RESUMEN
BACKGROUND: In lung transplant recipients (LTRs), restrictive ventilation disorder may be present due to respiratory muscle dysfunction that may reduce exercise capacity. This might be mediated by pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). OBJECTIVE: We investigated lung respiratory muscle function as well as circulating pro-inflammatory cytokines and exercise capacity in LTRs. METHODS: Fifteen LTRs (6 female, age 56 ± 14 years, 63 ± 45 months post-transplantation) and 15 healthy controls matched for age, sex, and body mass index underwent spirometry, measurement of mouth occlusion pressures, diaphragm ultrasound, and recording of twitch transdiaphragmatic (twPdi) and gastric pressures (twPgas) following magnetic stimulation of the phrenic nerves and the lower thoracic nerve roots. Exercise capacity was quantified using the 6-min walking distance (6MWD). Plasma IL-6 and TNF-α were measured using enzyme-linked immunosorbent assays. RESULTS: Compared with controls, patients had lower values for forced vital capacity (FVC; 81 ± 30 vs.109 ± 18% predicted, p = 0.01), maximum expiratory pressure (100 ± 21 vs.127 ± 17 cm H2O, p = 0.04), diaphragm thickening ratio (2.2 ± 0.4 vs. 3.0 ± 1.1, p = 0.01), and twPdi (10.4 ± 3.5 vs. 17.6 ± 6.7 cm H2O, p = 0.01). In LTRs, elevation of TNF-α was related to lung function (13 ± 3 vs. 11 ± 2 pg/mL in patients with FVC ≤80 vs. >80% predicted; p < 0.05), and lung function (forced expiratory volume after 1 s) was closely associated with diaphragm thickening ratio (r = 0.81; p < 0.01) and 6MWD (r = 0.63; p = 0.02). CONCLUSION: There is marked restrictive ventilation disorder and respiratory muscle weakness in LTRs, especially inspiratory muscle weakness with diaphragm dysfunction. Lung function impairment relates to elevated levels of circulating TNF-α and diaphragm dysfunction and is associated with exercise intolerance.
Asunto(s)
Diafragma/diagnóstico por imagen , Tolerancia al Ejercicio/fisiología , Interleucina-6/sangre , Trasplante de Pulmón , Fuerza Muscular/fisiología , Complicaciones Posoperatorias/fisiopatología , Trastornos Respiratorios/fisiopatología , Factor de Necrosis Tumoral alfa/sangre , Adulto , Anciano , Fibrosis Quística/cirugía , Diafragma/fisiopatología , Femenino , Humanos , Masculino , Presiones Respiratorias Máximas , Persona de Mediana Edad , Complicaciones Posoperatorias/sangre , Enfermedad Pulmonar Obstructiva Crónica/cirugía , Fibrosis Pulmonar/cirugía , Trastornos Respiratorios/sangre , Músculos Respiratorios , Capacidad Vital , Prueba de PasoRESUMEN
BACKGROUND: Follicular lymphoma (FL) is the most frequent indolent lymphoma subtype in adults. Maintenance therapy with rituximab is frequently applied to FL patients with complete or partial response following initial chemoimmunotherapy. However, radioimmunotherapy with 90 Y-ibritumomab-tiuxetan represents a therapeutic alternative. METHODS: To compare the clinical and the prognostic impact of both therapies, a study collective of n = 56 patients diagnosed with indolent B-cell lymphoma was retrospectively investigated. The study collective was subdivided into two groups: n = 36 patients treated with rituximab maintenance therapy vs n = 20 patients treated with 90 Y-ibritumomab-tiuxetan. RESULTS: No prognostic differences for performance status, FLIPI score, gender, or B-symptoms were found for 90 Y-ibritumomab-tiuxetan or rituximab maintenance therapy. Overall survival rates and progression-free survival did not differ between both maintenance therapies. CONCLUSION: Our retrospective single-center analysis of two patient groups without major differences in prognostic parameters revealed similar outcome with two different maintenance therapies. Hence, 90 Y-ibritumomab-tiuxetan therapy might offer a valuable alternative treatment option for FL patients with partial response. However, large prospective trials are needed to confirm the reported findings.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Inmunoconjugados/uso terapéutico , Linfoma Folicular/terapia , Radioisótopos de Itrio/uso terapéutico , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Terapia Combinada , Femenino , Humanos , Inmunoconjugados/administración & dosificación , Inmunoconjugados/efectos adversos , Linfoma Folicular/mortalidad , Linfoma Folicular/patología , Quimioterapia de Mantención , Masculino , Persona de Mediana Edad , Imagen Multimodal , Estadificación de Neoplasias , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Histoplasmosis in central Europe is a rare fungal disease with diverse clinical presentations. Apart from acute pulmonary histoplasmosis and involvement of the central nervous system, the most serious clinical presentation is progressive disseminated histoplasmosis which is generally associated with severe immunodeficiency and, in particular, advanced human immunodeficiency virus infection. Here, we report on an immunocompetent female residing in a non-endemic area, presenting with progressive disseminated histoplasmosis after a remote travel history to Thailand and Costa Rica. Diagnosis was delayed by several months due to misinterpretation of epithelioid cell granulomatosis of the intestine as Crohn's disease and of similar lung lesions as acute sarcoidosis. Prompted by clinical deterioration with signs and symptoms consistent with hemophagocytic lymphohistiocytosis, a bone marrow aspiration was performed that documented hemophagocytosis and intracellular organisms interpreted as Leishmania sp., but later identified by molecular methods as Histoplasma capsulatum. Treatment with liposomal amphotericin B followed by posaconazole led to prompt clinical improvement and ultimately cure.
Asunto(s)
Células Epitelioides/patología , Histoplasmosis/complicaciones , Histoplasmosis/diagnóstico , Linfohistiocitosis Hemofagocítica/complicaciones , Linfohistiocitosis Hemofagocítica/diagnóstico , Biomarcadores , Biopsia , Médula Ósea/patología , Endoscopía , Femenino , Humanos , Ganglios Linfáticos/patología , Linfohistiocitosis Hemofagocítica/terapia , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos XRESUMEN
HIV-positive patients with acquired immunodeficiency syndrome (AIDS) often require treatment on intensive care units (ICUs). We aimed to present data from a German, low-incidence region cohort, and subsequently evaluate factors measured during the first 24 h of ICU stay to predict short- and long-term survival, and compare with data from high-incidence regions. We documented 62 patient courses between 2009 and 2019, treated on a non-operative ICU of a tertiary care hospital, mostly due to respiratory deterioration and co-infections. Of these, 54 patients required ventilatory support within the first 24 h with either nasal cannula/mask (n = 12), non-invasive ventilation (n = 16), or invasive ventilation (n = 26). Overall survival at day 30 was 77.4%. While ventilatory parameters (all p < 0.05), pH level (c/o 7.31, p = 0.001), and platelet count (c/o 164,000/µL, p = 0.002) were significant univariate predictors of 30-day and 60-day survival, different ICU scoring systems, such as SOFA score, APACHE II, and SAPS 2 predicted overall survival (all p < 0.001). Next to the presence or history of solid neoplasia (p = 0.026), platelet count (HR 6.7 for <164,000/µL, p = 0.020) and pH level (HR 5.8 for <7.31, p = 0.009) remained independently associated with 30-day and 60-day survival in multivariable Cox regression. However, ventilation parameters did not predict survival multivariably.
Asunto(s)
VIH-1 , Humanos , Centros de Atención Terciaria , Pronóstico , Unidades de Cuidados Intensivos , Factores de Riesgo , Estudios RetrospectivosRESUMEN
Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide and its most important risk factor is tobacco smoking. While smoking is associated with inferior outcome in NSCLC patients, smoking also correlates with a higher tumor mutational burden. In contrast to adenocarcinomas (ADC) of non-smokers, that frequently harbor targetable gain-of-function mutations, NSCLC smokers largely present with non-targetable loss-of-function mutations of genes associated with DNA-damage repair. The transcription factor Pit-1, Oct1/2, Unc-86 (POU) domain class 2 transcription factor 1 (POU2F1) is a widely expressed bipotential stabilizer of repressed and inducible transcriptional states and frequently deregulated in cancer. Methods: Via immunohistochemistry, we evaluated POU2F1 protein expression on a tissue micro array of 217 operable stage I-III NSCLC patients. Findings were reproduced in a gene expression database of 1144 NSCLC patients, filtered for POU2F1 mRNA expression. After retroviral overexpression of POU2F1 in A549 cells, we evaluated for clonogenic growth and proliferation. Additionally, CRISPR-Cas9 mediated POU2F1 knockdown in A549 cells was likewise analyzed. Results: High protein expression of POU2F1 in 217 NSCLC patients resulted in improved outcome of smokers with ADC [hazard ratio (HR) 0.30 (0.09-0.99), P=0.035]. Moreover, gene expression analysis confirmed favorable outcome of high POU2F1 mRNA expression in smokers with ADC [HR 0.41 (0.24-0.69), P<0.001]. Other than that, retrovirally induced overexpression of POU2F1 in A549 cells significantly reduced both, clonogenic growth as well as proliferation of NSCLC cells, whereas CRISPR-Cas9 mediated knockdown of the protein did not have any impact. Conclusions: Our data suggest that high expression of POU2F1 mediates a less aggressive cancer phenotype in smokers with ADC NSCLC. Pharmacological induction of genes and signaling pathways controlled by POU2F1 may provide novel avenues for future targeted NSCLC therapies in smokers.
RESUMEN
BACKGROUND: Central airway obstruction (CAO) is one of the most challenging, potentially lethal complications in malignant and benign respiratory diseases. Worsening dyspnea is also a relevant cause for reduced quality of life in such patients. Here, we present our data on the application of covered, self-expanding Y-carina nitinol stents due to benign and malignant diseases. METHODS: We retrospectively identified 27 patients who had undergone 31 rigid bronchoscopies with implantation of covered Y-carina nitinol stents over a period of 10 years in order to evaluate indication, clinical course, and outcome. RESULTS: Short-term survival of successfully stented patients with palliative and curative treatment goal did not differ, allowing for diagnosis independent indication. With respect to overall survival, patients with endoluminal obstruction benefited most compared to patients with fistula and/or external compression. Granulation tissue formation (61.3%) and mucus plugging (80.6%) were the most frequent complications. Material defect (6.5%) and migration (3.2%) were rare complications that could be handled by revisional rigid bronchoscopy and stent exchange in some cases. CONCLUSIONS: Implantation of self-expanding covered Y-carina nitinol stents via rigid bronchoscopy is a feasible and safe treatment option for benign and malignant central airway obstruction. Especially in palliative, malignant airway stenosis, stenting might facilitate additional treatment options and optimize dyspnea and eventually quality of life.
Asunto(s)
Obstrucción de las Vías Aéreas , Calidad de Vida , Obstrucción de las Vías Aéreas/etiología , Obstrucción de las Vías Aéreas/cirugía , Aleaciones , Broncoscopía/métodos , Humanos , Estudios Retrospectivos , Stents/efectos adversos , Resultado del TratamientoRESUMEN
Via immunohistochemistry (IHC) on tissue micro arrays (TMA) clinical and prognostic impact of p53 co-playing 5'-Nucleotidase Domain-Containing Protein 2 (NT5DC2) protein expression was evaluated in 252 NSCLC patients. Confirmatory, gene expression database. mRNA levels of NT5DC2 were studied in 1925 NSCLC patients. High protein expression of NT5DC2 resulted in reduced median overall survival (OS) of patients with stage I-III adenocarcinoma (ADC) (Log Rank p = 0.026, HR 2.04 (1.08−3.87)), but not in squamous cell carcinoma (SCC) (p = 0.514, HR 0.87 (0.57−1.33)). Findings on OS were reproduced via gene expression analysis in ADC (p < 0.001, HR 1.64 (1.30−2.08)) and SCC (p = 0.217, HR 0.86 (0.68−1.09)). Yet, NT5DC2 mRNA levels were higher in SCC compared to ADC (p < 0.001) and in pN2 tumors compared to pN0/1 tumors (p = 0.001). Likewise, NT5DC2 protein expression associated with high-grade SCC. Moreover, NT5DC2 expression was positively correlated with p53 protein (p = 0.018) and TP53 gene expression (p < 0.001) and its survival effect was p53 dependent. While p53 expression was negatively associated with the presence of CD34+ cancer associated fibroblasts (CAFs), NT5DC2 expression insignificantly tended to higher levels of SMA+ CAFs (p = 0.065).
RESUMEN
OBJECTIVES/HYPOTHESIS: Recurrent respiratory papillomatosis (RRP) is a primarily benign disease affecting the entire respiratory tract. Treatment is challenging and usually involves surgical interventions and adjuvant medications. Previously, promising results on systemic administration of bevacizumab have been reported. However, experience on long-term systemic use in patients with RRP is not yet available. Here, we present our long-term follow-up on RRP patients undergoing systemic bevacizumab treatment. STUDY DESIGN: Case series. METHODS: To describe experience on long-term systemic bevacizumab administration, we performed the underlying investigation. Clinical, radiological, and bronchoscopy data were collected. RESULTS: To date, a total of n = 5 patients has been treated with systemic bevacizumab at Muenster University Hospital. With a median follow-up since first systemic bevacizumab administration of 95.5 months long-term follow-up is illustrated. Following bevacizumab treatment partial remission or very good partial remission were achieved in all patients. After papilloma recurrence/progression due to bevacizumab discontinuation, further response was documented in all patients in whom bevacizumab was started again. In one patient, bevacizumab was discontinued due to loss of efficacy. Lung cancer developed in one patient with pulmonary papillomatosis prior to bevacizumab administration whereas three patients suffered from malignant transformation during bevacizumab treatment. Systemic bevacizumab led to long-term reduction in surgical interventions in all patients. Except from mild proteinuria and hypertension in two patients therapy was well tolerated. CONCLUSIONS: Systemic bevacizumab represents a promising long-term treatment option for aggressive forms of papillomatosis. Rate of malignant transformation under bevacizumab treatment, optimal treatment schedule, and influence on survival should be further evaluated in clinical trials. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1926-E1933, 2021.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Bevacizumab/uso terapéutico , Infecciones por Papillomavirus/tratamiento farmacológico , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Adolescente , Adulto , Niño , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide underlining the urgent need for new biomarkers and therapeutic targets for this disease. Long noncoding RNAs are critical players in NSCLC but the role of small RNA species is not well understood. In the present study, we investigated the role of H/ACA box small nucleolar RNAs (snoRNAs) and snoRNA-bound ribonucleoproteins (snoRNPs) in the tumorigenesis of NSCLC. H/ACA box snoRNPs including the NOP10 core protein were highly expressed in NSCLC. High levels of either NOP10 mRNA or protein were associated with poor prognosis in NSCLC patients. Loss of NOP10 and subsequent reduction of H/ACA box snoRNAs and rRNA pseudouridylation inhibited lung cancer cell growth, colony formation, migration, and invasion. A focused CRISPR/Cas9 snoRNA knockout screen revealed that genomic deletion of SNORA65, SNORA7A, and SNORA7B reduced proliferation of lung cancer cells. In line, high levels of SNORA65, SNORA7A, and SNORA7B were observed in primary lung cancer specimens with associated changes in rRNA pseudouridylation. Knockdown of either SNORA65 or SNORA7A/B inhibited growth and colony formation of NSCLC cell lines. Our data indicate that specific H/ACA box snoRNAs and snoRNA-associated proteins such as NOP10 have an oncogenic role in NSCLC providing new potential biomarkers and therapeutic targets for the disease.
Asunto(s)
Neoplasias Pulmonares/genética , ARN Nucleolar Pequeño/genética , Ribonucleoproteínas Nucleolares Pequeñas/genética , Línea Celular Tumoral , Movimiento Celular/genética , Nucléolo Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/patología , Pronóstico , Procesamiento Postranscripcional del ARN/genética , ARN Mensajero/genéticaRESUMEN
BACKGROUND: T cell infiltration in non-small cell lung cancer (NSCLC) is essential for the immunological response to malignant tissue, especially in the era of immune-checkpoint inhibition. To investigate the prognostic impact of CD4+ T helper cells (Th), CD8+ cytotoxic (Tc) and FOXP3+ regulatory T (Treg) cells in NSCLC, we performed this analysis. METHODS: By counterstaining of CD4, CD8 and FOXP3 we used immunohistochemistry on tissue microarrays (TMA) to evaluate peritumoral Th cells, Treg cells and Tc cells in n=294 NSCLC patients with pTNM stage I-III disease. RESULTS: Strong CD4+ infiltration was associated with higher tumor stages and lymphonodal spread. However, strong CD4+ infiltration yielded improved overall survival (OS) (P=0.014) in adenocarcinoma (ADC) and large cell carcinoma (LCC) but not in squamous cell carcinoma (SCC). A CD4/CD8 ratio <1 was associated with high grade NSCLC tumors (P=0.020). High CD8+ T cell infiltration was an independent prognostic factor for OS (P=0.040) and progression-free survival (PFS) (P=0.012) in the entire study collective. The OS benefit of high CD8+ infiltration was especially prominent in PD-L1 negative NSCLC (P=0.001) but not in PD-L1 positive tissue (P=0.335). Moreover, positive FOXP3+ expression in tumor infiltrating lymphocytes was associated with increased OS (P=0.007) and PFS (P=0.014) in SCC but not in ADC and LCC (all P>0.05). Here, prognostic effects were prominent in PD-L1 positive SCC (P=0.023) but not in PD-L1 negative SCC (P=0.236). CONCLUSIONS: High proportion of CD8+ Tc cells correlated with improved prognostic outcome in stage I-III NSCLC. Th cells and Treg cells have implications on outcome with respect to tumor histology and biology.
RESUMEN
Background: Alpha-1 antitrypsin deficiency (AATD) is of importance in the pathogenesis of pulmonary emphysema, chronic obstructive pulmonary diseases (COPD), and bronchiectasis. Various pulmonary disorders are a typical feature of primary immunodeficiency disease (PID). This includes recurrent pulmonary infections, immunodysregulation, and autoinflammatory diseases. As a result, incidence of acute and chronic pulmonary diseases is higher. Interestingly, pulmonary morbidity in PID and AATD share similar features. To study the coexistence of AATD in patients suffering from PID, we performed the underlying investigation. Methods: We evaluated a study group of 149 patients (n = 149) with PID. In total, serum AAT concentrations were available for 110 patients (n = 110). For the identified patients, we analyzed both clinical associations and interactions. Results: Among the investigated patients, reduced serum AAT levels were detected in 7 patients. With regard to the genotype, PI∗ZZ was found in 2 patients, whereas PI∗MZ was observed in 5 patients. Independent of the underlying phenotype, obstructive lung diseases were found in 2 patients with PI∗ZZ and 2 patients with PI∗MZ. Conclusions: In Germany, the estimated percentage for PI∗ZZ and PI∗MZ is 0.01% and 1.9%, respectively. As demonstrated, the ratio in our study group was even higher. We identified seven patients with AATD. Since AATD contributes to pulmonary morbidity in PID patients, systematic underdiagnosis of the coexistence might yield a strong clinical impact. Hence, AAT analysis should be offered to all patients with confirmed PID diagnoses. To strengthen this finding, we suggest the investigation of larger databases.
Asunto(s)
Enfermedades de Inmunodeficiencia Primaria , Enfermedad Pulmonar Obstructiva Crónica , Infecciones del Sistema Respiratorio , Deficiencia de alfa 1-Antitripsina , Bronquiectasia/diagnóstico , Bronquiectasia/etiología , Errores Diagnósticos/prevención & control , Femenino , Estudios de Asociación Genética , Alemania/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/epidemiología , Enfermedades de Inmunodeficiencia Primaria/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/etiología , Recurrencia , Infecciones del Sistema Respiratorio/epidemiología , Infecciones del Sistema Respiratorio/inmunología , alfa 1-Antitripsina/genética , Deficiencia de alfa 1-Antitripsina/diagnóstico , Deficiencia de alfa 1-Antitripsina/epidemiología , Deficiencia de alfa 1-Antitripsina/genética , Deficiencia de alfa 1-Antitripsina/inmunologíaRESUMEN
BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is a crucial step in lung cancer pathogenesis. Among others, cancer-associated fibroblasts (CAFs) are reported to regulate this process. OBJECTIVES: To investigate the prognostic and clinical impact, we analyzed CD34+ and SMA+ CAFs in non-small cell lung cancer (NSCLC). METHODS: Retrospectively, immunohistochemistry was performed to study stromal protein expression of both CD34 and SMA in 304 NSCLC patients with pTNM stage I-III disease. All tissue samples were embedded on tissue microarrays (TMAs). RESULTS: Our analysis revealed an association for CD34+ CAFs with G1/2 tumors and adenocarcinoma histology. Moreover CD34+ CAFs were identified as an independent prognostic factor (both for progression free survival [PFS] and overall survival [OS] in stage I-III NSCLC). Besides, SMA+ expression correlated with higher pTNM-tumor stages and lymphatic spread (pN stage). In turn, SMA-negativity was associated with improved PFS, but no prognostic impact was found on OS. Of interest, neither CD34+ CAFs nor SMA+ CAFs were associated with the primary tumor size, localization and depth of infiltration (pT stage). CONCLUSIONS: CD34 was identified as an independent prognostic marker in pTNM stage I-III NSCLC. Moreover, loss of CD34+ CAFs might influence the dedifferentiation of the NSCLC tumor from its cell origin. Finally, SMA+ CAFs are more prevalent in NSCLC tumors of higher stages and lymphonodal positive NSCLC. KEY POINTS: Expression of CD34 on cancer associated fibroblasts (CAFs) is an independent prognostic factor in stage I-III NSCLC. SMA+ cancer associated fibroblasts are associated with higher tumor stages in NSCLC and might contribute to tumor progression in NSCLC.
Asunto(s)
Actinas/metabolismo , Antígenos CD34/metabolismo , Biomarcadores de Tumor/metabolismo , Fibroblastos Asociados al Cáncer/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Anciano , Fibroblastos Asociados al Cáncer/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/terapia , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
MUC1 (CD227), an established tumor marker, is expressed on glandular epithelia and on epithelial tumors. Tumor MUC1 differs from normal MUC1 by modified glycan side chains. Recently, a novel carbohydrate-induced conformational tumor-associated MUC1 epitope (TA-MUC1) was described, whose clinical relevance in lung cancer is not known. Eighty-five paraffin embedded tissue sections of non-small cell lung cancer (NSCLC) patients (73% male; mean age 64+/-9 years) were stained with the monoclonal antibody PankoMab (against TA-MUC1) and compared with the established antibodies E29 and 214D4 regarding prognostic relevance. TA-MUC1 is virtually absent in bronchial epithelium. As shown by multivariate analysis, only staining with PankoMab, but not with E29 or 214D4, was correlated with patients' survival (p=0.029). Moreover, when regarding interactions of MUC1 antibody staining results and clinico-pathological parameters, patients with lymph node metastasis lacking PankoMab staining were attributed the highest risk by far (Hazard ratio=4.6, 95% CI: 2.1-9.7, p=0.000). In summary, the presence of TA-MUC1 is a favorable prognostic factor in this cohort of NSCLC patients, in particular if lymph node metastases are present. This is in contrast to the results for E29 and 214D4, which recognize less or not glycosylation dependent epitopes. As this is the first report on a well-defined MUC1 epitope associated with improved survival in NSCLC, a more differentiated view on MUC1 may be mandatory.
Asunto(s)
Anticuerpos/química , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Mucina-1/biosíntesis , Anciano , Anticuerpos Monoclonales/química , Epítopos/química , Epítopos/metabolismo , Femenino , Humanos , Inmunohistoquímica/métodos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Mucina-1/química , Pronóstico , Resultado del TratamientoRESUMEN
BACKGROUND: The advantage of tissue microarray (TMA) is its ability to efficiently analyze large numbers of tissue specimens in a methodologically uniform way. The reliability of TMAs, especially with regard to clinicopathological characterizations, when compared to conventional immunohistochemistry (IHC) was evaluated. MATERIALS AND METHODS: Seventy-two embedded tissue sections from lung cancer specimens were stained with monoclonal antibodies against the tumor-associated markers TA-MUC1 and Lewis Y. Three representative cores of every tumor were embedded in a paraffin array multiblock. The IHC was evaluated by the immunoreactive score (IRS). RESULTS: The data for the TMA IHC and the conventional IHC were concordant (kappa > or = 80%) for both markers. Likewise, discordance (McNemar's test) was low, and sensitivity and specificity were above 80% for both markers. In the samples with high positive expression, the concordance increased (kappa > or = 90%), discordance disappeared (McNemar p = 1.0), and sensitivity and specificity increased above 90% for both markers. Using Cox regression models, all the clinicopathological dependencies were equivalent for both techniques and both markers. CONCLUSION: Immunohistochemistry with tissue microarrays is valid and provides results equivalent to conventional immunohistochemistry with respect to expression patterns and clinicopathological characterizations.
Asunto(s)
Neoplasias Pulmonares/patología , Análisis de Matrices Tisulares/métodos , Anciano , Anticuerpos Monoclonales/química , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Pequeñas/patología , Femenino , Humanos , Inmunohistoquímica , Antígenos del Grupo Sanguíneo de Lewis/análisis , Masculino , Persona de Mediana Edad , Mucina-1/análisis , Pronóstico , Coloración y Etiquetado/métodosRESUMEN
Lung cancer is the leading cause of cancer-related deaths worldwide. With a focus on histology, there are two major subtypes: Non-small cell lung cancer (NSCLC) (the more frequent subtype), and small cell lung cancer (SCLC) (the more aggressive one). Even though SCLC, in general, is a chemosensitive malignancy, relapses following induction therapy are frequent. The standard of care treatment of SCLC consists of platinum-based chemotherapy in combination with etoposide that is subsequently enhanced by PD-L1-inhibiting atezolizumab in the extensive-stage disease, as the addition of immune-checkpoint inhibition yielded improved overall survival. Although there are promising molecular pathways with potential therapeutic impacts, targeted therapies are still not an integral part of routine treatment. Against this background, we evaluated current literature for potential new molecular candidates such as surface markers (e.g., DLL3, TROP-2 or CD56), apoptotic factors (e.g., BCL-2, BET), genetic alterations (e.g., CREBBP, NOTCH or PTEN) or vascular markers (e.g., VEGF, FGFR1 or CD13). Apart from these factors, the application of so-called 'poly-(ADP)-ribose polymerases' (PARP) inhibitors can influence tumor repair mechanisms and thus offer new perspectives for future treatment. Another promising therapeutic concept is the inhibition of 'enhancer of zeste homolog 2' (EZH2) in the loss of function of tumor suppressors or amplification of (proto-) oncogenes. Considering the poor prognosis of SCLC patients, new molecular pathways require further investigation to augment our therapeutic armamentarium in the future.
RESUMEN
BACKGROUND: Severe pulmonary hemorrhage is a life-threatening complication in critically ill patients. Due to tracheobronchial obstruction, ventilation is often impaired. Traditionally, rigid bronchoscopy is an option for recanalization. However, in comparison to flexible bronchoscopy, the application of rigid bronchoscopy is more complex. Against this background we evaluated the use of flexible cryo-probes for blood clot removal in critically ill patients. METHODS: Retrospectively, we identified 16 patients (median age: 60 years, 69% male patients), who suffered from severe airway obstruction due to blood clots. All patients required invasive ventilation and 11 patients depended on extracorporeal membrane oxygenation (ECMO). To remove blood clots, flexible bronchoscopic cryoextraction was performed in n=27 cases, whereas rigid bronchoscopy was only needed in two cases. RESULTS: Whereas in 9 cases single flexible cryoextraction was successful immediately, the procedure had to be repeated again in 7 patients. In all cases, tracheobronchial obstruction was treated with success and conditions of invasive ventilation were improved. In no case severe complications were observed. CONCLUSIONS: In consideration of the underlying evaluation, we highly recommend flexible cryoextraction as both a safe and less complex technique for blood clot removal in critically ill patients.
RESUMEN
OBJECTIVES: In patients with testicular Germ Cell Tumors (GCT) noncaseating granulomatous diseases such as Sarcoid Like Lesions (SLL) or Sarcoidosis can mimic metastasis due to hilar or mediastinal lymphadenopathy. Due to the clinical and prognostic impact, exclusion of malignant diseases is mandatory. MATERIAL AND METHODS: Retrospectively, data from 636 GCT patients, who were seen in the course of tumor surveillance/follow-up were collected. Focus was put on the detection of tumor relapse vs. noncaseating granulomatous reactions. For the differential diagnosis of thoracic lymphadenopathy or pulmonary infiltrates either bronchoscopy (e.g., endobronchial ultrasound-guided transbronchial needle aspiration, endobronchial ultrasound-guided transbronchial needle aspiration) or thoracic surgery was performed. Both GCT patients with either tumor relapse or coexisting SLL were compared to GCT patients without SLL and tumor relapse. RESULTS: Twenty-nine patients suffered from suspected tumor relapse. Whereas thoracic relapses were suspected in 15 patients on chest computed tomography, thoracic relapse was confirmed in 5 cases by open surgery. In 2 cases open surgery yielded reactive lymphadenitis, and in 8 cases SLL was diagnosed either via EBUS-TBNA (nâ¯=â¯7) or thoracoscopic wedge resection plus lymphadenectomy (nâ¯=â¯1). With focus on overall survival, no relevant difference was found between all tested subgroups (Pâ¯=â¯0.265; logrank test). CONCLUSIONS: In GCT patients, the coexistence of noncaseating granulomatous disease is common. Minimal invasive bronchoscopic techniques can serve for the cytopathologic exclusion of malignant thoracic manifestations. In our monocenter patient group the coexistence of SLL did not have any prognostic impact on overall survival.
Asunto(s)
Neoplasias de Células Germinales y Embrionarias/patología , Adolescente , Adulto , Humanos , Masculino , Estudios Retrospectivos , Adulto JovenRESUMEN
INTRODUCTION: Besides invasive or non-invasive ventilation, treatment of severe forms of interstitial lung diseases (ILD) includes immunosuppressive medication. In case of refractory organ- or life-threatening courses of disease, cyclophosphamide pulse therapy can serve as a rescue treatment option. OBJECTIVES: To investigate therapeutic and prognostic effects of cyclophosphamide for the treatment of severe forms of ILD on intensive care unit (ICU) we performed this analysis. METHODS: Between 2009 and 2017 we identified 14 patients, who were treated on intensive care unit (ICU) with severe forms of ILD. Retrospectively, clinical, radiologic and prognostic data were collected and evaluated. RESULTS: Our analysis demonstrated a prognostic impact of cyclophosphamide on the ILD in general. Whereas pulmonary manifestations of both systemic sclerosis (SSc) and ANCA-associated vasculitis had an improved outcome, a reduced overall survival was found for Goodpasture syndrome (GPS), dermatomyositis (DM), cryptogenic organizing pneumonia (COP) and drug reaction with eosinophilia and systemic symptoms (DRESS; p=0.040, logrank test). Besides, additional plasmapheresis and initiation of cyclophosphamide within ten days following initial diagnosis of ILD were associated with improved prognosis. CONCLUSION: Positive prognostic effects of cyclophosphamide pulse therapy in ICU treated patients suffering from severe respiratory failure due to pulmonary manifestations of both SSc and ANCA-associated-vasculitis were observed. Further prognostic and therapeutic data are needed for cyclophosphamide for this indication in order to prevent patients from its toxic side-effects, who most likely will not benefit from its application.
Asunto(s)
Ciclofosfamida/administración & dosificación , Inmunosupresores/administración & dosificación , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Pulmón/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Ciclofosfamida/efectos adversos , Femenino , Humanos , Inmunosupresores/efectos adversos , Pulmón/inmunología , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/inmunología , Masculino , Persona de Mediana Edad , Quimioterapia por Pulso , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto JovenRESUMEN
Soluble Triggering Receptor Expressed on Myeloid Cells 1 (sTREM-1) can be found in the sera of patients with infectious, autoimmune and malignant diseases. The primary objective of this study was to investigate the prognostic significance of sTREM-1 in lung cancer patients. We analyzed the sera of 164 patients with lung cancer of all histologies and all stages at the time of diagnosis. We employed an ELISA using the anti-TREM-1 clone 6B1.1G12 mAb and recombinant human TREM-1. Patient data was collected retrospectively by chart review. In ROC-analysis, a sTREM-1 serum level of 163.1 pg/ml showed the highest Youden-Index. At this cut-off value sTREM-1 was a marker of short survival in patients with NSCLC (median survival 8.5 vs. 13.3 months, p = 0.04). A Cox regression model showed stage (p < 0.001) and sTREM-1 (p = 0.011) to indicate short survival. There were no differences in sTREM-1 serum values among patients with or without infection, pleural effusion or COPD. sTREM-1 was not associated with metastasis at the time of diagnosis and was not a predictor of subsequent metastasis. In SCLC patients sTREM-1 levels were lower than in NSCLC patients (p = 0.001) and did not predict survival. sTREM-1 did not correlate with CRP or the number of neutrophils. In non-small cell lung cancer patients, sTREM-1 in serum has prognostic significance.
Asunto(s)
Carcinoma Broncogénico/metabolismo , Neoplasias Pulmonares/metabolismo , Receptor Activador Expresado en Células Mieloides 1/sangre , Anciano , Biomarcadores/sangre , Carcinoma Broncogénico/diagnóstico , Carcinoma Broncogénico/tratamiento farmacológico , Carcinoma Broncogénico/epidemiología , Comorbilidad , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/epidemiología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Derrame Pleural Maligno/diagnóstico , Pronóstico , Modelos de Riesgos Proporcionales , Análisis de Regresión , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Aminopeptidase N (CD13) is expressed on tumor vasculature and tumor cells. It represents a candidate for targeted therapy, e.g., by truncated tissue factor (tTF)-NGR, binding to CD13, and causing tumor vascular thrombosis. We analyzed CD13 expression by immunohistochemistry in 97 patients with STS who were treated by wide resection and uniform chemo-radio-chemotherapy. Using a semiquantitative score with four intensity levels, CD13 was expressed by tumor vasculature, or tumor cells, or both (composite value, intensity scores 1-3) in 93.9% of the STS. In 49.5% tumor cells, in 48.5% vascular/perivascular cells, and in 58.8%, composite value showed strong intensity score 3 staining. Leiomyosarcoma and synovial sarcoma showed low expression; fibrosarcoma and undifferentiated pleomorphic sarcoma showed high expression. We found a significant prognostic impact of CD13, as high expression in tumor cells or vascular/perivascular cells correlated with better relapse-free survival and overall survival. CD13 retained prognostic significance in multivariable analyses. Systemic tTF-NGR resulted in significant growth reduction of CD13-positive human HT1080 sarcoma cell line xenografts. Our results recommend further investigation of tTF-NGR in STS patients. CD13 might be a suitable predictive biomarker for patient selection.