Contemporary Concise Review 2023: Advances in lung cancer and interventional pulmonology.

Eligibility criteria for lung cancer screening increasingly need to consider family history of lung cancer, as well as age and smoking status. Lung cancer screening will reveal a multitude of incidental findings, of variable clinical significance, and with a need for clear pathways of management. Pulmonary nodule sampling is enhanced by intra-procedural imaging and cutting-edge robotic technology. Systematic thoracic lymph node sampling has implications for treatment efficacy. Bronchoscopic ablative techniques are feasible for peripheral lung cancers. Bronchoscopic sampling continues to have a high yield for lung cancer molecular characterization. Immunotherapy indications have expanded to include early stage and resectable lung cancer.

The TSANZ and Lung Foundation Australia 2023 landscape survey of lung cancer care across Australia and Aotearoa New Zealand.

BACKGROUND AND OBJECTIVE: Unwarranted variations in lung cancer care have been well described in both Australia and Aotearoa New Zealand, with shortfalls in hospital-based workforce and infrastructure previously demonstrated. A survey of lung cancer clinicians was performed to gain an updated understanding of current workforce and infrastructure. METHODS: An online Qualtrics survey included questions on institutional demographics, estimated lung cancer case load, multidisciplinary team (MDT) characteristics including workforce and local infrastructure. We sought to obtain one response from every institution treating lung cancer in Australia and Aotearoa New Zealand. RESULTS: Responses were received from 89 institutions, estimated to include 85% centres treating lung cancer in Australia and 100% of public hospitals in Aotearoa New Zealand. Lung cancer nurse specialist and Nuclear Medicine are poorly represented in multidisciplinary teams (MDTs) with just 34/88 (38%) institutions fulfilling recommended core workforce for MDT meetings. Case presentation is low with 32/88 (36%) regularly discussing all lung cancer patients at MDT. Metropolitan institutions appear to have a more comprehensive range of services on site, compared to non-metropolitan institutions. Few (4/88) institutions have embedded smoking cessation services. Compared to the previous 2021 Landscape Survey, thoracic surgery representation and core MDT workforce have improved, with modest change in specialist nurse numbers. CONCLUSION: This wide-reaching survey has identified persistent deficiencies and variations in lung cancer workforce and gaps in infrastructure. Multidisciplinary collaboration and care coordination are needed to ensure all patients can access timely and equitable lung cancer care.

Contemporary Concise Review 2021: Pulmonary nodules from detection to intervention.

The US Preventive Task Force (USPSTF) has updated screening criteria by expanding age range and reducing smoking history required for eligibility; the International Lung Screen Trial (ILST) data have shown that PLCOM2012 performs better for eligibility than USPSTF criteria. Screening adherence is low (4%-6% of potential eligible candidates in the United States) and depends upon multiple system and patient/candidate-related factors. Smoking cessation in lung cancer improves survival (past prospective trial data, updated meta-analysis data); smoking cessation is an essential component of lung cancer screening. Circulating biomarkers are emerging to optimize screening and early diagnosis. COVID-19 continues to affect lung cancer treatment and screening through delays and disruptions; specific operational challenges need to be met. Over 70% of suspected malignant lesions develop in the periphery of the lungs. Bronchoscopic navigational techniques have been steadily improving to allow greater accuracy with target lesion approximation and therefore diagnostic yield. Fibre-based imaging techniques provide real-time microscopic tumour visualization, with potential diagnostic benefits. With significant advances in peripheral lung cancer localization, bronchoscopically delivered ablative therapies are an emerging field in limited stage primary and oligometastatic disease. In advanced stage lung cancer, small-volume samples acquired through bronchoscopic techniques yield material of sufficient quantity and quality to support clinically relevant biomarker assessment.

Excess iron promotes emergence of foamy macrophages that overexpress ferritin in the lungs of silicosis patients.

BACKGROUND AND OBJECTIVE: Inhalation of high concentrations of respirable crystalline silica (RCS) can lead to silicosis. RCS contains varying levels of iron, which can cause oxidative stress and stimulate ferritin production. This study evaluated iron-related and inflammatory markers in control and silicosis patients. METHODS: A cohort of stone benchtop industry workers (n = 18) were radiologically classified by disease severity into simple or complicated silicosis. Peripheral blood and bronchoalveolar lavage (BAL) were collected to measure iron, ferritin, C-reactive protein, serum amyloid A and serum silicon levels. Ferritin subunit expression in BAL and transbronchial biopsies was analysed by reverse transcription quantitative PCR. Lipid accumulation in BAL macrophages was assessed by Oil Red O staining. RESULTS: Serum iron levels were significantly elevated in patients with silicosis, with a strong positive association with serum ferritin levels. In contrast, markers of systemic inflammation were not increased in silicosis patients. Serum silicon levels were significantly elevated in complicated disease. BAL macrophages from silicosis patients were morphologically consistent with lipid-laden foamy macrophages. Ferritin light chain (FTL) mRNA expression in BAL macrophages was also significantly elevated in simple silicosis patients and correlated with systemic ferritin. CONCLUSION: Our findings suggest that elevated iron levels during the early phases of silicosis increase FTL expression in BAL macrophages, which drives elevated BAL and serum ferritin levels. Excess iron and ferritin were also associated with the emergence of a foamy BAL macrophage phenotype. Ferritin may represent an early disease marker for silicosis, where increased levels are independent of inflammation and may contribute to fibrotic lung remodelling.

Unexpected case of accelerated silicosis in a female quarry worker.

Silicosis is a progressive and irreversible fibrotic occupational lung disease caused by inhalation of respirable crystalline silica (RCS). Recently, outbreaks have been reported in industries involving direct work with high silica-containing materials, such as artificial stone. Here, we describe an unexpected diagnosis made in an asymptomatic 33-year-old female worker employed for 4 years at a quarry for rhyodacite and rhyolite which contain 70% silicon dioxide. Chest computed tomography demonstrated small nodules in the upper lobes and larger ill-defined areas of opacity. Bronchoalveolar lavage revealed fine birefringent material within the cytoplasm of alveolar macrophages, representing silica. Transbronchial biopsies of lung parenchyma and endobronchial ultrasound-guided transbronchial needle aspiration of mediastinal lymph nodes did not reveal features of sarcoidosis, tuberculosis, or malignancy. As such, a diagnosis of accelerated silicosis was confirmed and represents the first reported case in a female worker at a rhyodacite and rhyolite quarry.

Lung cancer screening in Australia and New Zealand: the evidence and the challenge.

Lung cancer remains the commonest cause of cancer death in Australia and New Zealand. Targeted screening of individuals at highest risk of lung cancer aims to detect early stage disease, which may be amenable to potentially curative treatment. While current policy recommendations in Australia and New Zealand have acknowledged the efficacy of lung cancer screening in clinical trials, there has been no implementation of national programmes. With the recent release of findings from large international trials, the evidence and experience in lung cancer screening has broadened. This article discusses the latest evidence and implications for Australia and New Zealand.

Silica-associated lung disease: An old-world exposure in modern industries.

Despite silica dust exposure being one of the earliest recognized causes of lung disease, Australia, USA, Israel, Turkey and other countries around the world have recently experienced significant outbreaks of silicosis. These outbreaks have occurred in modern industries such as denim jean production, domestic benchtop fabrication and jewellery polishing, where silica has been introduced without recognition and control of the hazard. Much of our understanding of silica-related lung disease is derived from traditional occupations such as mining, whereby workers may develop slowly progressive chronic silicosis. However, workers in modern industries are developing acute and accelerated silicosis over a short period of time, due to high-intensity silica concentrations, oxidative stress from freshly fractured silica and a rapid pro-inflammatory and pro-fibrotic response. Appropriate methods of screening and diagnosis remain unclear in these workers, and a significant proportion may go on to develop respiratory failure and death. There are no current effective treatments for silicosis. For those with near fatal respiratory failure, lung transplantation remains the only option. Strategies to reduce high-intensity silica dust exposure, enforced screening programmes and the identification of new treatments are urgently required.

Short-Term Clinical Outcomes and Safety Associated With Percutaneous Radiofrequency Treatment for Excessive Sweating.

BACKGROUND: Primary excessive sweating of the axilla affects approximately 3.12% of the US population and has a negative impact on individuals' lives. OBJECTIVES: We report the safety and effectiveness up to 90 days after treating excessive sweating with percutaneous radiofrequency when using a standardized protocol. METHODS: Twenty adult subjects (13 females, 7 males) aged 18-49 years with excessive sweating were enrolled in a single-center, single-treatment unblinded prospective study conducted at the FACES+ Aesthetic Facility. Forty axilla were treated using the ThermiGen ThermiRF device. The Dermatology Quality of Life Index (DLQI), the Hyperhidrosis Disease Severity Scale (HDSS), and the Odor Scale (OS) were used for qualitative assessment. RESULTS: Primary and secondary exploratory evaluations were favorable at 90 days, indicating a significant improvement in quality of life and a significant reduction in both sweating and odor. The DLQI demonstrated an average improvement of 10.8 points at day 30, 10.7 at day 60, and 11.1 at day 90 (P = 0.0001). At day 90, 100% of individuals had ≥50% improvement in their excessive sweating based on the HDSS. At the conclusion of the study, 15 subjects had a ≥1-point drop in their OS, whereas 5 subjects had no change (P = 0.0002). There were no serious adverse events reported during this study. All adverse events were classified as mild and moderate and resolved within 2 months. CONCLUSIONS: The addition of the ThermiRF temperature-controlled radiofrequency device to the algorithm of hyperhidrosis treatments reduces sweating and odor with minimal downtime.

Clinical Outcomes and Complications Associated with Fractional Lasers: A Review of 730 Patients.

BACKGROUND: Fractional lasers were introduced to provide increased safety, while maintaining high efficacy and patient satisfaction. Patients with virtually all Fitzpatrick skin types could be safely treated using a wide spectrum of wavelengths and a broad array of skin conditions, and aging could be addressed. Although safety studies have been reported for ablative CO2 and erbium lasers, surprisingly few data are available on adverse events and complications associated with fractional lasers. OBJECTIVE: We report the frequency of adverse events, skin improvement and complications in a broad range of skin types using a standardized protocol that can be safely tailored to the patient's presenting complaints by varying the laser wavelength and number of treatments. MATERIALS AND METHODS: The medical records of 730 patients (>90% females, age ranged from 50.5. to 59.9 years.) who had been treated at FACES+ Aesthetic Facility were reviewed. Patients were followed from 1 to 10 months and were reviewed to determine the frequency of complications, as well as their frequency, type, cause, treatment and resolution thereof. Patients were categorized by Fitzpatrick skin type (I-IV) to determine whether skin type was related to the frequency of complications. Improvement in skin condition (wrinkles, nasolabial folds and pigment) was rated by a technician before and after treatment using a Likert scale, 0-5, with 0 being no change and 5 being the most improvement. RESULTS: Seven hundred thirty patients underwent procedures using fractional lasers in our center. Procedures were carried out with 3 different laser wavelengths, depending on the condition(s) treated (wrinkling vs. pigmentation issues, etc.) and the patients' desired length of downtime. The fractional Fraxel 1927-nm laser was used in 224 patients [Fitzpatrick skin type I (2.2%), II (38.4%), III (46.0%), IV (12.5%)]; the fractional Fraxel 1550-nm laser was used in 334 [type I (4.5%), II (31.9%), III (50.0%), IV (13.3%)], and the fractional Fraxel CO2 laser was used in 172 [type 1 (4.7%), II (49.7%), III (41.5%), IV (4.1%)]. The Fraxel CO2 laser showed greater improvement in wrinkles and naso-labial fold (p < 0.001). The greatest improvement in pigmentation was seen with the Fraxel 1927-nm laser (p < 0.001). Adverse events and complications occurred in 31 of 730 patients (4.2%). There was no significant difference in the rate of complications among the three treatments (p = 0.26). Complications were generally minor, and all resolved completely with treatment. Complications occurred in 4.0% of patients having the fractional Fraxel 1927-nm laser, 3.3% of patients having the fractional Fraxel 1550 nm and 6.4% of patients having the fractional Fraxel CO2 laser. Complications included 5 herpes simplex virus breakouts, 13 acne eruptions, 1 abrasion, 1 bacterial infection, 9 dermatitis, 1 drug eruption, 4 prolonged erythema, 1 hyperpigmentation, 1 increased swelling and 1 telangiectasia. There was no significant relationship between Fitzpatrick skin type and incidence of complications (p = 0.37). CONCLUSIONS: Fractional lasers in general have reduced complication rates, while maintaining high degrees of patient satisfaction. Since their inception in early 2004, our clinic has utilized fractional lasers to treat patients from a variety of ethnic backgrounds and diverse skin types with an overall complication rate of 4.2%, all of which resolved. Comprehensive care of patients with facial aging is not limited to surgery alone and should include these types of strategies to appropriately and safely address photo-damage and photo-aging. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Regenerative Cells For Facial Surgery: Biofilling and Biocontouring.

Zuk et al in 2001 identified stem and regenerative cells within the stromal vascular fraction of fat. In preclinical studies, these cells appeared to stimulate angiogenesis and reduce inflammation, and soon thereafter, clinical use of stromal vascular fraction (SVF) evolved as researchers such as Rigotti, Coleman, Mojallal, our group, and others demonstrated that fat can be used for both therapeutic and aesthetic indications. The regenerative effects of fat and its contents on facial aesthetics have been shown at the histologic and cellular level. Regeneration of elastin and collagen fibers as well as improvement in capillary density and reduction of inflammation have been reported. We review our current approach to the use of regenerative cells and different types of fat grafts in facial surgery. The fat graft is classified, both from a regenerative point of view as well as a tissue product that can be modified into different tissue characteristics, depending on the area and condition treated. Clinical use of SVF enriched fat, millifat, microfat, and nanofat grafts as well as composite fat grafts are reviewed. Based on clinical experience and evidence to date, it appears that the regenerative effects seen with the use of SVF in aesthetic surgery are modest, but there appear to be definite histologic findings of regeneration. These improvements may not be clinically apparent to a patient when cell enriched fat grafts are compared to fat grafts alone. However, the subtle changes seen in histology may be cumulative over time. Three types of fat grafts are defined: millifat (parcel size 2.4<), microfat (1.2<), and nanofat (400-600 µm). Each are characterized by their injectability ratings and emulsification parcel size as well as amount of sSVF cells. Newer concepts of periosteal fat grafting, buccal fat pad grafting, pyriform aperture fat grafting, intraorbital fat grafting, and nanofat grafting are discussed. Composite fat grafts are presented as a new concept as is biofilling and biocontouring. The use of regenerative cells in facial surgery is evolving rapidly. Our understanding of the anatomic changes that occur with aging has become more precise and our ability to target histologic changes seen with aging has become more effective. Deep fat compartment grafting, superficial fat grafting, nanofat, and SVF are becoming important components of contemporary facial rejuvenation. The use of regenerative approaches in facial rejuvenation is a logical step in changing the paradigm from surgical treatment of aging to a more proactive prevention and maintenance approach that keeps up with changes in the tissues as they age.

Diagnostic utility and accuracy of rapid on-site evaluation of bronchoscopic brushings.

The aim of the study was to determine the accuracy of rapid on-site examinations, performed on transbronchial brushings of peripheral pulmonary lesions, in determining final bronchoscopic diagnosis. In addition to determining if rapid on-site examination impacts procedural outcomes. A prospective cohort study of consecutive patients with peripheral pulmonary lesions, which had been located by radial endobronchial ultrasound, was undertaken. Bronchoscopy was terminated if rapid on-site examination demonstrated diagnostic malignant material. Non-diagnostic rapid on-site examination resulted in further bronchoscopic sampling, including transbronchial lung biopsy and/or sampling from different locations. 128 peripheral pulmonary lesions were located by endobronchial ultrasound in 118 patients. The final bronchoscopic diagnoses included nonsmall cell lung cancer (n=76), carcinoid (n=3), and metastatic malignancy (n=3). Procedure times were significantly shorter for procedures when rapid on-site examinations demonstrated malignancy compared to those where rapid on-site examination was non-diagnostic (19±8 min versus 31±11 min, respectively; p<0.0001). In four procedures, initial negative rapid on-site examination results prompted redirection of sampling from alternate bronchial segments, resulting in positive diagnostic tissue being obtained. Positive and negative predictive value of rapid on-site examination for a malignant bronchoscopic diagnosis was 63 (97%) out of 65, and 43 (68%) out of 63, respectively. Rapid on-site examination of brushing specimens has a very high, positive, predictive value for bronchoscopic diagnosis of cancer and shortens the bronchoscopy procedure times. It has the potential to reduce complications, improve cost-effectiveness, and may improve diagnostic performance via live feedback.

Nebulised granulocyte-macrophage colony-stimulating factor (GM-CSF) in autoimmune pulmonary alveolar proteinosis: a systematic review and meta-analysis.

BACKGROUND: Autoimmune pulmonary alveolar proteinosis (aPAP) results from impaired macrophage-mediated clearance of alveolar surfactant lipoproteins. Whole lung lavage has been the first-line treatment but recent reports suggest the efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF). We aimed to review the efficacy and safety of nebulised GM-CSF in aPAP. METHODS: We conducted a systematic review and meta-analysis searching Embase, CINAHL, MEDLINE and Cochrane Collaborative databases (1946-1 April 2022). Studies included patients aged >18 years with aPAP receiving nebulised GM-CSF treatment and a comparator cohort. Exclusion criteria included secondary or congenital pulmonary alveolar proteinosis, GM-CSF allergy, active infection or other serious medical conditions. The protocol was prospectively registered with PROSPERO (CRD42021231328). Outcomes assessed were St George's Respiratory Questionnaire (SGRQ), 6-min walk test (6MWT), gas exchange (diffusing capacity of the lung for carbon monoxide (D LCO) % predicted) and arterial-alveolar oxygen gradient. RESULTS: Six studies were identified for review and three for meta-analysis, revealing that SGRQ score (mean difference -8.09, 95% CI -11.88- -4.3, p<0.0001), functional capacity (6MWT) (mean difference 21.72 m, 95% CI -2.76-46.19 m, p=0.08), gas diffusion (D LCO % predicted) (mean difference 5.09%, 95% CI 2.05-8.13%, p=0.001) and arterial-alveolar oxygen gradient (mean difference -4.36 mmHg, 95% CI -7.19- -1.52 mmHg, p=0.003) all significantly improved in GM-CSF-treated patients with minor statistical heterogeneity (I2=0%). No serious trial-related adverse events were reported. CONCLUSIONS: Patients with aPAP treated with inhaled GM-CSF demonstrated significant improvements in symptoms, dyspnoea scores, lung function, gas exchange and radiology indices after treatment with nebulised GM-CSF of varying duration. There is an important need to review comparative effectiveness and patient choice in key clinical outcomes between the current standard of care, whole lung lavage, with the noninvasive treatment of nebulised GM-CSF in aPAP.

Overexpression of MRPL19 in predicting poor prognosis and promoting the development of lung adenocarcinoma.

Background: Mitochondrial ribosomal protein L19 (MRPL19) is a member of the mitochondrial ribosomal protein (MRP) family. MRPs have a role in the progression of many cancers. However, the role of MRPL19 in lung adenocarcinoma (LUAD) is yet unknown. Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, real-time polymerase chain reaction, and immunohistochemistry (IHC) were used to assess MRPL19 expression and clinical relevance. Gene Expression Profiling Interactive Analysis (GEPIA) and the online Kaplan-Meier (KM) Plotter database were used to determine the prognostic significance. Through use of LinkedOmics, genes that were coexpressed with MRPL19 and its regulators were identified. The biological roles of MRPL19 were investigated through R-implemented packages and RNA interference. The Tumor Immune Estimation Resource (TIMER) was employed to assess the connection between MRPL19 expression and infiltrated immune cells in LUAD. Results: MRPL19 expression in LUAD was upregulated and was correlated with lymph node metastasis, differentiation level, and tumor status. MRPL19 was prognostic and associated with poor prognosis. Functional network analysis revealed that MRPL19 may be associated with the cell cycle, cell adhesion molecules, spliceosome, and T-helper cell differentiation and was regulated by several microRNA and the E2F family. The gene set enrichment analysis (GSEA) and protein-protein interaction (PPI) network indicated that MRPL19 was correlated with cancer proliferation signaling pathways. The immune infiltration analysis revealed a correlation between MRPL19 expression and the extent of B cells, CD4+ T cells, and dendritic cells' infiltration in LUAD. Additionally, MRPL19 knockdown in LUAD cells substantially reduced cell growth, migration, and invasion of malignant cells. Conclusions: The poor prognosis and immunological infiltration in LUAD were significantly associated with MRPL19, which may have pro-oncogenic effects on the disease.

Heterogeneity of tumour mutational burden in metastatic NSCLC demonstrated by endobronchial ultrasound sampling.

Introduction: Tumour mutational burden (TMB) is an important emerging biomarker for immune checkpoint inhibitors (ICI). The stability of TMB values across distinct EBUS tumour regions is not well defined in advanced lung cancer patients. Methods: This study included a whole-genome sequencing cohort (n=11, LxG cohort) and a targeted Oncomine TML panel cohort (n=10, SxD cohort), where paired primary and metastatic samples were obtained by endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA). Results: The LxG cohort displayed a strong correlation between the paired primary and metastatic sites, with a median TMB score of 7.70 ± 5.39 and 8.31 ± 5.88 respectively. Evaluation of the SxD cohort demonstrated greater inter-tumoural TMB heterogeneity, where Spearman correlation between the primary and metastatic sites fell short of significance. Whilst median TMB scores were not significantly different between the two sites, 3 out of 10 paired samples were discordant when using a TMB cut-off of 10 mutations per Mb. In addition, PD-L1 copy number and KRAS mutations were assessed, demonstrating the feasibility of performing multiple molecular tests relevant to ICI treatment using a single EBUS sample. We also observed good consistency in PD-L1 copy number and KRAS mutation, where cut-off estimates were consistent across the primary and metastatic sites. Conclusions: Assessment of TMB acquired by EBUS from multiple sites is highly feasible and has the potential to improve accuracy of TMB panels as a companion diagnostic test. We demonstrate similar TMB values across primary and metastatic sites, however 3 out of 10 samples displayed inter-tumoural heterogeneity that would alter clinical management.

Differential organ-specific tumor response to first-line immune checkpoint inhibitor therapy in non-small cell lung cancer-a retrospective cohort study.

Background: Immune checkpoint inhibitors (ICIs) possess remarkable clinical effectiveness in non-small cell lung cancer (NSCLC). Different immune profiles of tumors may play a key role in the efficacy of treatment with ICIs. This article aimed to determine the differential organ responses to ICI in individuals with metastatic NSCLC. Methods: This research analyzed data of advanced NSCLC patients receiving first-line treatment with ICIs. Major organs such as the liver, lung, adrenal glands, lymph nodes and brain were assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and RECIST-improved organ-specific response criteria. Results: A retrospective analysis was conducted on a total of 105 individuals with advanced NSCLC with programmed death ligand-1 (PD-L1) expression ≥50% who received single agent anti-programmed cell death protein 1 (PD-1)/PD-L1 monoclonal antibodies as first-line therapy. Overall, 105 (100%), 17 (16.2%), 15 (14.3%), 13 (12.4%), and 45 (42.8%) individuals showed measurable lung tumors and liver, brain, adrenal, and other lymph node metastases at baseline. The median size of the lung, liver, brain, adrenal gland, and lymph nodes were 3.4, 3.1, 2.8, 1.9, and 1.8 cm, respectively. The results recorded mean response times of 2.1, 3.4, 2.5, 3.1, and 2.3 months, respectively. Organ-specific overall response rates (ORRs) were 67%, 30.6%, 34%, 39%, and 59.1%, respectively, with the liver having the lowest remission rate and lung lesions having the highest remission rate. There were 17 NSCLC patients with liver metastasis at baseline, and 6 had different responses to ICI treatment, with remission in the primary lung site and progressive disease (PD) in the metastatic liver site. At baseline, the mean progression-free survival (PFS) of the 17 patients with liver metastasis and 88 patients without liver metastasis was 4.3 and 7 months, respectively (P=0.02, 95% CI: 0.691 to 3.033). Conclusions: The liver metastases of NSCLC may be less responsive to ICIs than other organs. The lymph nodes respond most favorably to ICIs. Further strategies may include additional local treatment in case of oligoprogression in these organs in patients with otherwise sustained treatment benefit.