE: To assess the real-world effectiveness and clinical remission rates of anti-IL-5R therapy in EGPA. METHODS: We performed a retrospective cohort analysis of patients with EGPA, who commenced treatment with benralizumab. Clinical remission, assessed at 1 year and 2 years after the initiation of benralizumab, was defined as an absence of active vasculitis (Birmingham Vasculitis Activity Score of 0) and an oral corticosteroid (OCS) dose of ≤4 mg/d of prednisolone. "Super-responders" were defined as patients in remission and free of any significant relapses (asthma or extrapulmonary) over the preceding 12 months. The corticosteroid-sparing capacity of benralizumab, patient-reported outcome measures, and characteristics associated with clinical remission and super-responder status were also analyzed. RESULTS: A total of 70 patients completed at least 1 year of treatment with benralizumab, of whom 53 completed 2 years. Of 70 patients, 47 (67.1%) met the definition for clinical remission at 1 year, with a similar proportion in remission at 2 years. Excluding asthma-related relapses, 61 of 70 (87.1%) patients were relapse free at 1 year, and of the 53 who completed 2 years, 45 (84.9%) were relapse free. A total of 67.9% of patients no longer needed any OCS for disease control. No significant difference was seen between antineutrophilic cytoplasmic antibody (ANCA)-positive and ANCA-negative subgroups. CONCLUSIONS: In this real-world setting of patients with EGPA, treatment with benralizumab was well tolerated and resulted in corticosteroid-free clinical remission for the majority of patients.

Secretory Carcinoma with ETV6-NTRK3 Gene Fusion and Lymph Node Metastasis in Maxillary Gingiva: A Case Report with Pathological and Molecular Correlative Studies.

Secretory carcinoma (SC), also known as mammary analogue secretory carcinoma (MASC), is a rare salivary gland neoplasm with distinctive morphology that harbors a diagnostic ETV6 gene rearrangement. MASC was first described as a type of salivary gland neoplasm in 2010 and resembles breast secretory carcinoma. It is often mistaken for other neoplasms. It usually acts as an indolent tumor but can occasionally behave in an aggressive manner. We present a rare case of a patient with an aggressive SC/MASC of maxillary gingivobuccal sulcus with microcystic, solid and papillary patterns that showed ETV6 gene rearrangement by fluorescence in situ hybridization. Next-generation sequencing revealed t(12;15)(p13;q25) ETV6-NTRK3 translocation. Because SC/MASCs harbor the ETV6-NTRK3 translocation, molecular studies and immunostains are crucial to confirm the diagnosis and direct therapy.

Fine-needle aspiration of scalp masses: A review of 30 cases.

INTRODUCTION: Scalp masses are often the initial presentation of a widely disseminated malignancy. Fine-needle aspiration (FNA) is an optimal method for obtaining an accurate tissue diagnosis, in these patients with initial presentation and those with a known malignancy. MATERIALS AND METHODS: We reviewed all FNAs of skin and soft tissue lesions from the scalp at our institution over a period of 31 years (1990-2021). Relevant clinical information was obtained from the review of computerized patient record. The histologic type, presentation, previous diagnoses, and survival after the diagnosis were correlated. RESULTS: Thirty patients with scalp masses were identified. All the patients were males with a median age of 61 years (27-81 years). The scalp masses ranged from 0.4 to 6 cm in size. Ten cases (33%) were benign, but the majority of cases (n = 20, 67%) were malignant. Of the malignant lesions sampled, 1 case was a primary squamous-cell carcinoma (SCC), and the remaining 19 cases were metastatic tumors. Of these, 13 cases (68.4%) had a previously diagnosed malignancy. Most of the 19 metastatic lesions were adenocarcinomas or poorly differentiated carcinomas (n = 12, 63.2%), followed by melanoma (n = 4), SCC (n = 1), alveolar soft part sarcoma (n = 1) and large cell lymphoma (n = 1). The most common site of primary was the gastrointestinal tract (6/19, 31.5%) and lung (6/19, 31.5%). The average survival after the diagnosis of these scalp metastases was around 6.3 months, signifying a poor prognosis. CONCLUSION: In our patient population, most scalp masses were metastatic tumors. Metastasis to the scalp signals advanced disease and is associated with a very poor prognosis. FNA is an easy, safe, rapid, cost effective and precise modality for diagnosing these masses. It can also yield material for molecular testing for newer directed therapies, if needed.

The Impact of Telehealth on Primary Care Physician Panel Sizes: A Modeling Study.

INTRODUCTION: Most research on the use of telehealth in lieu of in-office visits has focused on its growth, its impact on access, and the experience of physicians and patients. One important issue that has not gotten much attention is the potential for telehealth to significantly increase physician capacity by reducing nonvalue adding activities and patient no-shows. We explore this in this article. METHODS: We use data from the electronic health records of 2 health care systems and information gathered from family medicine physician focus groups to develop estimates of visit durations and no-show rates for tele-visits. We use these in a simulation model to determine how patient panel sizes could be increased while maintaining high levels of access by substituting tele-visits for in-person visits. RESULTS: We found that tele-visits reduce the nonvalue-added time physicians spend with patients as well as patient no-shows. At current levels of tele-visit utilization, the use of tele-visits may translate into more than a 10% increase in patient panel sizes assuming a modest reduction in visit durations and no-shows, and as much as a 30% increase assuming that half of all visits could be effectively conducted virtually and result in a greater reduction in visit durations and no-shows. DISCUSSION: Our study provides evidence that a major benefit of using telehealth for many routine encounters is a reduction in wasted physician time and a substantial increase in the number of patients that a primary care physician can care for without jeopardizing access to care.

Metastatic hepatocellular carcinoma to the bone diagnosed by fine needle aspiration in a veteran population.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and it may present initially with extrahepatic spread in 5%-15% cases. It most commonly metastasizes to lungs, lymph nodes and adrenal glands. Skeletal metastases from HCC are uncommon and carry a very poor prognosis. METHODS: We retrospectively reviewed all fine needle aspiration (FNA) specimens of metastatic HCC at our institution from January 1994 to March 2021 using the SNOMED search computer option. Relevant clinical information was obtained from the review of patient's electronic medical records. RESULTS: There were 36 FNAs of metastatic HCC over a period of 27 years. Six patients (16.7%) were found to have skeletal metastases. All six patients were males with a median age of 59 years (54-71 years) and their lesions were osteolytic. The most common site of metastases was vertebra (3/50%). Most patients (67%) had bone metastases as an initial presentation, without prior history of HCC. The mean survival after the diagnosis of skeletal metastases was only 8 months. CONCLUSION: Detection of extrahepatic HCC to bone is important to avoid any unwanted surgical intervention. In our patient population, the most common site of skeletal metastases from HCC was vertebra, therefore in FNAs of vertebral lytic masses, metastatic HCC should be considered. On FNA, extrahepatic metastases of HCC can mimic other poorly differentiated tumors. They behave in an aggressive fashion, resulting in a grim prognosis. Cytological substrates can be used for future molecular testing, if needed.

Novel acute hypersensitivity pneumonitis model induced by airway mycosis and high dose lipopolysaccharide.

BACKGROUND: Inhalation of fungal spores is a strong risk factor for severe asthma and experimentally leads to development of airway mycosis and asthma-like disease in mice. However, in addition to fungal spores, humans are simultaneously exposed to other inflammatory agents such as lipopolysaccharide (LPS), with uncertain relevance to disease expression. To determine how high dose inhalation of LPS influences the expression of allergic airway disease induced by the allergenic mold Aspergillus niger (A. niger). METHODS: C57BL/6J mice were intranasally challenged with the viable spores of A. niger with and without 1 µg of LPS over two weeks. Changes in airway hyperreactivity, airway and lung inflammatory cell recruitment, antigen-specific immunoglobulins, and histopathology were determined. RESULTS: In comparison to mice challenged only with A. niger, addition of LPS (1 µg) to A. niger abrogated airway hyperresponsiveness and strongly attenuated airway eosinophilia, PAS+ goblet cells and TH2 responses while enhancing TH1 and TH17 cell recruitment to lung. Addition of LPS resulted in more severe, diffuse lung inflammation with scattered, loosely-formed parenchymal granulomas, but failed to alter fungus-induced IgE and IgG antibodies. CONCLUSIONS: In contrast to the strongly allergic lung phenotype induced by fungal spores alone, addition of a relatively high dose of LPS abrogates asthma-like features, replacing them with a phenotype more consistent with acute hypersensitivity pneumonitis (HP). These findings extend the already established link between airway mycosis and asthma to HP and describe a robust model for further dissecting the pathophysiology of HP.

Chest Wall Swelling in a Baby Boomer: An Unusual Presentation of Primary Hepatocellular Carcinoma.

Primary hepatocellular carcinoma (HCC) is one of the most frequently diagnosed cancers in adult men and a leading cause of cancer-related deaths worldwide. It also has an association with patients with hepatitis C-related cirrhosis. HCC usually metastasizes within the liver as well as to the lungs, regional lymph nodes, and adrenal glands, whereas the involvement of the chest wall and thoracic musculoskeletal system are more unusual. Herein, we report the case of a 58-year-old man who presented with swelling of the right anterolateral lower chest wall. The final diagnosis was primary HCC with distant metastases involving the right anterolateral ribs and left scapula. Such a presentation of extrahepatic HCC of this size and at this site is unique and has never before been reported in the literature. It reinforces the urgency and importance of screening all adults (18 years and above), particularly baby boomers, because three out of 100 have been infected with hepatitis C, at least once in their lifetime. It is also a wake-up call, as the incidence of primary HCC secondary to hepatitis C-associated cirrhosis has doubled, with a resultant increase in mortality. This HCC-related death might have been prevented if the patient had been screened for hepatitis C virus in his lifetime, as recommended by the American Association for the Study of Liver Diseases. We also discuss the latest developments in the diagnosis and management of HCC.

Real-World Effectiveness of Anti-IL-5/5R Therapy in Severe Atopic Eosinophilic Asthma with Fungal Sensitization.

BACKGROUND: Severe asthma with fungal sensitization (SAFS) is a complex clinical phenotype associated with poorly controlled type 2 inflammation and significant morbidity from both the disease itself and a high steroid burden. OBJECTIVE: To assess the effectiveness of biologic therapies targeting eosinophilic inflammation in SAFS. METHODS: We assessed the effectiveness of treatment with mepolizumab or benralizumab in patients with SAFS, and compared outcomes with patients with severe atopic asthma without fungal sensitization and patients with severe nonatopic asthma. Baseline clinical characteristics and clinical outcomes at 48 weeks were evaluated. A subgroup analysis was performed of patients who met the criteria for allergic bronchopulmonary aspergillosis (ABPA) rather than SAFS. RESULTS: A total of 193 patients treated with mepolizumab (n = 63) or benralizumab (n = 130) were included. Patients with SAFS had higher baseline IgE level compared with patients with severe atopic asthma without fungal sensitization and severe nonatopic asthma (733 ± 837 IU/mL vs 338 ± 494 and 142 ± 171, respectively; both P < .001). There were no other significant baseline differences in clinical characteristics between groups. At 48 weeks, there were significant improvements in 6-item asthma control questionnaire score and exacerbation frequency, and reduction in maintenance oral corticosteroid dose across all groups (all P < .05). No significant between-group differences in outcomes were observed at 48 weeks. Patients with ABPA (n = 9) had a significant reduction in exacerbation frequency (P = .013) with treatment. CONCLUSIONS: Treatment with eosinophil-targeting biologics led to improvements in exacerbation frequency, oral corticosteroid requirements, and patient-reported outcomes in patients with SAFS, with a reduction in exacerbations in the subgroup of patients with ABPA. These data highlight the potential clinical utility of targeting eosinophilic inflammation in SAFS and ABPA.

Real-World Effectiveness of Benralizumab in Severe Eosinophilic Asthma.

BACKGROUND: Benralizumab is an IL5-receptor monoclonal antibody licensed for the treatment of severe eosinophilic asthma (SEA). It has demonstrated efficacy in clinical trials in reducing asthma exacerbation rates and maintenance oral corticosteroids (mOCSs). RESEARCH QUESTION: What is the real-world effectiveness of benralizumab and what baseline characteristics are associated with response to therapy? STUDY DESIGN AND METHODS: We assessed outcomes in all SEA patients who began benralizumab treatment at our specialist center. At each dosing visit, exacerbation history, mOCS dose, spirometry, and Asthma Control Questionnaire (ACQ6) and Mini-Asthma Quality of Life Questionnaire (mAQLQ) scores were recorded. Response to treatment was defined as a reduction of ≥ 50% in annualized exacerbation rate (AER) or in mOCS dose after 48 weeks of treatment. Super response was defined as zero exacerbations and no mOCSs for asthma. RESULTS: One hundred thirty patients were included in the analysis. At 48 weeks, a 72.8% reduction in AER was noted, from 4.92 ± 3.35 per year in the year preceding biologic treatment to 1.34 ± 1.71 per year (P < .001), including 57 patients (43.8%) who were exacerbation-free with benralizumab. In those receiving mOCSs (n = 74 [56.9%]), the median daily prednisolone dose fell from 10 mg (interquartile range, 5-20 mg) to 0 mg (interquartile range, 0-5 mg; P < .001), and 38 of 74 patients (51.4%) were able to discontinue mOCS therapy. Clinically and statistically significant improvements were found in ACQ6 scores, mAQLQ scores, and FEV1. Overall, 51 patients (39%) met the super responder definition and 112 patients (86%) met the responder definition. The optimal regression model of super responders vs other responders included baseline characteristics associated with a strongly eosinophilic phenotype and less severe disease. Eighteen patients (13.8%) were nonresponders to benralizumab. Evidence of chronic airway infection was observed in 6 of 18 patients, and an increase in the blood eosinophil count consistent with the development of anti-drug antibodies was observed in 5 of 18 patients. INTERPRETATION: In a large real-world SEA cohort, benralizumab led to significant improvements in all clinical outcome measures. A lack of response was seen in a minority of patients and should be a focus for future investigation.

Functional Dyspepsia and Duodenal Eosinophil Count and Degranulation: A Multiethnic US Veteran Cohort Study.

BACKGROUND: Duodenal eosinophilia may play a role in functional dyspepsia (FD), but existing study results are conflicted. We investigated the association between duodenal eosinophils (count and degranulation) and FD symptoms, accounting for atopic conditions, medications, and seasonal variations. METHODS: In a cross-sectional study conducted in the Michael E. DeBakey VA Medical Center in Houston, Texas, we analyzed duodenal histopathology of 436 patient samples from a prospective cohort with a validated symptom survey data and chart reviews. FD was defined using Rome II symptom criteria. Eosinophil count was number per 5 high-power fields (HPF), and eosinophil degranulation was eosinophilic granules in the stroma both determined by two independent investigators. RESULTS: The study cohort was predominantly male (87.4%) with a mean age of 59.3 (standard deviation (SD) ± 9.8). Mean and median eosinophil counts were 75.5 (± 47.8) and 63 (IQR: 43, 101) per five HPF, respectively. Duodenal eosinophilia (defined as ≥ 63 per 5 HPF) and eosinophil degranulation were present in 50.5% and 23.1% of patient samples, respectively. FD was observed in 178 patients (41.7%), but neither the mean eosinophil count nor duodenal eosinophilia was associated with FD. Eosinophil degranulation was independently associated with FD overall (OR 1.74; 95% CI 1.08, 2.78; p = 0.02) and early satiety (OR 2.04; 95% CI 1.26, 3.30; p = 0.004). CONCLUSIONS: In this large, ethnically diverse cohort of adult patients, we found no significant association between duodenal eosinophilia and FD. However, the presence of duodenal eosinophilic degranulation, an activated eosinophil marker, was significantly associated with FD, especially early satiety.

Steroid-sparing effects of benralizumab in patients with eosinophilic granulomatosis with polyangiitis.

Benralizumab reduces oral corticosteroid requirements in patients with EGPA and leads to improved patient-reported outcome measures https://bit.ly/2GI0vhf.