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Annals of Oncology : Official Journal... Aug 2018Neoadjuvant anti-PD-1 may improve outcomes for patients with resectable NSCLC and provides a critical window for examining pathologic features associated with response....
Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC).
BACKGROUND
Neoadjuvant anti-PD-1 may improve outcomes for patients with resectable NSCLC and provides a critical window for examining pathologic features associated with response. Resections showing major pathologic response to neoadjuvant therapy, defined as ≤10% residual viable tumor (RVT), may predict improved long-term patient outcome. However, %RVT calculations were developed in the context of chemotherapy (%cRVT). An immune-related %RVT (%irRVT) has yet to be developed.
PATIENTS AND METHODS
The first trial of neoadjuvant anti-PD-1 (nivolumab, NCT02259621) was just reported. We analyzed hematoxylin and eosin-stained slides from the post-treatment resection specimens of the 20 patients with non-small-cell lung carcinoma who underwent definitive surgery. Pretreatment tumor biopsies and preresection radiographic 'tumor' measurements were also assessed.
RESULTS
We found that the regression bed (the area of immune-mediated tumor clearance) accounts for the previously noted discrepancy between CT imaging and pathologic assessment of residual tumor. The regression bed is characterized by (i) immune activation-dense tumor infiltrating lymphocytes with macrophages and tertiary lymphoid structures; (ii) massive tumor cell death-cholesterol clefts; and (iii) tissue repair-neovascularization and proliferative fibrosis (each feature enriched in major pathologic responders versus nonresponders, P < 0.05). This distinct constellation of histologic findings was not identified in any pretreatment specimens. Histopathologic features of the regression bed were used to develop 'Immune-Related Pathologic Response Criteria' (irPRC), and these criteria were shown to be reproducible amongst pathologists. Specifically, %irRVT had improved interobserver consistency compared with %cRVT [median per-case %RVT variability 5% (0%-29%) versus 10% (0%-58%), P = 0.007] and a twofold decrease in median standard deviation across pathologists within a sample (4.6 versus 2.2, P = 0.002).
CONCLUSIONS
irPRC may be used to standardize pathologic assessment of immunotherapeutic efficacy. Long-term follow-up is needed to determine irPRC reliability as a surrogate for recurrence-free and overall survival.
Topics: Adult; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Feasibility Studies; Humans; Ipilimumab; Lung; Lung Neoplasms; Neoadjuvant Therapy; Neoplasm, Residual; Nivolumab; Pneumonectomy; Prognosis; Programmed Cell Death 1 Receptor; Reproducibility of Results; Treatment Outcome
PubMed: 29982279
DOI: 10.1093/annonc/mdy218 -
Journal For Immunotherapy of Cancer May 2021Checkpoint inhibitors targeting programmed death receptor-1 (PD-1) have been tested in the neoadjuvant setting for the treatment of locoregionally advanced head and neck...
Neoadjuvant immunoradiotherapy results in high rate of complete pathological response and clinical to pathological downstaging in locally advanced head and neck squamous cell carcinoma.
BACKGROUND
Checkpoint inhibitors targeting programmed death receptor-1 (PD-1) have been tested in the neoadjuvant setting for the treatment of locoregionally advanced head and neck squamous cell carcinoma (HNSCC); however, response rates are modest. We hypothesized that adding stereotactic body radiation therapy (SBRT) to anti-PD-1 would be safe prior to definitive surgical resection and would enhance pathological response compared with historical cohorts of patients with locoregionally advanced HNSCC treated with checkpoint inhibitor alone.
METHODS
The Neoadjuvant Immuno-Radiotherapy Trial was an investigator-initiated single institution phase Ib clinical trial that enrolled patients with previously untreated locally advanced HPV-positive and HPV-negative HNSCC between 2018 and 2019. Eligible patients were treated with neoadjuvant SBRT at a total dose of either 40 Gy in 5 fractions or 24 Gy in 3 fractions, delivered in a 1-week timespan, with or without nivolumab, prior to definitive surgical resection. Patients were then planned for treatment with adjuvant nivolumab for 3 months. The primary safety endpoint was unplanned delay in surgery considered to be at least possibly related to neoadjuvant treatment. The primary efficacy endpoints included pathological complete response (pCR), major pathological response (mPR), and the rate of clinical to pathological downstaging after neoadjuvant treatment.
RESULTS
Twenty-one patients underwent neoadjuvant treatment, which was well tolerated and did not delay surgery, thus meeting the primary endpoint. Tissue responses were characterized by robust inflammatory infiltrates in the regression bed, plasma cells and cholesterol clefts. Among the entire study group, the mPR and pCR rate was 86% and 67%, respectively. Clinical to pathological downstaging occurred in 90% of the patients treated.
CONCLUSION
These data demonstrate that radiation delivered only to the gross tumor volume combined with immunotherapy was safe, resulted in a high rate of mPR and should be further evaluated as a locally focused neoadjuvant therapy for patients with head and neck cancer.
TRIAL REGISTRATION NUMBER
This study is registered with clinicaltrials.gov (NCT03247712) and is active, but closed to patient accrual.
Topics: Aged; Dose Fractionation, Radiation; Female; Head and Neck Neoplasms; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Nivolumab; Oregon; Programmed Cell Death 1 Receptor; Radiosurgery; Radiotherapy, Adjuvant; Squamous Cell Carcinoma of Head and Neck; Time Factors; Treatment Outcome
PubMed: 33963014
DOI: 10.1136/jitc-2021-002485 -
Chest Jun 2012Reports of pulmonary fibrosis, emphysema, and, more recently, pulmonary alveolar proteinosis (PAP) in indium workers suggested that workplace exposure to indium...
BACKGROUND
Reports of pulmonary fibrosis, emphysema, and, more recently, pulmonary alveolar proteinosis (PAP) in indium workers suggested that workplace exposure to indium compounds caused several different lung diseases.
METHODS
To better understand the pathogenesis and natural history of indium lung disease, a detailed, systematic, multidisciplinary analysis of clinical, histopathologic, radiologic, and epidemiologic data for all reported cases and workplaces was undertaken.
RESULTS
Ten men (median age, 35 years) who produced, used, or reclaimed indium compounds were diagnosed with interstitial lung disease 4-13 years after first exposure (n = 7) or PAP 1-2 years after first exposure (n = 3). Common pulmonary histopathologic features in these patients included intraalveolar exudate typical of alveolar proteinosis (n = 9), cholesterol clefts and granulomas (n = 10), and fibrosis (n = 9). Two patients with interstitial lung disease had pneumothoraces. Lung disease progressed following cessation of exposure in most patients and was fatal in two. Radiographic data revealed that two patients with PAP subsequently developed fibrosis and one also developed emphysematous changes. Epidemiologic investigations demonstrated the potential for exposure to respirable particles and an excess of lung abnormalities among coworkers.
CONCLUSIONS
Occupational exposure to indium compounds was associated with PAP, cholesterol ester crystals and granulomas, pulmonary fibrosis, emphysema, and pneumothoraces. The available evidence suggests exposure to indium compounds causes a novel lung disease that may begin with PAP and progress to include fibrosis and emphysema, and, in some cases, premature death. Prospective studies are needed to better define the natural history and prognosis of this emerging lung disease and identify effective prevention strategies.
Topics: Adult; Biomarkers; Bronchoscopy; Diagnosis, Differential; Disease Progression; Humans; Indium; Lung Diseases; Male; Occupational Diseases; Occupational Exposure; Pancreatitis-Associated Proteins; Respiratory Function Tests; Risk Factors; Tomography, X-Ray Computed
PubMed: 22207675
DOI: 10.1378/chest.11-1880 -
Internal Medicine (Tokyo, Japan) Dec 2017A 40-year-old female dental technician visited our hospital for the investigation of a chest X-ray abnormality. Chest computed tomography demonstrated centrilobular...
A 40-year-old female dental technician visited our hospital for the investigation of a chest X-ray abnormality. Chest computed tomography demonstrated centrilobular nodules and lung volume reduction, and her serum KL-6 level was elevated. A histological analysis of the specimens obtained on a surgical lung biopsy showed peribronchiolar fibrosis with pigmented macrophages and cholesterol clefts. An energy-dispersive X-ray analysis showed that these lung tissues contained some metals, including indium. The serum indium level was also elevated. We diagnosed this patient with pneumoconiosis caused by exposure to sandblasting certain dental metals. This is the first reported case of pneumoconiosis in a dental technician associated with exposure to indium.
Topics: Adult; Dental Materials; Dental Technicians; Female; Humans; Lung; Occupational Diseases; Pneumoconiosis; Tomography, X-Ray Computed
PubMed: 29021460
DOI: 10.2169/internalmedicine.8860-17 -
International Journal of Molecular... Oct 2022Pericytes are multipotent mesenchymal stromal cells playing an active role in angiogenesis, vessel stabilisation, maturation, remodelling, blood flow regulation and are... (Review)
Review
Pericytes are multipotent mesenchymal stromal cells playing an active role in angiogenesis, vessel stabilisation, maturation, remodelling, blood flow regulation and are able to trans-differentiate into other cells of the mesenchymal lineage. In this review, we summarised recent data demonstrating that pericytes play a key role in the pathogenesis and development of atherosclerosis (AS). Pericytes are involved in lipid accumulation, inflammation, growth, and vascularization of the atherosclerotic plaque. Decreased pericyte coverage, endothelial and pericyte dysfunction is associated with intraplaque angiogenesis and haemorrhage, calcification and cholesterol clefts deposition. At the same time, pericytes can be used as a novel therapeutic target to promote vessel maturity and stability, thus reducing plaque vulnerability. Finally, we discuss recent studies exploring effective AS treatments with pericyte-mediated anti-atherosclerotic, anti-inflammatory and anti-apoptotic effects.
Topics: Atherosclerosis; Cholesterol; Humans; Lipids; Neovascularization, Pathologic; Pericytes; Plaque, Atherosclerotic
PubMed: 36232962
DOI: 10.3390/ijms231911663 -
Oxidative Medicine and Cellular... 2015Atherosclerosis is a multifactorial, multistep disorder of large- and medium-sized arteries involving, in addition to age, gender and menopausal status, a complex... (Review)
Review
Atherosclerosis is a multifactorial, multistep disorder of large- and medium-sized arteries involving, in addition to age, gender and menopausal status, a complex interplay between lifestyle and genetic risk factors. Atherosclerosis usually begins with the diffusion and retention of atherogenic lipoproteins into the subendothelial space of the artery wall where they become oxidized by local enzymes and accumulate, leading to the formation of a cushion called atheroma or atheromatous or fibrofatty plaque, composed of a mixture of macrophages, lymphocytes, smooth muscle cells (SMCs), cholesterol cleft, necrotic debris, and lipid-laden foam cells. The pathogenesis of atherosclerosis still remains incompletely understood but emerging evidence suggests that it may involve multiple cellular events, including endothelial cell (EC) dysfunction, inflammation, proliferation of vascular SMCs, matrix (ECM) alteration, and neovascularization. Actually, a growing body of evidence indicates that autophagy along with the chronic and acute overproduction of reactive oxygen species (ROS) is integral to the development and progression of the disease and may represent fruitful avenues for biological investigation and for the identification of new therapeutic targets. In this review, we give an overview of ROS and autophagy in atherosclerosis as background to understand their potential role in this vascular disease.
Topics: Aorta; Atherosclerosis; Autophagy; Humans; Myocytes, Smooth Muscle; NADPH Oxidase 4; NADPH Oxidases; Oxidative Stress; Reactive Oxygen Species
PubMed: 25866599
DOI: 10.1155/2015/130315 -
Surgical Neurology International 2022Sellar xanthogranulomas are rare intracranial lesions comprising <1% of all sellar lesions. They were described as a separate entity by the World Health Organization in...
BACKGROUND
Sellar xanthogranulomas are rare intracranial lesions comprising <1% of all sellar lesions. They were described as a separate entity by the World Health Organization in 2000. Because of the paucity of sellar xanthogranuloma cases reported in the literature, they remain a diagnostic challenge with indefinite origin, clinical course, and outcome. The present study reports a case of sellar xanthogranuloma describing the clinical presentation, radiological/pathological characteristics, and outcome.
CASE DESCRIPTION
A 43-year-old female, known to have diabetes, hypothyroidism, and polycystic ovarian syndrome, presented with a 2-week history of sudden right-sided facial deviation, periorbital pain, and moderate-intensity headache. The patient also reported amenorrhea not improving with polycystic ovarian syndrome treatment. Neurologic examination showed bilateral visual field defects and impaired visual acuity. Computed tomography scan, without contrast, revealed a hypodense sellar lesion with areas of hyperdensity. Magnetic resonance imaging showed a well-defined sellar lesion, exhibiting high signals on T1-weighted and T2-weighted images. The patient underwent microscopic trans-nasal trans-sphenoidal excision of the lesion. Histological sections of the sellar lesion revealed fibrous connective tissue with chronic inflammatory cells and cholesterol clefts, suggestive of xanthogranuloma. The patient is currently followed up at neurosurgery, endocrinology, and ophthalmology clinics with periodic laboratory/radiological investigations.
CONCLUSION
Sellar xanthogranulomas remain rare intracranial lesions with few cases reported in the literature. Patients mostly present with severe hypopituitarism and visual dysfunction. They show no characteristic radiological features. The diagnosis is confirmed histopathologically, and the prognosis is generally favorable.
PubMed: 35399894
DOI: 10.25259/SNI_1180_2021 -
Journal of Dermatological Case Reports Aug 2009Cutaneous cholesterol embolization syndrome occurs as a result of cholesterol embolization from atherosclerotic plaques lining the walls of arteries and arterioles. It...
BACKGROUND
Cutaneous cholesterol embolization syndrome occurs as a result of cholesterol embolization from atherosclerotic plaques lining the walls of arteries and arterioles. It can occur sporadically but is more commonly associated with iatrogenic manipulation via invasive vascular procedures or therapies (anticoagulation or thrombolytics) The three most common organ systems afflicted by cholesterol emboli include the kidneys, gastrointestinal system, and skin.
MAIN OBSERVATIONS
We present two patients with cutaneous cholesterol embolization A 74-year-old with no prior disease or trauma was referred to the hospital with the acute chest pain. After 24-48 he developed livedo reticularis, followed by necrotic areas like bilaterally on hips and in the lumbar region. The second patient, 69-year-old man with a history of hyperglycemia, hyperlipidaemia, and hypertension was referred with weight loss, bilateral livedo reticularis, severe pain of lower extremities and impaired renal function. The toes first became cyanotic and than skin necrosis developed. Skin biopsy revealed presence of cholesterol clefts in the lumina of small arteries and arterioles. In both patients the necrotic skin and subcutaneous tissue had been debrided. Daily dressing was applied and tissue defects underwent secondary healing.
CONCLUSION
The diagnosis of cholesterol embolization relies on clinical and histologic examination. Both, diagnosis and treatment needs a multidisciplinary approach, especially in cases of multi-organ involvement.
PubMed: 21886725
DOI: 10.3315/jdcr.2009.1031 -
World Journal of Gastrointestinal... Jan 2021Xanthogranulomatous inflammation is characterized histologically by a collection of lipid-laden macrophages admixed with lymphocytes, plasma cells, neutrophils, and...
BACKGROUND
Xanthogranulomatous inflammation is characterized histologically by a collection of lipid-laden macrophages admixed with lymphocytes, plasma cells, neutrophils, and often multinucleated giant cells with or without cholesterol clefts.
AIM
To review the medical literature on xanthogranulomatous appendicitis (XGA).
METHODS
We present a patient with XGA and review published articles on XGA accessed the PubMed, MEDLINE, Google Scholar, and Google databases. Keywords used were "appendix vermiformis," "appendectomy," "acute appendicitis," and "XGA." The search included articles published before May 2020, and the publication language was not restricted. The search included letters to the editor, case reports, review articles, original articles, and meeting presentations. Articles or abstracts containing adequate information about age, sex, clinical presentation, white blood cells, initial diagnosis, surgical approach, histopathological and immunohistochemical features of appendectomy specimens were included in the study.
RESULTS
A total of 29 articles involving 38 patients with XGA, were retrospectively analyzed. Twenty (52.6%) of the 38 patients, aged 3 to 78 years (median: 34; IQR: 31) were female, and the remaining 18 (47.4%) were male. Twenty-five patients were diagnosed with acute appendicitis, ruptured appendicitis, or subacute appendicitis, and the remaining 13 patients underwent surgery for tumoral lesions of the ileocecal region. Twenty-two of the patients underwent urgent or semi-urgent surgery, and the remaining 16 patients underwent interval appendectomy.
CONCLUSION
Xanthogranulomatous inflammation rarely affects the appendix vermiformis. It is associated with significant diagnostic and therapeutic dilemmas due to its variable presentation. It is often associated with interval appendectomies, and a significant number of patients require bowel resection due to the common presentation of a tumoral lesion. XGA is usually identified retrospectively on surgical pathology and has no unique features in preoperative diagnostic studies.
PubMed: 33552395
DOI: 10.4240/wjgs.v13.i1.76