Clinical course of longer than five years after definitive radiotherapy for nasopharyngeal carcinoma.

BACKGROUND: This study aimed to reveal the long-term outcomes and late toxicities (> 5 years) after definitive intensity-modulated radiation therapy (IMRT) in patients with nasopharyngeal carcinoma (NPC). METHODS: Data from 43 patients (median age, 55 years; range, 17-72 years) with NPC who underwent definitive IMRT between 2001 and 2018 were analyzed. All patients were alive and disease-free 5 years after IMRT. A total dose of 70 (range, 66-70) Gy was delivered in 35 (33-35) fractions with concurrent cisplatin chemotherapy. RESULTS: The median follow-up duration was 119 (range, 61.5-242.1) months. Three patients developed locoregional failure at 79, 92, and 149 months after IMRT, respectively. Of these, 2 patients died of disease progression at 136 and 153 months after IMRT. One patient died of aspiration pneumonia 141 months after IMRT, despite salvage of the recurrent tumor by re-irradiation. In addition, one patient died of aspiration pneumonia 62 months after the IMRT. Thus, the 10-year overall survival, progression-free survival, and locoregional control rates were 98%, 92%, and 94%, respectively. Grade ≥ 2 and ≥ 3 late toxicities were observed in 28 (65%) and 9 (21%) patients, respectively. Nine second primary cancers, including five tongue cancers and two external auditory canal carcinomas, were observed in seven (16%) patients. CONCLUSION: Late recurrences, severe late toxicities, and second primary cancers were observed > 5 years after IMRT. A long-term follow-up of > 5 years is needed in patients with NPC.

Aspiration pneumonia in head and neck cancer patients undergoing concurrent chemoradiation from India: Findings from a post hoc analysis of a phase 3 study.

BACKGROUND: There are limited data from low- to middle-income countries (LMIC) on the incidence, risk factors, treatment outcomes, and antibiotic susceptibility spectrum of aspiration pneumonia (AsP). METHODS: We conducted a post hoc analysis of a randomized control trial in which adult patients with locally advanced head and neck cancers had received 66-70 Gy of radiation combined with cisplatin 30 mg/m2 weekly for 6-7 weeks or cisplatin at the same dose with nimotuzumab 200 mg once weekly till the completion of radiation. The following data were extracted and analyzed-the incidence of AsP, time to the onset of AsP, risk factors, treatment outcomes of AsP, and its impact on progression-free survival (PFS), locoregional control (LRC) rates, and overall survival (OS). RESULTS: Out of 536 patients enrolled in the study, 151 (28.3%, 95% confidence interval [CI] 24.5-2.1) patients developed AsP. The median time to develop AsP was 39 days (95% CI 34-44). Only baseline dysphagia (odds ratio = 3.76, 95% CI 1.05-13.51, p = 0.042) was associated with a significant risk of development of AsP. Among the patients in which pathogenic organism was isolated (69 patients), gram-negative species was isolated in 63 patients (89%). Cisplatin at 200 mg/m2 or more was delivered in 312 (81%) patients in the non-AsP cohort versus 107 (70.9%) patients in AsP cohort (p = 0.014). There was no statistical difference in LRC (hazard ratio [HR] = 1.057; 95% CI 0.771-1.448), PFS (HR = 1.176; 95% CI 0.89-1.553), and OS (HR = 1.233; 95% CI 0.939-1.618) between the two cohorts. CONCLUSION: Aspiration pneumonia is a common complication in head and neck malignancies and patients with baseline dysphagia are at high risk. Gram-negative bacteria are the predominant causative agents. The use of broad-spectrum antibiotics results in resolution of symptoms.

Assessment of cough in head and neck cancer patients at risk for dysphagia-An overview.

BACKGROUND: This literature review explores the terminology, the neurophysiology, and the assessment of cough in general, in the framework of dysphagia and regarding head and neck cancer patients at risk for dysphagia. In the dysphagic population, cough is currently assessed perceptually during a clinical swallowing evaluation or aerodynamically. RECENT FINDINGS: Recent findings have shown intra and inter-rater disagreements regarding perceptual scoring of cough. Also, aerodynamic measurements are impractical in a routine bedside assessment. Coughing, however, is considered to be a clinically relevant sign of aspiration and dysphagia in head and cancer patients treated with concurrent chemoradiotherapy. CONCLUSION: This article surveys the literature regarding the established cough assessment and stresses the need to implement innovative methods for assessing cough in head and neck cancer patients treated with concurrent chemoradiotherapy at risk for dysphagia.

[Analysis of the major clinical-pathological discrepancies in autopsies of adults in a tertiary referral hospital between 2008-2017]. / Análisis de las principales discrepancias clínico-patológicas mayores en adultos en los estudios de autopsia de un hospital de tercer nivel en la década 2008-2017.

OBJECTIVE: To compare and contrast clinical diagnoses with autopsy findings in order to identify unexpected, relevant discrepancies. MATERIAL AND METHOD: A retrospective observational study of the revision of autopsies of adults and their respective medical records in order to classify them according to referral department and Goldman's classification was carried out at the Central University Hospital of Asturias between 2008-2017. RESULTS: 694 (52.6%) of 1320 autopsies were included in the study. Discrepancies were observed in 57.6% of cases, although the majority (39.3%) were minor. Type I discrepancies were identified in 63 autopsies (9.1%); malignant neoplasms being the main pathology observed (57.1%), mainly of gastrointestinal origin (about 28%). The second most common discrepancy was found in cases of infectious diseases (23.8%) followed by pulmonary embolism (15.9%). 64 autopsies were classified as type II discrepancies (9.2%), with myocardial infarct the most common (37.5%), especially acute myocardial infarction (18 cases), followed by bronchoaspirations (18.7%), DIC (15.6%), massive haemorrhages (9.4%) and other conditions. It was considered that both the ICU and the Internal Medicine Service were responsible for the largest number of major discrepancies (type I and II), accounting for about 45% of type I and slightly more than 56% for type II. CONCLUSION: Autopsies are an essential means of identifying ante-mortem clinical errors. The incidence of major discrepancies in the Central University Hospital of Asturias (18.3%) is comparable to that of leading hospitals worldwide.

Ethnogeographic and inter-individual variability of human ABC transporters.

ATP-binding cassette (ABC) transporters constitute a superfamily of 48 structurally similar membrane transporters that mediate the ATP-dependent cellular export of a plethora of endogenous and xenobiotic substances. Importantly, genetic variants in ABC genes that affect gene function have clinically important effects on drug disposition and can be predictors of the risk of adverse drug reactions and efficacy of chemotherapeutics, calcium channel blockers, and protease inhibitors. Furthermore, loss-of-function of ABC transporters is associated with a variety of congenital disorders. Despite their clinical importance, information about the frequencies and global distribution of functionally relevant ABC variants is limited and little is known about the overall genetic complexity of this important gene family. Here, we systematically mapped the genetic landscape of the entire human ABC superfamily using Next-Generation Sequencing data from 138,632 individuals across seven major populations. Overall, we identified 62,793 exonic variants, 98.5% of which were rare. By integrating five computational prediction algorithms with structural mapping approaches using experimentally determined crystal structures, we found that the functional ABC variability is extensive and highly population-specific. Every individual harbored between 9.3 and 13.9 deleterious ABC variants, 76% of which were found only in a single population. Carrier rates of pathogenic variants in ABC transporter genes associated with autosomal recessive congenital diseases, such as cystic fibrosis or pseudoxanthoma elasticum, closely mirrored the corresponding population-specific disease prevalence, thus providing a novel resource for rare disease epidemiology. Combined, we provide the most comprehensive, systematic, and consolidated overview of ethnogeographic ABC transporter variability with important implications for personalized medicine, clinical genetics, and precision public health.

Unusual trifecta of infections, aspiration, and metastatic prostatic adenocarcinoma in a bronchoalveolar lavage specimen.

Bronchoalveolar lavage (BAL) is a useful procedure to evaluate lung infiltrates in order to identify infection, foreign body aspiration, and neoplasms. However, it is indeed unusual to find all three in the same sample. We report such a case in a 68-year-old male with a history of metastatic prostate adenocarcinoma and longstanding chronic obstructive pulmonary disease who presented with features of pneumonia. BAL revealed Aspergillus and parainfluenza infections, food particle aspiration pneumonia, as well as metastatic prostatic adenocarcinoma. The food particles were initially confused for yeast infection, but we finally identified them as nut products. This may be the first documented case of nut product aspiration diagnosed on BAL. The potential pitfalls that may complicate the evaluation are also discussed.

Chronic granulomatous pneumonia and lung rupture secondary to aspiration of activated charcoal in a French Bulldog.

A 4-year-old, spayed female French Bulldog was presented for respiratory distress and suspected aspiration pneumonia after oral administration of activated charcoal for possible ingestion of a suspected toxic dose of trazodone. The patient had a moderate volume of pleural effusion, which contained free and intracellular black particulate matter consistent with charcoal. Due to presumed charcoal aspiration with subsequent lung rupture, the right middle and right caudal lung lobes were surgically removed. Histology revealed abundant black debris consistent with charcoal and severe granulomatous inflammation. Based on the clinical, gross, and histologic findings, a diagnosis of severe, chronic, locally extensive, aspiration pneumonia and lung rupture with secondary pleuritis and mediastinitis due to charcoal aspiration was made. Aspiration pneumonia is the main complication of activated charcoal administration, which can incite extensive, granulomatous inflammation in the respiratory tract. To the authors' knowledge, this is the first report describing the cytologic and histologic findings associated with inadvertent charcoal aspiration in a veterinary species.

Changes in the pattern of fibrosis in the rat lung with repetitive orotracheal instillations of gastric contents: evidence of persistent collagen accumulation.

Recurrent aspiration of gastric contents has been associated with several interstitial lung diseases. Despite this association, the pathogenic role of aspiration in these diseases has been poorly studied and little is known about extracellular matrix (ECM) changes in animal models of repetitive events of aspiration. Our aim was to study the repair phase of lung injury induced by each of several instillations of gastric fluid in Sprague-Dawley rats to evaluate changes in ECM and their reversibility. Anesthetized animals received weekly orotracheal instillations of gastric fluid for 1, 2, 3, and 4 wk and were euthanized at day 7 after last instillation. For reversibility studies, another group received 7 weekly instillations and was euthanized at day 7 or 60 after last instillation. Biochemical and histological measurements were used to evaluate ECM changes. Lung hydroxyproline content increased progressively and hematoxylin and eosin, Masson's trichrome, and alpha-SMA stains showed that after a single instillation, intra-alveolar fibrosis predominated, whereas with repetitive instillations this fibrosis pattern became less prominent and interstitial fibrosis progressively became evident. Both type I and III collagen increased in intra-alveolar and interstitial fibrosis. Imbalance between matrix metalloproteinase-2 (MMP-2) activity and tissue inhibitor of metalloproteinase-2 (TIMP-2) expression was observed, favoring either collagen degradation or accumulation depending on the number of instillations. Caspase-3 activation was also dose dependent. ECM changes were partially reversible at long-term evaluation, since Masson bodies, granulomas, and foreign body giant cells disappeared, whereas interstitial collagen accumulated. In conclusion, repetitive lung instillations of gastric fluid induce progressive fibrotic changes in rat lung ECM that persist at long-term evaluation.

Persistence of parenchymal and perivascular T-cells in treatment-refractory anti-N-methyl-D-aspartate receptor encephalitis.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disease mediated by IgG1 or IgG3 antibodies to the GluN1 subunit of the NMDAR, resulting in downregulation of NMDARs. Early diagnosis, prompt reduction of anti-NMDAR antibodies, and removal of associated ovarian tumors when identified are important drivers of prognosis. Immunohistochemical studies were carried out to evaluate B cell, plasma cell, and T-cell infiltrates in the brain of a 3-year-old patient with anti-NMDAR encephalitis who failed to show improvement after plasma exchange and Rituximab treatment. Complement activation was evaluated by C4d staining. Plasma cells and B-cells were rarely detected in the brain. In contrast, persistent intraparenchymal infiltrates and perivascular CD3+ T cells and evidence of complement activation were detected. Activated microglia and microglial nodules were also detected in the frontal lobes and the basal ganglia. The role of T cells and complement activation should be investigated in patients who do not respond to plasma exchange and Rituximab treatment.

Congenital myopathy due to myosin heavy chain 2 mutation presenting as chronic aspiration pneumonia in infancy.

A 7-week-old infant presented with persistent noisy breathing and aspirations during swallowing. Neurological examination and brain MRI were normal. His 12-year-old brother underwent pneumonectomy at the age of 10 years due to recurrent aspirations leading to severe lung damage. The older brother developed subsequently ophthalmoplegia and nystagmus along with mild weakness of the neck flexors and proximal muscles. Exome analysis revealed homozygosity for a novel truncating mutation p.G800fs27* in the Myosin Heavy Chain 2 (MYH2) gene in both brothers, while parents and an unaffected sibling were heterozygous. A muscle biopsy from the older brother showed absence of type-2 muscle fibers and predominance of type-1 fibers. The aspirations causing pneumonia likely result from weakness of the laryngeal muscles, normally rich in type-2 fibers. The findings expand the phenotypic spectrum of MYH2 deficiency. MYH2 mutations should be included in the differential diagnosis of infants presenting with recurrent aspirations.

Transbronchial Cryobiopsy in Diffuse Parenchymal Lung Disease: Retrospective Analysis of 74 Cases.

BACKGROUND: Diagnostic evaluation of patients with diffuse parenchymal lung disease (DPLD) is best achieved by a multidisciplinary team correlating clinical, radiological, and pathologic features. Surgical lung biopsy remains the gold standard for histopathologic diagnosis of idiopathic interstitial pneumonias. Emerging data suggest an increasing role for transbronchial cryobiopsy (TBC) in DPLD evaluation. We describe our experience with TBC in patients with DPLD. METHODS: We retrospectively reviewed medical records of patients with radiographic features of DPLD who underwent TBC at Mayo Clinic in Rochester, Minnesota from June 2013 to September 2015. RESULTS: Seventy-four patients (33 women [45%]) with a mean age of 63 years (SD, 13.8) were included. The mean maximal diameter of the samples was 9.2 mm (range, 2-20 mm [SD, 3.9]). The median number of samples per procedure was three (range, one to seven). Diagnostic yield was 51% (38 of 74 specimens). The most frequent histopathologic patterns were granulomatous inflammation (12 patients) and organizing pneumonia (OP) (11 patients), resulting in the final diagnoses of hypersensitivity pneumonitis (six patients), cryptogenic OP (six patients), connective tissue disease-associated OP (three patients), drug toxicity (three patients), infection-related OP (two patients), sarcoidosis (two patients), and aspiration (one patient). Other histopathologic patterns included respiratory bronchiolitis (three patients), acute fibrinous and organizing pneumonia (two patients), desquamative interstitial pneumonia (1 patient), diffuse alveolar damage (one patient), pulmonary alveolar proteinosis (one patient), amyloidosis (one patient), eosinophilic pneumonia (one patient), necrotizing vasculitis (one patient), bronchiolitis with food particles (one patient), and malignancy (three patients). Pneumothorax developed in one patient (1.4%), and bleeding occurred in 16 patients (22%). CONCLUSIONS: Our single-center cohort demonstrated a 51% diagnostic yield from TBC; the rates of pneumothorax and bleeding were 1.4% and 22%, respectively. The optimal use of TBC needs to be determined.

Bone-marrow-derived mesenchymal stem cells inhibit gastric aspiration lung injury and inflammation in rats.

Gastric aspiration lung injury is one of the most common clinical events. This study investigated the effects of bone-marrow-derived mesenchymal stem cells (BMSCs) on combined acid plus small non-acidified particle (CASP)-induced aspiration lung injury. Enhanced green fluorescent protein (EGFP(+) ) or EGFP(-) BMSCs or 15d-PGJ2 were injected via the tail vein into rats immediately after CASP-induced aspiration lung injury. Pathological changes in lung tissues, blood gas analysis, the wet/dry weight ratio (W/D) of the lung, levels of total proteins and number of total cells and neutrophils in bronchoalveolar lavage fluid (BALF) were determined. The cytokine levels were measured using ELISA. Protein expression was determined by Western blot. Bone-marrow-derived mesenchymal stem cells treatment significantly reduced alveolar oedema, exudation and lung inflammation; increased the arterial partial pressure of oxygen; and decreased the W/D of the lung, the levels of total proteins and the number of total cells and neutrophils in BALF in the rats with CASP-induced lung injury. Bone-marrow-derived mesenchymal stem cells treatment decreased the levels of tumour necrosis factor-α and Cytokine-induced neutrophil chemoattractant (CINC)-1 and the expression of p-p65 and increased the levels of interleukin-10 and 15d-PGJ2 and the expression of peroxisome proliferator-activated receptor (PPAR)-γ in the lung tissue in CASP-induced rats. Tumour necrosis factor-α stimulated BMSCs to secrete 15d-PGJ2 . A tracking experiment showed that EGFP(+) BMSCs were able to migrate to local lung tissues. Treatment with 15d-PGJ2 also significantly inhibited CASP-induced lung inflammation and the production of pro-inflammatory cytokines. Our results show that BMSCs can protect lung tissues from gastric aspiration injury and inhibit lung inflammation in rats. A beneficial effect might be achieved through BMSC-derived 15d-PGJ2 activation of the PPAR-γ receptor, reducing the production of proinflammatory cytokines.

Could prominent airway-centered fibroblast foci in lung biopsies predict underlying chronic microaspiration in idiopathic pulmonary fibrosis patients?

Chronic occult aspiration of small droplets (microaspiration) due to gastroesophageal reflux disease (GERD) and/or hiatal hernia is postulated to be a contributing factor in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Usual interstitial pneumonia (UIP) is the histopathologic correlate of IPF. We hypothesized that chronic microaspiration may manifest as prominent airway-centered fibroblastic foci (FFs) in IPF. UIP cases diagnosed by wedge biopsies over a 6-year period (2006-2011) were identified and scored (1-3) for the prominence of airway-centered FFs by 2 authors blinded for clinical history. Relevant clinical information was obtained. Thirty-seven patients (22 men) were diagnosed with IPF by multidisciplinary approach. Thirteen cases (35.1%) demonstrated high airway-centered FF score (score 3). Twenty (54.1%) patients carried a clinical diagnosis of GERD, and 3 patients (8.1%) had hiatal hernia. High airway-centered FF score was significantly associated with hiatal hernia diagnosis (P=.037) but not with a diagnosis of GERD or the use of proton pump inhibitors/histamine-2 receptor antagonists. High airway-centered FF score was associated with airway-centered acute inflammation (P=.028) and peribronchiolar granulomas (P=.042). In summary, IPF cases with hiatal hernia were more likely to have a prominent airway-centered FF. Given the strong association between hiatal hernia and GERD and their risk for developing chronic microaspiration, the prominent airway-centered FF in UIP might predict the presence of chronic microaspiration, acknowledging that GERD and proton pump inhibitor/histamine-2 receptor antagonist use failed to demonstrate a significant association. Larger studies are warranted for further investigation.

Gingipains: Critical Factors in the Development of Aspiration Pneumonia Caused by Porphyromonas gingivalis.

Aspiration pneumonia is a life-threatening infectious disease often caused by oral anaerobic and periodontal pathogens such as Porphyromonas gingivalis. This organism produces proteolytic enzymes, known as gingipains, which manipulate innate immune responses and promote chronic inflammation. Here, we challenged mice with P. gingivalis W83 and examined the role of gingipains in bronchopneumonia, lung abscess formation, and inflammatory responses. Although gingipains were not required for P. gingivalis colonization and survival in the lungs, they were essential for manifestation of clinical symptoms and infection-related mortality. Pathologies caused by wild-type (WT) P. gingivalis W83, including hemorrhage, necrosis, and neutrophil infiltration, were absent from lungs infected with gingipain-null isogenic strains or WT bacteria preincubated with gingipain-specific inhibitors. Damage to lung tissue correlated with systemic inflammatory responses, as manifested by elevated levels of TNF, IL-6, IL-17, and C-reactive protein. These effects were unequivocally dependent on gingipain activity. Gingipain activity was also implicated in the observed increase in IL-17 in lung tissues. Furthermore, gingipains increased platelet counts in the blood and activated platelets in the lungs. Arginine-specific gingipains made a greater contribution to P. gingivalis-related morbidity and mortality than lysine-specific gingipains. Thus, inhibition of gingipain may be a useful adjunct treatment for P. gingivalis-mediated aspiration pneumonia.

Aspiration pneumonia in an infant with neurological sequelae - case report.

Aspiration pneumonia is a frequent cause of morbidity and mortality in children with neurological deficits. We present the case of a 4-month-old infant from the Foster Care Center, with severe psychomotor retardation, blindness, and associated cardiac malformation, who was admitted to the Pediatrics Clinic of the Emergency County Hospital of Craiova, Romania, presenting aspiration pneumonia and moderate respiratory insufficiency. Under sustained, early instituted treatment, the evolution was towards death. The chest radiography and histopathological examination of the pulmonary tissue confirmed the diagnosis. The neurological impairment was not only a favoring factor for aspiration, through the deglutition disorders, but it was also an aggravating one, through the bacterial colonization of the lungs.

Diffuse aspiration bronchiolitis: analysis of 20 consecutive patients.

OBJECTIVE: Aspiration can cause a variety of pulmonary syndromes, some of which are not well recognized. The objective of this study was to assess the demographic, clinical, radiological, and histopathological correlates of diffuse aspiration bronchiolitis (DAB), a bronchiolocentric disorder caused by recurrent aspiration. METHODS: This was a retrospective study of 20 consecutive patients with DAB seen at the Mayo Clinic in Rochester, Minnesota, between January 1, 1998 and June 30, 2014. RESULTS: The median age of the patients was 56.5 years (range, 22-76 years), and the male/female ratio was 2.3:1.0. In 18 patients, the diagnosis of DAB was based on the results of a lung biopsy; in the 2 remaining patients, it was based on clinical and radiological features, together with documented aspiration observed in a videofluoroscopic swallow study. In 19 patients (95%), we identified predisposing factors for aspiration, including gastroesophageal reflux disease (GERD), drug abuse, and dysphagia. Common presenting features included cough, sputum production, dyspnea, and fever. Twelve patients (60%) had a history of recurrent pneumonia. In all of the patients, chest CT revealed bilateral pulmonary infiltrates consisting of micronodules and tree-in-bud opacities. In the majority of patients, interventions aimed at preventing recurrent aspiration (e.g., anti-GERD therapies) led to improvement in the symptoms of DAB. CONCLUSIONS: Young to middle-aged subjects with recognizable predisposing factors for aspiration and who report a history of recurrent pneumonia are at increased risk for DAB. Although DAB is not well recognized, certain chest CT features are characteristic of the disorder.