International Tailored Chemotherapy Adjuvant (ITACA) trial, a phase III multicenter randomized trial comparing adjuvant pharmacogenomic-driven chemotherapy versus standard adjuvant chemotherapy in completely resected stage II-IIIA non-small-cell lung cancer.

BACKGROUND: Several strategies have been investigated to improve the 4% survival advantage of adjuvant chemotherapy in early-stage non-small-cell lung cancer (NSCLC). In this investigator-initiated study we aimed to evaluate the predictive utility of the messenger RNA (mRNA) expression levels of excision repair cross complementation group 1 (ERCC1) and thymidylate synthase (TS) as assessed in resected tumor. PATIENTS AND METHODS: Seven hundred and seventy-three completely resected stage II-III NSCLC patients were enrolled and randomly assigned in each of the four genomic subgroups to investigator's choice of platinum-based chemotherapy (C, n = 389) or tailored chemotherapy (T, n = 384). All anticancer drugs were administered according to standard doses and schedules. Stratification factors included stage and smoking status. The primary endpoint of the study was overall survival (OS). RESULTS: Six hundred and ninety patients were included in the primary analysis. At a median follow-up of 45.9 months, 85 (24.6%) and 70 (20.3%) patients died in arms C and T, respectively. Five-year survival for patients in arms C and T was of 65.4% (95% CI (confidence interval): 58.5% to 71.4%) and 72.9% (95% CI: 66.5% to 78.3%), respectively. The estimated hazard ratio (HR) was 0.77 (95% CI: 0.56-1.06, P value: 0.109) for arm T versus arm C. HR for recurrence-free survival was 0.89 (95% CI: 0.69-1.14, P value: 0.341) for arm T versus arm C. Grade 3-5 toxicities were more frequently reported in arm C than in arm T. CONCLUSION: In completely resected stage II-III NSCLC tailoring adjuvant chemotherapy conferred a non-statistically significant trend for OS favoring the T arm. In terms of safety, the T arm was associated with better efficacy/toxicity ratio related to the different therapeutic choices in the experimental arm.

[Successful treatment of a geriatric COVID-19 patient with severe chest trauma : An interdisciplinary case report]. / Erfolgreiche Behandlung des schweren Thoraxtraumas einer geriatrischen COVID-19-Patientin : Ein Fallbericht von interdisziplinärer Bedeutung.

The coronavirus disease 2019 (COVID-19) has spread rapidly worldwide and leads to high morbidity and mortality. Clinical experience regarding the surgical management in COVID-19 patients is limited. We report the interdisciplinary approach in a COVID-19 patient with severe thoracic trauma and pulmonary symptoms, who was admitted to the emergency unit after blunt chest trauma with dislocated serial rib fractures and concomitant hemothorax.

Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials.

BACKGROUND: Afatinib 40 mg/day is approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). In the case of drug-related grade ≥3 or selected prolonged grade 2 adverse events (AEs), the dose can be reduced by 10 mg decrements to a minimum of 20 mg. Here, we evaluate the influence of afatinib dose reduction on AEs, pharmacokinetics and progression-free survival (PFS) in the phase III LUX-Lung 3 and 6 (LL3/6) trials. PATIENTS AND METHODS: Treatment-naïve patients with advanced EGFR mutation-positive NSCLC in LL3 (global) and LL6 (China, Thailand, South Korea) were randomized to afatinib or chemotherapy. All afatinib-treated patients (LL3, n = 229; LL6, n = 239) were included in the post hoc analyses. Incidence and severity of common AEs before and after afatinib dose reduction were assessed. Afatinib plasma concentrations were compared in patients who reduced to 30 mg versus those remaining at 40 mg. PFS was compared between patients who dose reduced within the first 6 months of treatment and those who did not. RESULTS: Dose reductions occurred in 53.3% (122/229) and 28.0% (67/239) of patients in LL3 and LL6, respectively; most (86.1% and 82.1%) within the first 6 months of treatment. Dose reduction led to decreases in the incidence of drug-related AEs, and was more likely in patients with higher afatinib plasma concentrations. On day 43, patients who dose reduced to 30 mg (n = 59) had geometric mean afatinib plasma concentrations of 23.3 ng/ml, versus 22.8 ng/ml in patients who remained on 40 mg (n = 284). The median PFS was similar in patients who dose reduced during the first 6 months versus those who did not {LL3: 11.3 versus 11.0 months [hazard ratio (HR) 1.25]; LL6: 12.3 versus 11.0 months (HR 1.00)}. CONCLUSIONS: Tolerability-guided dose adjustment is an effective measure to reduce afatinib-related AEs without affecting therapeutic efficacy. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifiers: NCT00949650 and NCT0112393.

Inhalative steroids as an individual treatment in symptomatic lung cancer patients with radiation pneumonitis grade II after radiotherapy - a single-centre experience.

PURPOSE: To assess efficacy of our single-centre experience with inhalative steroids (IS) in lung cancer patients with symptomatic radiation pneumonitis (RP) grade II. MATERIAL AND METHODS: Between 05/09 and 07/10, 24 patients (female, n = 8; male, n = 16) with lung cancer (non-small cell lung carcinoma [NSCLC]: n = 19; small cell lung cancer [SCLC]: n = 3; unknown histology: n = 2) and good performance status (ECOG ≤1) received definitive radiotherapy to the primary tumour site and involved lymph nodes with concurrent chemotherapy (n = 18), sequential chemotherapy (n = 2) or radiation only (n = 4) and developed symptomatic RP grade II during follow-up. No patient presented with oxygen requiring RP grade III. The mean age at diagnosis was 66 years (range: 50-82 years). Nine patients suffered from chronic obstructive pulmonary disease (COPD) before treatment, and 18 patients had a smoking history (median pack years: 48). The mean lung dose was 15.5 Gy (range: 3.0-23.1 Gy). All patients were treated with IS. If a patient's clinical symptoms did not significantly improve within two weeks of IS therapy initiation, their treatment was switched to oral prednisolone. RESULTS: All 24 patients were initially treated with a high dose IS (budesonide 800 µg 1-0-1) for 14 days. Of the patients, 18 showed a significant improvement of clinical symptoms and 6 patients did not show significant improvement of clinical symptoms and were classified as non-responders to IS. Their treatment was switched to oral steroids after two weeks (starting with oral prednisolone, 0.5 mg/kg bodyweight; at least 50 mg per day). All of these patients responded to the prednisolone. None of non-responders presented with increased symptoms of RP and required oxygen and / or hospitalization (RP grade III). The median follow-up after IS treatment initiation was 18 months (range: 4-66 months). The median duration of IS treatment and prednisolone treatment was 8.2 months (range: 3.0-48.3 months) and 11.4 months (range: 5.0-44.0 months), respectively. Of the 18 IS treatment responders, 2 (11.1 %) patients with pre-existing grade 2 COPD still required IS (400 µg twice a day) 45.0 and 48.3 months after radiotherapy, respectively. For the remaining 16 responders (88.9 %), IS therapy was stopped after 7.7 months (range: 3.0-18.2 months). None of the patients treated with IS developed any specific IS-related side effects such as oral candidiasis. CONCLUSION: This single-centre experience shows that high-dose IS is an individual treatment option for radiation-induced pneumonitis grade II in patients with a good performance status.

CD4 T cells are required for both development and maintenance of disease in a new mouse model of reversible colitis.

Current therapies to treat inflammatory bowel diseases have limited efficacy, significant side effects, and often wane over time. Little is known about the cellular and molecular mechanisms operative in the process of mucosal healing from colitis. To study such events, we developed a new model of reversible colitis in which adoptive transfer of CD4(+)CD45RB(hi) T cells into Helicobacter typhlonius-colonized lymphopenic mice resulted in a rapid onset of colonic inflammation that was reversible through depletion of colitogenic T cells. Remission was associated with an improved clinical and histopathological score, reduced immune cell infiltration to the intestinal mucosa, altered intestinal gene expression profiles, regeneration of the colonic mucus layer, and the restoration of epithelial barrier integrity. Notably, colitogenic T cells were not only critical for induction of colitis but also for maintenance of disease. Depletion of colitogenic T cells resulted in a rapid drop in tumor necrosis factor α (TNFα) levels associated with reduced infiltration of inflammatory immune cells to sites of inflammation. Although neutralization of TNFα prevented the onset of colitis, anti-TNFα treatment of mice with established disease failed to resolve colonic inflammation. Collectively, this new model of reversible colitis provides an important research tool to study the dynamics of mucosal healing in chronic intestinal remitting-relapsing disorders.

Severe ARDS induced by fusobacterial infections: a rare clinical presentation of Lemierre syndrome.

Acute respiratory distress syndrome (ARDS) poses a major challenge in intensive care settings. The main underlying causes of ARDS are trauma, pancreatitis, and pulmonary manifestation of systemic inflammatory response syndrome/sepsis.Lemierre syndrome represents a nearly forgotten entity arising from oropharyngeal infections with Fusobacterial species, and it is of renewed and increasing interest because of evolving antibiotic resistances.We report two cases of young female patients afflicted by Lemierre syndrome with additional severe ARDS and present an overview of the current literature.

Simultaneous cardiac and lung surgery for incidental solitary pulmonary nodule: learning from the past.

BACKGROUND: Incidental solitary pulmonary nodules (ISPN) detected prior to scheduled cardiac surgery are rare but challenging. We evaluated the long-term outcome of patients with ISPN undergoing simultaneous cardiac and lung surgery. METHODS: The clinical records of 33 consecutive patients with ISPN undergoing cardiac and lung surgery, either simultaneously (n = 30) or sequentially (n = 3), were retrospectively evaluated and completed by detailed follow-up. RESULTS: On histological examination, 14 cases (42.4%) of primary NSCLC were identified. Benign findings consisted mostly of hamartoma and inflammation. Malignant ISPN were larger in size (22.5 ± 12.4 vs. 13.6 ± 8.6 mm) and ISPN with a diameter >10 mm had a higher incidence of malignancy compared to those ≤10 mm (56.0% vs. 0%). Patients undergoing concomittant heart and lung surgery received either a wedge resection (n = 26) or a lobectomy (n = 4). The 5-year survival of patients with malignant ISPN was lower than that of patients with benign ISPN (43.6% vs. 85.6%). CONCLUSIONS: Our results corroborate a high incidence of malignancy in ISPN detected prior to scheduled cardiac surgery. Simultaneous cardiac and lung surgery for NSCLC appears to be associated with a poor long-term outcome.

Multiple inflammatory myofibroblastic tumors involving lung and mediastinum: a rare clinical entity.

OBJECTIVE: Inflammatory myofibroblastic tumors (IMT) are a rare clinical entity. We retrospectively reviewed the clinicopathological characteristics and prognosis for all patients with surgically resected IMTs of the lung at our institution. MATERIAL AND METHOD: From January 1995 through February 2007, 16 patients, 9 men and 7 women ranging in age from 18 to 64 years with a median age of 46 years, were admitted to our hospital for IMT of the lung, mediastinum and thoracic outlet. Nine of them (56.3 %) had a history of pneumonia, while in the rest it was documented as an incidental finding on chest X-ray. Five of our patients (31.3 %) were under immunosuppressive therapy. CT scan was the diagnostic tool routinely used and PET performed turned out to be positive in 5 cases. Wedge resection was performed in the majority of cases along with 2 lobectomies and 2 segmentectomies. The resected lesions were studied histologically and immunohistochemically. There were no operative deaths. Follow-up was complete in all patients and ranged from 9 months to 135 months. No recurrence was observed. RESULTS: Overall 5-year survival was 93.8 %. Fifteen patients are still alive and the cause of death in one case was not related to the pseudotumor. Cox regression analysis was performed for different factors such as age, sex, previous pneumonia and immunosuppression. None of them was found to play a role in the development of an IMT. The type of intervention also did not seem to affect the prognosis in our series. CONCLUSION: IMTs are a rare clinical entity. An accurate preoperative diagnosis is difficult and complete resection remains the treatment of choice and leads to an excellent survival.

[Immunisation strategies for the management of severe acute respiratory syndrome (SARS)]. / Impfstrategien bei Schwerem Akutem Respiratorischem Syndrom (SARS).

Most patients with severe acute respiratory syndrome (SARS) develop antibodies against the SARS coronavirus and survive the infection. This suggests that active or passive immunisation might be an effective option in preventing or treating SARS. Therefore, the development of SARS vaccination strategies belongs to the most important targets of SARS research. The present study analyses data-bases for the current knowledge on vaccination strategies. Both, passive and active immunisation protocols are presently being developed. Passive immunisation with sera from surviving patients leads to partial success. Whereas the passive immunisation exhibits a promising therapeutic tool, only active immunisation can successfully prevent infection. A number of approaches has been used on the basis of inactivated SARS coronaviruses, recombinant subunits, recombinant DNA, and viral vectors. However, all recently developed candidates need to be evaluated critically before clinical use. The so-called "antibody-dependent enhancement" can improve viral uptake into host cells resulting in increased viral load and exacerbation of disease.

[Pharmacotherapy of severe acute respiratory syndrome (SARS)]. / Pharmakotherapie bei Schwerem Akutem Respiratorischem Syndrom (SARS).

Severe acute respiratory syndrome (SARS) constitutes the first new infectious disease of the current millennium. It is caused by the novel SARS-Coronavirus (SARS-CoV). SARS is related to a high morbidity and mortality and first appeared during an epidemic in 2002 - 2003. To date no specific therapy against the SARS-CoV is available. Due to the rapid spread of SARS during the epidemics in 2002 - 2003, randomised and controlled multicentre studies were not performed. Therefore, general guidelines have not been developed. Since the outbreak, scientists have been testing potential antiviral substances using in vitro and animal models. This study analyses the presently available in vitro and in vivo data on the pharmacotherapy of SARS.

Randomized phase III study of gemcitabine and vinorelbine versus gemcitabine, vinorelbine, and cisplatin in the treatment of advanced non-small-cell lung cancer: from the German and Swiss Lung Cancer Study Group.

PURPOSE: To evaluate whether cisplatin-based chemotherapy (gemcitabine, vinorelbine, and cisplatin [GVP]) prolongs overall survival in comparison to cisplatin-free chemotherapy (gemcitabine and vinorelbine [GV]) as first-line treatment in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Between September 1999 and June 2001, 300 patients with NSCLC stage IIIB with malignant pleural effusion or stage IV disease were randomly assigned to receive GV (gemcitabine 1000 mg/m(2) + vinorelbine 25 mg/m(2) on days 1 and 8 every 3 weeks) or GVP (gemcitabine 1000 mg/m(2) + vinorelbine 25 mg/m(2) on days 1 and 8 + cisplatin 75 mg/m(2) on day 2 every 3 weeks). Primary end point of the study was overall survival. RESULTS: Two hundred eighty-seven patients (GV, 143 patients; GVP, 144 patients) were eligible for analysis. At the time of analysis, April 15, 2002, 209 patients (GV, 103 patients; GVP, 106 patients) of 287 patients had died (73%). No statistically significant difference was observed for overall survival (P =.73; median survival, 35.9 versus 32.4 weeks; 1-year survival rate, 33.6% versus 27.5%) as well as for event-free survival (P =.35; median time-to-event, 19.3 versus 22.3 weeks) between GV and GVP. Two hundred fourteen patients were assessable for best response. The overall response rates were 13.0% for GV versus 28.3% for GVP (P =.004; complete responders, 0% versus 3.8%; partial responders, 13.0% versus 24.5%). Hematologic and nonhematologic toxicity was significantly lower in the GV treatment arm compared with GVP. No statistically significant difference in quality of life was observed. CONCLUSION: In this phase III study, the cisplatin-based GVP regimen showed no survival benefit as first-line chemotherapy in advanced NSCLC when compared with the cisplatin-free GV regimen, which was substantially better tolerated.

[Diagnosis of multiple myeloma by demonstrating plasma cells in bronchoalveolar lavage]. / Diagnose eines Multiplen Myeloms durch den Nachweis von Plasmazellen in der bronchoalveolären Lavage.

HISTORY AND CLINICAL FINDINGS: A 61-year-old man was transferred from a peripheral hospital with the diagnosis of interstitial lung disease and an unclear mediastinal tumour. At the time of admission the patient had congestive heart disease NYHA class IV. INVESTIGATIONS: The echocardiogram showed a small left ventricle with concentric hypertrophy and a left ventricular ejection fraction of 35 %. The myocardium was relatively echo-rich with solid structures inside. Chest X-ray showed a massive rightsided pleural effusion. The abdominal ultrasound demonstrated ascites and hepatomegaly. The bronchoalveolar lavage showed an increased part of CD3 negative and CD16/CD56 positive cells, which were identified as plasma cells by light and electron microscopy. Aspiration and investigation of the bone marrow verified the diagnosis of a IgG multiple myeloma, highly differentiated characterised by monoclonal expression of light-lambda chains. Additionally Bence-Jones-proteins were found in the urine and osteolysis in the x-ray of the skull and the humerus. DIAGNOSIS: Multiple myeloma, IgG-lambda, stage IIA. THERAPY AND CLINICAL COURSE: Chemotherapy with prednisolone and melphalan was initiated. His general condition increased after administration of the first cycle of chemotherapy. CONCLUSION: Cardiopulmonary involvement is seldom seen in multiple myeloma but should be excluded when clinical symptoms are present.

Gemcitabine, vinorelbine and cisplatin combination chemotherapy in advanced non-small cell lung cancer: a phase II trial.

The purpose of this phase II trial was to investigate the efficacy and safety of a combination chemotherapy with gemcitabine, vinorelbine and cisplatin in the first-line treatment of advanced non-small cell lung cancer (NSCLC). Patients with NSCLC stage IIIB or IV disease received 1000 mg/m(2) gemcitabine and 25 mg/m(2) vinorelbine on days 1 and 8 and 75 mg/m(2) cisplatin on day 2, every 3 weeks. From December 1998 to May 1999, 31 patients (21 stage IV and 10 stage IIIB disease), with a median age of 59 years (range 40-72 years) were enrolled. The overall intent-to-treat response rate was 45% (95% confidence interval (CI): 27-64%) with 2 complete responders (CR) and 12 partial responders (PR), 7 patients had stable disease and 10 progressed. Median survival was 12.8 months (95% CI: 6.5-12.8+ months), median time to progression was 5.1 months (95% CI: 3.5-7.7 months), and the 1-year survival rate was 52.9% (95% CI: 36.7-76.2%). Patients with stage IIIB disease had a significantly longer overall survival than patients with stage IV disease (P=0.05). Transient World Health Organization (WHO) grade IV leucopenia, anaemia and thrombocytopenia occurred in 3 (10%), 2 (6%) and 3 (10%) patients, respectively. The predominant non-haematological toxicities were alopecia and nausea/vomiting. 15 patients (48%) had WHO grade II and III alopecia and 14 patients (45%) nausea/vomiting. The combination of gemcitabine, vinorelbine and cisplatin has demonstrated major antitumour efficacy in advanced NSCLC with a manageable toxicity profile.

[Automated quantitative image cytometry of bronchial washings in suspected lung cancer: comparison with cytology, histology and clinical diagnosis]. / Automatisierte quantitative Image-Zytometrie bronchialer Spülflüssigkeiten bei Verdacht auf broncho-pulmonale Tumoren: Vergleich mit Zytologie, Histologie und Klinischer Diagnose.

INTRODUCTION: Automated image cytometry represents a new method for the quantitative analysis of nuclear structure and DNA-content of exfoliative airway epithelial cells. In the present investigation, we examined the correlation between automated cytometry, conventional cytology and histopathology with the final diagnosis as the "gold standard". METHODS: In 142 patients (100 males and 42 females) with suspected lung cancer and 50 controls (COPD, asthma), bronchial washings (5-10 ml) were obtained during bronchoscopy before taking biopsies for cytological and/or histological examinations. The washings were collected in 20 ml Saccomanno's fixative and centrifuged (500 g, 15 min). The cell pellet was resuspended in Saccomanno's solution. Two specimens were stained according to Papanicolaou and another two using the Feulgen reaction with thionine. Image cytometry was performed by means of a special, trainable classifier for exfoliative cells of the respiratory tract, using the Cyto-Sacant (Oncometrics, Vancouver). RESULTS: In the patients with suspected lung cancer we found numerous abnormal nuclei in 97 samples, 36 samples contained normal cells only, and 9 samples were insufficient. In our control group there was no sample with abnormal nuclei, and all washings were evaluable. Compared to the final diagnosis of lung cancer, we found a sensitivity of 90% (92/102) and a specificity of 84% (26/31). For histology sensitivity was 91% (73/80) and specificity 100%, while we found a sensitivity of 92% (92/100) and specificity of 100% for cytology. For automated cytometry the positive predicted value was 95%, the negative predicted value 71%. CONCLUSIONS: In the investigation of patients with suspected lung cancer, automated image cytometry of bronchial washings is a sensitive and reliable method for the detection of malignant changes in the tracheobronchial mucosa. The automated procedure seems well suited not only for analysing bronchial washings, but also for a screening procedure.

[Protective pneumothorax in CT-guided mediastinal puncture]. / Protektiver Pneumothorax bei CT-gesteuerter Mediastinalpunktion.

PURPOSE: To achieve an extrapulmonary pathway for biopsy of mediastinal masses. METHODS: In 6 patients a protective, temporary pneumothorax was established before performing large-bore needle biopsies of mediastinal masses using a Verres-needle. RESULTS: Transpleural, extrapulmonary access was easy to achieve. One patient developed a tension pneumothorax after biopsy which was drained by percutaneous small chest tube. Another patient showed mediastinal tumor bleeding through the biopsy needle. As a prophylactic measure the bleeding was stopped by injection of tissue glue through the biopsy needle. CONCLUSION: The use of protective pneumothorax allows cutting needle biopsies of mediastinal masses where aspiration cytology yields no secure specific diagnosis.