Do Not Miss Acute Diffuse Panbronchiolitis for Tree-in-Bud: Case Series of a Rare Lung Disease.

Acute bronchiolitis is a common disease of infants affecting the small airways. Rarely, acute bronchiolitis may occur in adolescents and adults. Here, we present four unrelated adolescent patients with severe clinical presentation and unique CT imaging with extensive tree-in-bud pattern, representing a rare clinical phenotype of acute diffuse panbronchiolitis. This characteristic disease pattern caused by inhalation injury from waterpipes, smoked tobacco, and cannabinoids must be differentiated from e-cigarette or vaping product-use-associated lung injury (EVALI). Visual diagnosis of CT and an early diagnostic procedure for detection and differentiation of inhaled hazards, including sample storage for future identification of novel noxious agents, are warranted.

A spark of hope: histopathological and functional recovery after critical COVID-19.

BACKGROUND: There are substantial concerns about fibrotic and vascular pulmonary sequelae after coronavirus disease 2019 (COVID-19) associated acute respiratory distress syndrome (ARDS).AQ1 Histopathology reports of lung biopsies from COVID-19 survivors are scarce. CASE: We herein report results of functional and histopathological studies in a 70 year-old man undergoing a co-incidental tumor lobectomy six months after long-term mechanical ventilation for COVID-19 pneumonia. CONCLUSION: Despite several unfavorable risk factors, this case presentation shows a completed pulmonary recovery process within a few months.

Assessing global COPD awareness with Google Trends.

Although chronic obstructive pulmonary disease (COPD) prevalence and mortality rates rise continuously, patients often remain undiagnosed, probably due to a lack of disease-related awareness. The aim of this study was to quantify public interest in COPD by analysing the frequency of web queries via Google.Data from 2004 to 2018 were collected using the search engine query data analysis tool Google Trends. The relative search volume of the topic "chronic obstructive pulmonary disease" was compared with the relative search volume of nine topics representing the major causes of death in high-income countries according to the World Health Organization.Our analysis showed highest relative search volumes for the topics "diabetes mellitus", followed by "stroke" and "breast cancer". The topic "chronic obstructive pulmonary disease" ranked eighth and its relative search volume clearly displayed a seasonal variation, with peaks in the first and the fourth quarter of the year.This analysis reveals that COPD is highly under-represented in the public interest, while real-world prevalence constantly rises, indicating that there is still an urgent need to raise the levels of awareness for COPD.

Increase in antibody-dependent cellular cytotoxicity (ADCC) in a patient with advanced colorectal carcinoma carrying a KRAS mutation under lenalidomide therapy.

The failure of EGFR inhibitors in colorectal tumors with KRAS mutations requires the development of alternative treatment strategies for this patient subgroup. Among the hallmarks of cancer the disturbed immunosurveillance and cancer immune evasion have become emerging targets for cancer therapy. Due to their pleiotropic functions immunomodulatory drugs (IMiDs) are interesting agents for combination therapies in solid tumors. However, their possible contribution and a way of monitoring their biological effects have yet to be revealed. In a heavily pretreated patient with advanced colorectal cancer carrying mutations in APC and KRAS genes, we show an early metabolic response and enhanced NK cell activity to monotherapy with lenalidomide. After subsequent lenalidomide/cetuximab combination treatment, the patient had progressive disease. At the same time a reduced performance status, complicated by febrile neutropenia, occurred, as well as a slight increase in metabolic activity. Concordantly NK cell activity dropped back to baseline. Thus, laboratory measurements and metabolic response assessment correlated with clinical conditions. This case report describes the feasibility and potential of a functional assessment of patient derived immune competent cells in combination with functional imaging for the detection of a biological response.

Diagnostic and therapeutic challenges of a large pleural inflammatory myofibroblastic tumor.

We report a 48-year-old woman with a pleural pseudoneoplasm requiring different diagnostic and therapeutic strategies. After initial presentation with increasing dyspnoea, temperature, dry cough, and interscapular pain diagnostic processing showed a large mediastinal mass with marked pleural effusion and high metabolic activity in the 18F-FDG-PET/CT. Extensive CT-guided biopsy of the tumor reaching from the visceral pleura into the right upper lobe revealed no malignancy, but a marked inflammatory tissue reaction containing foam cells. Initial empiric antibiotic therapy was temporarily successful. However, in the further course the mass relapsed and was resistant to antibiotics and a corticosteroid trial. With the working hypothesis of an inflammatory myofibroblastic tumor the patient underwent surgical tumor resection, finally confirming the suspected diagnosis. Due to residual disease intravenous immunoglobulins were administered leading to sustained response. This case with a pleural localisation of a large inflammatory pseudotumor with responsiveness to immunomodulation after incomplete resection extends the reported spectrum of thoracopulmonary manifestations of this rare entity.

AKR1B10 expression is associated with less aggressive hepatocellular carcinoma: a clinicopathological study of 168 cases.

BACKGROUND/AIMS: The detoxification enzyme AKR1B10, a member of the aldo-keto reductase superfamily, is discussed as a new biomarker candidate for hepatocellular carcinoma (HCC). Only rare clinicopathological data on AKRB1B10 in HCC exist. This retrospective study determines the diagnostic and prognostic relevance of AKR1B10 expression in HCC and its relationship to a series of clinicopathological parameters including underlying aetiological factors. METHODS: A series of 168 patients with HCCs treated either by surgical resection (n=92) or liver transplantation (n=76) were investigated after construction of a tissue micro-array. Immunohistochemically confirmed AKR1B10 expression was correlated with clinicopathologically relevant parameters as well as proliferative activity (indicated by Ki-67 immunostaining) and apoptosis (terminal deoxyribonucleotide transferase-mediated dUTP nick-end labelling). RESULTS: AKR1B10 overexpression is significantly associated with lower pT-classification (P=0.030) and highly statistically associated with an underlying viral hepatitis (P<0.001) and the presence of cirrhosis (P<0.001). In addition, loss of AKR1B10 expression correlates with increased proliferative activity (Ki-67, P=0.001). Kaplan-Meier survival analysis of the resection group reveals a poorer prognosis in patients with AKR1B10-negative HCCs compared with patients with strongly positive HCCs (P=0.046). CONCLUSIONS: This study confirms and expands data on the expression of AKR1B10 in HCC, suggesting that this enzyme is a valuable novel biomarker candidate for staging of HCC, especially in patients with underlying virus hepatitis or cirrhosis, and may present a new therapeutic target for multimodal therapy concepts. We confirm its prognostic value and conclude that high expression of AKR1B10 reflects a less aggressive tumour behaviour.

Molecularly targeted therapies for colorectal cancer: Strategies for implementing translational research in clinical trials.

Few breakthroughs in preclinical research have translated into meaningful benefits, either in clinical terms or quality of life, for patients with advanced colorectal cancer, despite important preclinical discoveries regarding aberrant biological pathways associated with disease development and progression. The many reasons for the slow progress are diverse, ranging from the failure to codevelop biomarkers and targeted therapies, the regulatory burdens imposed on academic investigators, and the failure to collect serial tumor biopsies during clinical trials. This review discusses promising translational research that could help reduce the disparity between preclinical discovery and patient benefit, and advocate the concentration of efforts and resources on the most promising therapeutic targets in colorectal cancer, such as EGFR, VEGF and Fcγ receptor.

Identification of a 4.9-kilo base-pair Alu-mediated founder SDHD deletion in two extended paraganglioma families from Austria.

Hereditary paraganglioma (PGL) is characterized by the development of highly vascularized paraganglionic tumors as a result of germline mutations in the SDHB, SDHC or SDHD subunit genes of succinate dehydrogenase (SDH; mitochondrial complex II), or in the Von Hippel-Lindau tumor-suppressor gene. Although many PGL mutations have been described, gross SDHD deletions have not yet been implicated as founder mutations and are rarely characterized at the DNA sequence level. We investigated the genetic basis of head and neck PGLs observed in 20 subjects from two unrelated multiplex pedigrees from Austria and identified a 4944-base pair partial SDHD deletion, which escaped PCR-based detection methods. The deletion occurred between Alu elements and was present within the same haplotype context in both pedigrees, indicating a founder effect. The deletion caused tumors only after a paternal transmission similar to other conventional SDHD mutations, suggesting preservation of genomic imprinting mechanisms operating at this locus. These data describe a large SDHD deletion at the genomic sequence level and indicate that gross SDHD deletions could be a founder PGL mutation in certain populations.

Proteomic identification of aldo-keto reductase AKR1B10 induction after treatment of colorectal cancer cells with the proteasome inhibitor bortezomib.

Targeting the ubiquitin-proteasome pathway with the proteasome inhibitor bortezomib has emerged as a promising approach for the treatment of several malignancies. The cellular and molecular effects of this agent on colorectal cancer cells are poorly characterized. This study investigated the antiproliferative effect of bortezomib on colorectal cancer cell lines (Caco-2 and HRT-18). In order to define the proteins potentially involved in the mechanisms of action, proteome profiling was applied to detect the proteins altered by bortezomib. The in vitro efficacy of bortezomib as a single agent in colorectal cancer cell lines was confirmed. Proteome profiling with two-dimensional PAGE followed by mass spectrometry revealed the up-regulation of the major inducible isoform of heat shock protein 70 (hsp72) and lactate dehydrogenase B in both cell lines, as well as the induction of aldo-keto reductase family 1 member B10 (AKR1B10) in HRT-18 cells. Both AKR1B10 and hsp72 exert cell-protective functions. This study shows for the first time a bortezomib-induced up-regulation of AKR1B10. Small interfering RNA-mediated inhibition of this enzyme with known intracellular detoxification function sensitized HRT-18 cells to therapy with the proteasome inhibitor. To further characterize the relevance of AKR1B10 for colorectal tumors, immunohistochemical expression was shown in 23.2% of 125 tumor specimens. These findings indicate that AKR1B10 might be a target for combination therapy with bortezomib.

EGFR inhibition as a therapy for head and neck squamous cell carcinoma.

BACKGROUND: Improved understanding of disease biology of head and neck squamous cell carcinoma (HNSCC) with nearly universal expression of EGFR has led to the introduction of targeted therapies to interrupt signalling of this negative prognostic marker. OBJECTIVE: We performed a literature review on the mechanisms and efficacy of anti-EGFR antibodies and EGFR tyrosine kinase inhibitors in patients with locally advanced or recurrent/metastatic HNSCC. RESULTS/CONCLUSION: Clinical trials in HNSCC have administered EGFR directed drugs as single agents, in combination with chemotherapy or radiotherapy and demonstrated a good safety profile with antitumour activity in a subgroup of patients. The biology of responsiveness is still unclear, although there is growing evidence of an association of skin toxicity or presence of shorter EGFR intron 1 cytosine-adenine repeats with positive outcome.

Identification of the rare EGFR mutation p.G796S as somatic and germline mutation in white patients with squamous cell carcinoma of the head and neck.

BACKGROUND: Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) are involved in tumorigenesis and response to targeted therapies in distinct cancer types. Squamous cell carcinomas of the head and neck (HNSCC) show an incidence of EGFR mutations varying from 7% in Asians to 0% to 4% in white patients. Mutational screening predominantly focuses on the analysis of hotspot regions of EGFR (exons 19 and 21). METHODS: In a follow-up study, we screened for mutations in exons 18 to 21 of the EGFR gene in 127 patients. RESULTS: In this cohort, a mutation frequency of 2.4% (3/127) was detected. In addition to the previously reported mutation p.K745R, the otherwise rare EGFR mutation p.G796S occurred in 2 patients with HNSCC (2/127). CONCLUSION: EGFR kinase mutations are rare in white patients with HNSCC. Extension of mutational screening to exon 20 may clarify the frequency and impact of the mutation p.G796S.

Targeted therapies in non-small cell lung cancer: proven concepts and unfulfilled promises.

Targeted therapies focus on signaling pathways in cancer cells and other molecular processes involved in oncogenesis. Recent approaches affect the following major groups: the epidermal growth factor receptor (EGFR)-family, angiogenesis, the eicosanoid pathway, the PKC/ Ras/ MAPK pathway, the proteasome and inducers of apoptosis. Numerous phase I and II trials have provided promising results and recently, anti-EGFR and anti-VEGF treatments have proven their efficacy in phase III trials. However, others failed in phase III settings (e.g. PKC- and matrix metalloproteinase inhibitors) and it is a moot point, whether patients have been selected properly. The huge amount of new medications raises questions like when to use which strategy in which sequence. The successful implementation of targeted agents into clinical routine will depend on the verification of sufficient predictive markers, allowing their economically reasonable usage. In the current review the up-to-date knowledge concerning targeted therapies in NSCLC is summarized and their therapeutical potential is discussed.

Low incidence of mutations in EGFR kinase domain in Caucasian patients with head and neck squamous cell carcinoma.

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are associated with increased sensitivity to tyrosine kinase inhibitors (TKIs) and are present in 10-30% of non-small cell lung carcinoma depending on ethnic origin. EGFR protein is also overexpressed in about 90% of squamous cell carcinoma of head and neck (HNSCC), and treatment with TKIs has shown clinical benefit in a subgroup of these patients. Recently, EGFR mutations were described in three Asian patients with larynx cancer. We screened for EGFR tyrosine kinase mutations in tumour DNA of 100 patients of Caucasian origin with HNSCC by direct sequencing of the hotspot regions. Only one patient with larynx cancer displayed a novel, somatic EGFR missense mutation, K745R, affecting a highly conserved residue within the ATP cleft. Similar to reports in lung cancer, EGFR kinase domain mutations in HNSCC patients seem to show a lower incidence in patients of Caucasian origin.

Gefitinib-responsive EGFR-positive colorectal cancers have different proteome profiles from non-responsive cell lines.

Biomarkers that predict response to therapy with inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase remain largely uncharacterized. In order to define proteins involved in potential resistance mechanisms, we examined the effect of gefitinib (ZD1839, Iressa) in the EGFR-positive colon cancer cell lines Caco-2, DiFi, HRT-18 and HT-29. None of them exhibited an activating mutation in exons 19 or 21 of EGFR. Proteome profiling with two-dimensional polyacrylamide gel electrophoresis followed by mass spectrometry revealed 12 proteins differentially expressed in responsive and non-responsive cells. These proteins are involved in metabolic pathways, partially relevant in malignant growth and four of them are known to interact with the EGFR signalling pathway. Ubiquitin carboxyl-terminated hydrolase isozyme L1 (UCH-L1) and galectin-3 are overexpressed in the responsive cell line Caco-2, whereas fatty acid-binding protein (E-FABP) and heat shock protein (hsp) 27 are expressed more in the resistant cell lines HRT-18 and HT-29 suggesting a role in non-responsiveness of cells to gefitinib.

Different proteome pattern of epidermal growth factor receptor-positive colorectal cancer cell lines that are responsive and nonresponsive to C225 antibody treatment.

The monoclonal antibody C225 directed against the epidermal growth factor receptor (EGFR) blocks downstream mitogenic signaling and is effective in patients with advanced colorectal cancer. Clinical data, however, suggest the presence of primary and secondary resistance mechanisms that are hardly understood. To define proteins involved in EGFR-triggered growth regulation and potential resistance mechanisms, we characterized the proteome profile of two colorectal cancer cell lines with a high expression of functional EGFR but a different response to treatment with C225. In Caco-2 and HRT-18, a complete saturation of EGFR was achieved after incubation with C225; whereas Caco-2 showed inhibition of proliferation, growth of HRT-18 was not suppressed. Using two-dimensional electrophoresis and subsequent mass spectrometry, we identified 14 proteins differentially expressed in both cell lines. All proteins are involved in metabolic pathways and malignant growth. Expression of enzymes such as ubiquitin carboxyl-terminal hydrolase isozyme 1, glutathione S-transferase P, and chloride intracellular channel protein 1 does not seem to interfere with the antiproliferative effect of anti-EGFR antibody. On the other hand, expression of proteins such as fatty acid binding protein and heat shock protein 27 might constitute strong antiapoptotic effects contributing to the nonresponse of HRT-18 to C225 treatment. Proteome-based investigations can help us better understand the complex protein interactions involved in EGFR signaling and its blockage by therapeutic monoclonal antibodies.