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Surgery is the common treatment for early lung cancer with multiple pulmonary nodules, but it is often accompanied by the problem of significant malignancy of other nodules in non-therapeutic areas. In this study, we found that a combined treatment of local radiofrequency ablation (RFA) and melatonin (MLT) greatly improved clinical outcomes for early lung cancer patients with multiple pulmonary nodules by minimizing lung function injury and reducing the probability of malignant transformation or enlargement of nodules in non-ablated areas. Mechanically, as demonstrated in an associated mouse lung tumor model, RFA not only effectively remove treated tumors but also stimulate antitumor immunity, which could inhibit tumor growth in non-ablated areas. MLT enhanced RFA-stimulated NK activity and exerted synergistic antitumor effects with RFA. Transcriptomics and proteomics analyses of residual tumor tissues revealed enhanced oxidative phosphorylation and reduced acidification as well as hypoxia in the tumor microenvironment, which suggests reprogrammed tumor metabolism after combined treatment with RFA and MLT. Analysis of residual tumor further revealed the depressed activity of MAPK, NF-kappa B, Wnt, and Hedgehog pathways and upregulated P53 pathway in tumors, which was in line with the inhibited tumor growth. Combined RFA and MLT treatment also reversed the Warburg effect and decreased tumor malignancy. These findings thus demonstrated that combined treatment of RFA and MLT effectively inhibited the malignancy of non-ablated nodules and provided an innovative non-invasive strategy for treating early lung tumors with multiple pulmonary nodules. Trial registration: www.chictr.org.cn , identifier ChiCTR2100042695, http://www.chictr.org.cn/showproj.aspx?proj=120931 ., (© 2021. The Author(s).)

Purpose of Review: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare premalignant condition. Over the past decade, there has been increased recognition and reporting of DIPNECH in the literature. Currently, our understanding is that DIPNECH has a predilection to nonsmoking females around their sixth decade of life. The patients usually present with chronic cough, dyspnea, and computed tomography (CT) showing multifocal pulmonary nodules with associated mosaic attenuation. The clinic history is largely driven by constrictive obliterative bronchiolitis, which typically has an indolent course with progressive respiratory decline and difficult to treat symptoms., Recent Findings: DIPNECH has been found to be associated with carcinoid tumors. Recent data has found that symptomatic DIPNECH patients respond to somatostatin analog (SSA). SSAs provide improvement in symptoms and pulmonary function tests. According to small studies and case series SSAs can be used in conjunction with steroids and bronchodilators for the treatment of respiratory symptoms., Summary: DINPNECH is a premalignant condition that can transform into carcinoid tumors. Although the recent data suggest the potential efficacy of SSA, further studies are needed to validate such results in prospective fashion in addition to investigating other therapeutic agents., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Competing interests: None declared.

Objective: To evaluate the incidence of pulmonary metastases on chest computed tomography (CT) in patients with locally advanced pancreatic cancer (LAPC)., Methods: All patients diagnosed with LAPC in a single tertiary center (Erasmus MC) between October 2011 and December 2017 were reviewed. The staging chest CT scan and follow-up chest CT scans were evaluated. Pulmonary nodules were divided into three categories: apparent benign, too small to characterize, and apparent malignant., Results: In 124 consecutive patients diagnosed with LAPC, 119 (96%) patients underwent a staging chest CT scan at the initial presentation. In 88 (74%) patients no pulmonary nodules were found; in 16 (13%) patients an apparent benign pulmonary nodule was found, and in 15 (13%) patients a pulmonary nodule too small to characterize was found. Follow-up chest CT scan(s) were performed in 111 (93%) patients. In one patient with either no pulmonary nodule or an apparent benign pulmonary nodule at initial staging, an apparent malignant pulmonary nodule was found on a follow-up chest CT scan. However, a biopsy of the nodule was inconclusive. Of 15 patients in whom a pulmonary nodule too small to characterize was found at staging, 12 (80%) patients underwent a follow-up CT scan; in 4 (33%) of these patients, an apparent malignant pulmonary nodule was found., Conclusion: In patients with LAPC in whom at diagnosis a chest CT scan revealed either no pulmonary nodules or apparent benign pulmonary nodules, routine follow-up chest CT scans is not recommended. Patients with pulmonary nodules too small to characterize are at risk to develop apparent malignant pulmonary nodules during follow-up., (© 2020 The Authors. Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Background: Henoch-Schönlein purpura (HSP) is the most common vasculitis of childhood. It has a characteristic rash described as palpable purpura that most frequently affects the distal lower extremities and buttocks. HSP rarely presents with bullous rash nor pulmonary nodules., Case Presentation: We present a novel case of a 12-years-old female with recurrent pediatric HSP with a combination of the rare manifestations of bullous rash and pulmonary nodules. She initially presented with the bullous rash, chest pain, cough, and abdominal pain. Patient was successfully treated with intravenous pulse corticosteroids followed by a high dose oral corticosteroid taper, with resolution of the bullous rash and pulmonary nodules., Conclusion: The rare manifestations of scarring bullous rash and pulmonary nodules can be presenting features of pediatric HSP, the combination of which has not been previously reported. The treatment of intravenous corticosteroid resolved patient's abdominal symptoms, rash and pulmonary nodules.

An 18-year-old woman was admitted with abdominal pain and hematochezia. She was previously healthy until 15 years of age and was subsequently diagnosed with hypogammaglobulinemia, protein-losing enteropathy, a benign temporal lobe brain lesion/orbital fibroadenoma, autoimmune hepatitis, iron deficiency anaemia and hypothyroidism. She developed respiratory distress and hypoxemia. She was found to have nodules on chest CT scan. She was diagnosed with cytotoxic T-lymphocyte-associated antigen 4 deficiency via genetic testing., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: None declared.

Lymphomatoid granulomatosis (LYG) is a rare lung disorder diagnosed by radiological imaging of multiple pulmonary nodules and occasionally induced by methotrexate (MTX) use. To date, the treatment of LYG has not been standardized. We herein report the case of a patient with grade 3 MTX-related LYG who presented a bulky lung mass. Importantly, the disease condition only improved after the discontinuation of MTX and remained stable for more than 1 year. Chest physicians should be aware that LYG can develop as a single lung mass and spontaneously regress, even without aggressive chemotherapy, following the cessation of MTX.

Background: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare pulmonary condition, characterized by diffuse proliferation of neuroendocrine cells in the respiratory epithelium. DIPNECH lesions are less than 5 mm in size and are limited to the basement membrane with no invasion. There is limited information regarding epidemiology, natural history of disease progression, or the management of this rare entity. We present the experience of a center with extensive expertise in neuroendocrine disease., Methods: A cohort of patients (N = 13) with DIPNECH treated and followed at our institution was identified. We describe the our approach to their care, our disease management and also provide a review of DIPNECH pathophysiology., Results: Our patient cohort consisted of twelve females and one male with a mean age of 63 years at the time of diagnosis. Dyspnea on exertion and dry cough were the most common presenting symptoms. Two patients were under surveillance without treatment; three patients were treated with a short-acting somatostatin analog; three patients were treated with azithromycin alone; four were treated with a combination of long-acting monthly somatostatin analogs and azithromycin; one patient received a combination of long-acting somatostatin analog and everolimus. Five patients had concomitant bronchial carcinoids., Conclusions: DIPNECH is a rare pathology that can profoundly affect a patient's quality of life. Paroxysmal coughing episodes can be difficult to treat. Our limited single center experience shows encouraging response to use of somatostatin analogs, azithromycin, and everolimus in the management of debilitating DIPNECH associated symptoms.

Case Presentation: A 39-year-old male presented to the ED with a 2-day history of fever (Temperature-Maximum 39°C), nonbloody productive cough, and worsening right-sided pleuritic chest pain. The patient denied shortness of breath, nausea, vomiting, sinus symptoms, and abdominal pain. His medical history included type 2 diabetes mellitus (glycated hemoglobin, 11.1), hyperlipidemia, and depression. He smoked marijuana but denied tobacco or illicit drug use. He reported no recent travels. He reported a 1-week history of left molar pain that began after he siphoned stagnant water with a straw from a refrigerator drip pan. He lived in Ohio all of his life. He denied any sick contacts. His medications include Lantus insulin at night, metformin, glimepiride, pravastatin, and Remeron., (Published by Elsevier Inc.)

Introduction: Adjuvant chemotherapy after surgical resection of non-small cell lung cancer is associated with a survival advantage in several staging scenarios. T3 tumors associated with a separate tumor nodule in the same lobe (formerly "satellite nodules") have a significant risk for systemic failure, yet the efficacy of adjuvant chemotherapy in this setting is unknown. The survival of patients with T3 tumors and additional tumor nodules in the same lobe treated with and without postoperative chemotherapy was evaluated to understand the role of adjuvant chemotherapy in this setting., Methods: The National Cancer Data Base was queried for patients with T3 tumors with additional tumor nodules in the same lobe between 2010 and 2012. Primary outcomes were 3-year overall and relative survival (a surrogate of cancer-specific survival)., Results: A total of 1013 patients with T3 tumors and additional tumor nodules in the same lobe were identified; 56% received multiagent postoperative chemotherapy and 44% were treated with surgical resection only. The use of adjuvant chemotherapy versus resection alone was associated with improved 3-year overall survival (70% versus 59%, p < 0.001). A Cox model adjusting for patient, tumor, and treatment factors demonstrated that adjuvant chemotherapy was associated with a survival advantage compared with resection alone (hazard ratio = 0.544, p < 0.0001). Relative 3-year survival was also improved in the adjuvant chemotherapy subgroup (74% versus 64% for the surgery-only subgroup)., Conclusions: Adjuvant chemotherapy is associated with increased overall survival among patients with T3 tumors with additional pulmonary nodules. Further study is warranted to clarify the role of adjuvant chemotherapy in this setting., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare disease that is classically described as presenting with cough, dyspnea, and wheezing in non-smoker middle aged females. Pulmonary function tests commonly demonstrate an obstructive pattern and CT of chest usually reveals diffuse air trapping with mosaic pattern. We present a case of patient with DIPNECH manifesting with restrictive pattern and as usual interstitial pneumonia on imaging.

Rosai-Dorfman disease is a rare non-Langerhans cell histiocytosis, mainly involving cervical nodes. We present the case of a patient with a pulmonary form of Rosai-Dorfman disease without peripheral or intra-thoracic lymph nodes, characterized by the presence of pulmonary nodules and cysts associated with bilateral pleural effusions.

Background: A previously carried out randomized phase IIb, placebo-controlled trial of 1 year of inhaled budesonide, which was nested in a lung cancer screening study, showed that non-solid and partially solid lung nodules detected by low-dose computed tomography (LDCT), and not immediately suspicious for lung cancer, tended to regress. Because some of these nodules may be slow-growing adenocarcinoma precursors, we evaluated long-term outcomes (after stopping the 1-year intervention) by annual LDCT., Patients and Methods: We analyzed the evolution of target and non-target trial nodules detected by LDCT in the budesonide and placebo arms up to 5 years after randomization. The numbers and characteristics of lung cancers diagnosed during follow-up were also analyzed., Results: The mean maximum diameter of non-solid nodules reduced significantly (from 5.03 mm at baseline to 2.61 mm after 5 years) in the budesonide arm; there was no significant size change in the placebo arm. The mean diameter of partially solid lesions also decreased significantly, but only by 0.69 mm. The size of solid nodules did not change. Neither the number of new lesions nor the number of lung cancers differed in the two arms., Conclusions: Inhaled budesonide given for 1 year significantly decreased the size of non-solid nodules detected by screening LDCT after 5 years. This is of potential importance since some of these nodules may progress slowly to adenocarcinoma. However, further studies are required to assess clinical implications., Clinical Trial Number: NCT01540552., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Pyoderma gangrenosum (PG) is a rare ulcerative neutrophilic dermatologic disease that occasionally is accompanied by extracutaneous manifestations, amongst these is pulmonary involvement. The etiology is unknown. More than 50% of PG cases are associated with an underlying systemic disease such as inflammatory bowel disease, rheumatoid arthritis, hematological disorder or malignancy. Extracutaneous manifestations are rare and only 29 cases of pulmonary involvement have been reported previously in the literature. Pyoderma gangrenosum is usually diagnosed in the third to sixth decade, but early debut in childhood is also described. Skin manifestations are usually evident before pulmonary involvement, although primary lung affection is seen. Pulmonary involvement is diagnosed simultaneously or from a few weeks up to several years after the diagnosis of cutaneous PG. The most important differential diagnoses are lung cancer, lung abscess and Wegener's granulomatosis. Histological specimens will exclude these diagnoses. The treatment of PG is immune modulation, but due to the rarity of the disease, only one randomized treatment trials exists [1] and the long term course of PG with pulmonary involvement is unknown. We present two cases of pulmonary manifestations of pyoderma gangrenosum and a review of the literature., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

We report the case of a 45-year-old man who initially presented with chondrosarcoma of the left femur that was treated surgically. Follow-up chest computed tomography (CT) performed 3 years later showed multiple small nodules with a tree-in-bud branching pattern and larger elongated opacities with beaded contours. These findings raised the suspicion of intravascular tumor embolism. Pulmonary CT angiography demonstrated intravascular thrombosis and dilated and beaded peripheral pulmonary arteries. The tumoral origin of the thrombus was confirmed by lung biopsy.

A 10-year-old, intact female Yorkshire terrier had multiple pulmonary nodules on thoracic radiography and ultrasonography with no lesions elsewhere. Computed tomography (CT) and positron emission tomography and computed tomography (PET-CT) using 18F-fluorodeoxyglucose (FDG) were performed to identify metastasis and undetected primary tumors. On CT examination, pulmonary nodules had a hypoattenuating center with thin peripheral enhancement, suggesting ischemic or necrotizing lesion. In PET-CT at 47 min after intravenous injection of 11.1 MBq/kg of FDG, the maximum standardized uptake value of each pulmonary nodule was about from 3.8 to 6.4. There were no abnormal lesions except for four pulmonary nodules on the CT and PET-CT. Primary lung tumor was tentatively diagnosed, and palliative therapy using 2 mg/kg tramadol and 2.2 mg/kg carprofen twice per day was applied. After the dog's euthanasia due to deteriorated clinical signs and poor prognosis, undifferentiated pulmonary adenocarcinoma was diagnosed through histopathologic and immunochemistry examination. To the best of the authors' knowledge, this is the first study of CT and PET-CT features of canine pulmonary adenocarcinoma. In this case, multiple pulmonary adenocarcinoma could be determined on the basis of FDG PET-CT through screening the obvious distant metastasis and/or lymph node invasions and excluding unknown primary tumors.

Adult-onset Still's disease (AOSD) is a multisystemic inflammatory disorder, but pulmonary involvement is rare. We herein describe the case of a woman diagnosed with AOSD; treatment resolved her symptoms, but nine days later she was admitted with pyrexia and a productive cough. A chest X-ray revealed diffuse pulmonary nodules and patchy shadows. A high-resolution chest computed tomography scan confirmed diffuse infiltration in the pulmonary parenchyma, signs of alveolar nodules, distribution along the lobule center, several areas of tree-in-bud patterns, and bilateral pleural effusion. The patient was treated with high doses of corticosteroids, which rapidly reduced the size of her diffuse pulmonary nodules and dramatically improved her pleural effusion.

Syphilis is a sexually transmitted disease caused by Treponema pallidum. The prevalence of this disease has recently increased worldwide. However, pulmonary involvement in secondary syphilis is extremely rare. A 51-year-old heterosexual male patient presented with multiple pulmonary nodules with reactive serology from the Venereal Disease Research Laboratory test and positive fluorescent treponemal antibody absorption testing. A hematogenous metastatic malignancy was suspected and an excisional lung biopsy was performed. Histopathological examination showed only central necrosis with abscess and plasma cell infiltration, but no malignant cells. The patient reported sexual contact with a prostitute 8 weeks previously and a penile lesion 6 weeks earlier. Physical examination revealed an erythematous papular rash on the trunk. Secondary syphilis with pulmonary nodules was suspected, and benzathine penicillin G, 2.4 million units, was administered. Subsequently, the clinical signs of syphilis improved and the pulmonary nodules resolved. The final diagnosis was secondary syphilis with pulmonary nodular involvement.

Inflammatory myofibroblastic tumor (IMT) is a rare tumorous lesion that presents as a solitary nodule. Complete surgical resection is the standard treatment. However, due to its rarity, the optimal therapeutic strategy for multiple IMTs has not been defined. A 32-year-old man was referred to our hospital for evaluation of multiple pulmonary nodules. On computed tomography (CT) scan of the chest, there were a 3.0 × 1.7 cm mass with heterogeneous enhancement in the left upper lobe and multiple small nodules bilaterally. We performed wedge resection of the mass, and histopathology revealed IMT. He was treated with oral corticosteroids. The clinical and radiologic responses were so excellent that a CT scan showed complete resolution 1 month after the initiation of corticosteroid therapy. These observations suggest that corticosteroids may be the way to treat bilateral multiple IMT of the lung.

Screening CT identifies small peripheral lung nodules, some of which may be pre- or early invasive neoplasia. Secondary end point analysis of a previous chemoprevention trial in individuals with bronchial dysplasia showed reduction in size of peripheral nodules by inhaled budesonide. We performed a randomized, double-blind, placebo-controlled phase IIb trial of inhaled budesonide in current and former smokers with CT-detected lung nodules that were persistent for at least 1 year. A total of 202 individuals received inhaled budesonide, 800 μg twice daily or placebo for 1 year. The primary endpoint was the effect of treatment on target nodule size in a per person analysis after 1 year. The per person analysis showed no significant difference between the budesonide and placebo arms (response rate 2% and 1%, respectively). Although the per lesion analysis revealed a significant effect of budesonide on regression of existing target nodules (P = 0.02), the appearance of new lesions was similar in both groups and thus the significance was lost in the analysis of all lesions. The evaluation by nodule type revealed a nonsignificant trend toward regression of nonsolid and partially solid lesions after budesonide treatment. Budesonide was well tolerated, with no unexpected side effects identified. Treatment with inhaled budesonide for 1 year did not significantly affect peripheral lung nodule size. There was a trend toward regression of nonsolid and partially solid nodules after budesonide treatment. Because a subset of these nodules is more likely to represent precursors of adenocarcinoma, additional follow-up is needed., (©2010 AACR.)

Background: Screening-CT is able to discover small peripheral lung nodules. The nature of these nodules is uncertain but it is reasonable that some of them, in particular the non-solid ones, could represent precancerous lesions. A previous trial showed a reduction in size of peripheral nodules by inhaled budesonide in subjects with bronchial dysplasia., Objective: The primary objective of the study was the evaluation of the effect of budesonide as a chemopreventive agent for lung lesions. The primary endpoint was the modification of lung lesions at ld-CT scan (according to RECIST criteria) after one year of treatment in a person-specific analysis., Methods: We performed a randomized, double-blind, placebo controlled trial to evaluate whether inhaled budesonide was able to reduce size and number of persistent, undetermined CT-detected lung nodules in high-risk asymptomatic subjects currently undergoing a five-year CT scan screening program at the European Institute of Oncology., Results: Trial enrollment started in April 2006 and ended in July 2007 with the randomization of 202 current or former smokers with stable CT-detected lung nodules set to receive budesonide 800 μg or placebo twice daily for 12 months., Conclusion: Our trial represents the first phase II study of a chemopreventive intervention focusing on the peripheral lung, where the majority of lung cancers arise. The research was nested into a screening project with clear advantages in participant accrual and reduction of costs. This paper describes the rationale and design of the study, thus focusing on the methodology and operational aspects of the clinical trial. (Clinicaltrials.gov number. NCT00321893)., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Even people which have never smoked can develop lung cancer. In this population a mutation in the exons 19-21 of the Epidermal Growth Factor Receptor (EGFR) can be detected. For this patient group targeted therapies with EGFR tyrosinkinase inhibitors are available. In this case report we describe a 37 year old non-smoker who developed a non-small cell lung cancer. Following therapy with Erlotinib a partial response could be achieved.