Ki67 index is an independent prognostic factor in epithelioid but not in non-epithelioid malignant pleural mesothelioma: a multicenter study.

BACKGROUND: Estimating the prognosis in malignant pleural mesothelioma (MPM) remains challenging. Thus, the prognostic relevance of Ki67 was studied in MPM. METHODS: Ki67 index was determined in a test cohort of 187 cases from three centres. The percentage of Ki67-positive tumour cells was correlated with clinical variables and overall survival (OS). The prognostic power of Ki67 index was compared with other prognostic factors and re-evaluated in an independent cohort (n=98). RESULTS: Patients with Ki67 higher than median (>15%) had significantly (P<0.001) shorter median OS (7.5 months) than those with low Ki67 (19.1 months). After multivariate survival analyses, Ki67 proved to be-beside histology and treatment-an independent prognostic marker in MPM (hazard ratio (HR): 2.1, P<0.001). Interestingly, Ki67 was prognostic exclusively in epithelioid (P<0.001) but not in non-epithelioid subtype. Furthermore, Ki67 index was significantly lower in post-chemotherapy samples when compared with chemo-naive cases. The prognostic power was comparable to other recently published prognostic factors (CRP, fibrinogen, neutrophil-to-leukocyte ratio (NLR) and nuclear grading score) and was recapitulated in the validation cohort (P=0.048). CONCLUSION: This multicentre study demonstrates that Ki67 is an independent and reproducible prognostic factor in epithelioid but not in non-epithelioid MPM and suggests that induction chemotherapy decreases the proliferative capacity of MPM.

Unusual microbes in asthma exacerbation: Alcaligenes xylosoxidans and Leishmania.

Asthma is a chronic inflammatory condition characterised by a variable degree of airflow limitation. Exacerbations during the course of asthma often occur due to environmental factors or infectious, mostly viral, aetiology. The present study reports the case of a 61-yr-old male with severe asthma hospitalised due to increasing respiratory distress. Since recovery was delayed despite anti-obstructive/anti-inflammatory and antibiotic therapy, further diagnostic procedures, including bronchoscopy, were performed in order to attempt to identify the cause of the worsening respiratory condition. The surprising finding consisted of a rare coincidence of concomitant infection with the bacterial pathogen Alcaligenes xylosoxidans, grown from bronchoalveolar lavage fluid, and the protozoan parasite Leishmania spp., revealed by histopathological examination of bronchial mucosal biopsy specimens. This is the first report of an isolated bronchial mucosal involvement of Leishmania in an HIV-negative asthma patient following brief exposure in Leishmania-endemic regions. Further, to the best of the present authors' knowledge, this represents the first description of A. xylosoxidans in asthma, although it is questionable whether it was an infection or colonisation. The present observation identifies previously unreported microbial pathogens associated with asthma exacerbation. Further, the report highlights the importance of obtaining a thorough travel history and applying invasive diagnostic procedures in circumstances of treatment failure, even under unfavourable conditions.

[Tubercular osteomyelitis of the clivus and the nasopharynx]. / Tuberkulöse Osteomyelitis des Klivus mit Beteiligung des Nasopharynx.

Involvement of the skull base is rare in tuberculosis. We report here the case of a 28-year-old female patient with an osteolytic process of the clivus with compression of the brain stem and involvement of the nasopharynx. She reported suffering from headaches for the last 6 months, and diplopia had occurred 1 week before her diagnosis as a result of paresis of the VIth cranial nerve on the right side. A biopsy was obtained endoscopically via a transnasal approach, revealing a granulomatous inflammation with acid-fast rods and thus confirming the diagnosis of a tuberculoma. When the biopsy was taken there was no evidence of any further tuberculomas in this patient. The clinical picture, diagnosis, and treatment of tuberculosis of the skull base and nasopharynx are discussed and the literature on this rare clinical entity is reviewed with reference to this patient's case report.

Occurrence of a pulmonary carcinoid following allogeneic stem cell transplantation for chronic myelogenous leukemia: a case report.

Carcinoid tumors are relatively rare neuroendocrine malignancies with an indolent clinical behavior. The majority of cases arise within the gastrointestinal tract, but they may also be encountered in other organs such as the bronchial system. While occurrence of carcinoid tumors has been reported in association with the multiple endocrine neoplasia (MEN) type I syndrome, no clear-cut risk factors have been established for the development of these malignancies. We report the case of a 50-year-old woman who was diagnosed with a pulmonary carcinoid in 2001 after having undergone allogeneic stem cell transplantation for chronic myeloid leukemia (CML) in 1997. This is the first case report of a carcinoid tumor following allogeneic bone marrow transplantation. At the moment, however, an association with CML as well as a causative role of transplantation and intake of immunosuppressants remains speculative. Apart from highlighting the occurrence of a carcinoid in this setting, our case again underscores the importance of nuclear medicine methods, i.e., somatostatin receptor scintigraphy, in staging and follow-up of patients with carcinoid tumors.

A paraneoplastic syndrome mimicking extrauterine pregnancy.

We report on a 30-year-old female patient with a beta-human chorionic gonadotropin (beta-HCG)-producing lung tumour. Abdominal discomfort and vaginal bleeding were the presenting symptoms and, in conjunction with elevated beta-HCG levels, initially led to the diagnosis of extrauterine pregnancy. Bilateral ovarian cysts were detected on further diagnostic workup. Ultimately, a chest X-ray revealed a lung tumour. The paraneoplastic symptoms were completely reversible after resection of the lung lesion, and the ovarian cysts disappeared.

Intranasal treatment with a recombinant hypoallergenic derivative of the major birch pollen allergen Bet v 1 prevents allergic sensitization and airway inflammation in mice.

BACKGROUND: The major birch pollen allergen Bet v 1 represents one of the most prevalent environmental allergens responsible for allergic airway inflammation. OBJECTIVE: In the present study we sought to compare the complete recombinant Bet v 1 allergen molecule with genetically produced hypoallergenic fragments of Bet v 1 regarding mucosal tolerance induction in a mouse model of allergic asthma. METHODS: BALB/c mice were intranasally treated with recombinant Bet v 1 or with two recombinant Bet v 1 fragments (F I: aa 1-74; F II: aa 75-160) prior to aerosol sensitization with birch pollen and Bet v 1. RESULTS: Intranasal application of F II, containing the major T cell epitope, led to significant reduction of IgE/IgG1 antibody responses, in vitro cytokine production (IL-5, IFN-gamma, IL-10) and negative immediate cutaneous hypersensitivity reactions comparable to the pretreatment with the complete rBet v 1 allergen. Moreover, airway inflammation (eosinophilia, IL-5) was inhibited by the pretreatment with either the complete Bet v 1 or F II. However, for prevention of airway hyperresponsiveness the complete molecule was required. The mechanisms leading to immunosuppression seemed to differ in their dependence on the conformation of the molecules, since tolerance induced with the complete Bet v 1, but not with F II, was transferable with spleen cells and associated with increased TGF-beta mRNA levels. CONCLUSION: We conclude that mucosal tolerance induction with recombinant allergens and genetically engineered hypoallergenic derivatives thereof could provide a convenient and safe intervention strategy against type I allergy.

Successful lung transplantation for bronchiolitis obliterans after allogeneic marrow transplantation.

BACKGROUND: Bone marrow transplantation (BMT) is an established therapy for a variety of hematological diseases with curative potential. However, despite improvements in supportive care, pulmonary complications remain a significant cause of morbidity and mortality. METHODS: We report on a patient who received a double lung transplantation (LTX) for therapy-refractory bronchiolitis obliterans (BO) associated with extensive chronic graft-versus-host disease (GVHD) after allogeneic BMT. RESULTS: At present, 38 months after BMT and 23 months after LTX, the patient is in complete hematological and cytogenetic remission and without signs of respiratory distress. CONCLUSIONS: This case illustrates that lung transplantation could be a therapeutic option in selected patients with BO after allogeneic BMT that is associated with extensive chronic GVHD and who are refractory to conventional immunosuppressive therapy.

Aneuploidy of chromosome 7 can be detected in invasive lung cancer and associated premalignant lesions of the lung by fluorescence in situ hybridisation.

In the present study the chromosomal status of seven invasive non small cell lung cancer specimens and associated premalignant lesions was investigated. By fluorescence in situ hybridisation (FISH) with centromere specific probes, an increase in the percentage of aneuploid cells from pre-invasive to invasive lesions could be demonstrated (mean 8.5 and 59%, respectively, for chromosome 7). Furthermore, mean chromosome copy numbers were higher in invasive carcinomas as compared to premalignant lesions, indicating polyploidization during tumor development. Increasing evidence suggests that aberrations of chromosome 7 occur early in the development of lung cancer. Whether these aberrations can be used as a biomarker for future neoplastic progression remains to be determined.

A case of HIV-associated cerebral histoplasmosis successfully treated with fluconazole.

Clinically apparent involvement of the central nervous system is a rare event in cases of disseminated histoplasmosis, even in HIV-infected persons. Despite therapy with amphotericin B, mortality remains very high. Reported here is the case of an HIV-infected patient with a 3-month history of fever, cough, weight loss and miliary lung infiltrates. Four weeks after initiation of tuberculostatic therapy, high-grade fever, neurological symptoms, personality changes and respiratory deterioration occurred. Magnetic resonance imaging of the brain showed multiple mass lesions, and a chest radiograph revealed worsening of pulmonary infiltrates. Methenamine silver staining of a lung biopsy specimen demonstrated Histoplasma capsulatum. Subsequently, this pathogen was cultured from lavage fluid. Following high-dose intravenous fluconazole therapy (800 mg once daily), the patient's condition improved markedly within 10 days, followed by an almost complete resolution of pulmonary and cerebral mass lesions. This is believed to be the first documented case of rapid improvement of disseminated histoplasmosis with central nervous system involvement in an HIV-infected patient upon induction of therapy with fluconazole.

Evidence for a role of FGF-2 and FGF receptors in the proliferation of non-small cell lung cancer cells.

Basic fibroblast growth factor (FGF-2) has been implicated in the progression of human tumours via both autocrine and paracrine (angiogenic) activities. We investigated the expression of FGF-2 and FGF receptors (FGFR-1 to -4) in NSCLC cell lines (N = 16), NSCLC surgical specimens (N = 21) and 2 control cell lines. Our data show that almost all NSCLC cells produce elevated levels of FGF-2 and FGFR in vitro and in vivo. FGF-2 expression did correlate with a short doubling time as well as with potent anchorage-independent growth of NSCLC cell lines. In contrast with control cells, NSCLC cells did not secrete considerable amounts of FGF-2 into the extracellular space. Expression levels of FGFR-1 and -2 in NSCLC cell lines correlated with FGF-2 production. FGFR were located at the plasma membranes in some low FGF-2-producing NSCLC and control cell lines. These cells were sensitive to the proliferative effect of recombinant FGF-2 (rFGF-2). In NSCLC cell lines with an enhanced FGF-2 production, representing the majority studied, FGFR localisation was predominantly intracellular. These cells were insensitive to both the proliferative effect of rFGF-2 and growth inhibition by FGF-2-neutralising antibodies. In contrast, several agents antagonised FGF-2 intracellularly impaired growth of almost all NSCLC cell lines. Our data suggest a role of FGF-2 and FGFR in the growth stimulation of NSCLC cells possibly via an intracrine mechanism.

Comparison between mycophenolate mofetil- and azathioprine-based immunosuppressions in clinical lung transplantation.

BACKGROUND: The aim of the study was to assess the impact of mycophenolate mofetil (MMF) on the early phase after lung transplantation. PATIENTS AND METHODS: Thirty-eight consecutive patients between November 1994 and January 1997 were treated with cyclosporine, prednisolone, antithymocyte globuline induction therapy, and either MMF (n = 21) or azathioprine (Aza) (n = 17). Four patients from the MMF group and 2 patients from the Aza group were intubated and in the ICU prior to transplantation. Demographic data and primary diagnosis were comparable. MMF was administered at a dosage of 2 gm/day whereas Aza was initiated at 2 mg/kg/day and adapted by leukocyte count. Three-month survival and incidence of rejections and infections were compared. RESULTS: Six-month survival in the MMF group was 76% compared to 65% in the Aza group (n.s.). The mean number of acute rejection episodes in the MMF and Aza group were 0.29+/-0.10 and 1.53+/-0.29 (p<0.01) respectively. Transbronchial biopsy (TBB) results > or =grade 2 ISHLT were seen in 10% of MMF and in 43% of Aza-treated patients; completely free from rejection were 17 MMF and 3 Aza patients. The mean number of infections per patient in the MMF and Aza group were 1.57+/-0.29 and 2.29+/-0.40 respectively, bacterial (1.10 vs. 1.71), viral (0.35 vs. 0.33), and fungal (0.14 vs. 0.24) infections were the same in both groups. CONCLUSIONS: These data result suggest that mycophenolate mofetil therapy is more effective in preventing rejection episodes in patients early after lung transplantation than therapy with azathioprine. We therefore conclude that MMF is a safe and effective drug to optimize immunosuppressive therapy in the early phase after lung transplantation.

Necrotizing sarcoid granulomatosis in a 14-yr-old female.

A case of a 14-yr-old female with necrotizing sarcoid granulomatosis (NSG) is presented. She was referred because of chest pain and malaise, and radiography revealed multiple pulmonary nodules. Her history showed seasonal sensitization to aeroallergens and hay fever. Infectious agents or malignancies did not characterize these nodules. However, she was treated with macrolide antibiotics because of suspected infection with Chlamydia pneumoniae. Open lung biopsy showed histological findings of NSG, with epithelioid granulomatous inflammation, including giant cells, and vasculitis. No further treatment was performed, and symptoms disappeared within a few weeks. The chest radiograph showed gradual improvement. The aetiology of NSG is poorly understood, and is postulated to represent either sarcoidosis or rare forms of pulmonary vasculitis such as Wegener's granulomatosis or the Churg-Strauss syndrome. In the case presented, a coincidence of infection with Chlamydia pneumoniae suggests an involvement of infectious agents in the pattern of formation of immune complexes in the aetiology of NSG.

The TP53 genotype but not immunohistochemical result is predictive of response to cisplatin-based neoadjuvant therapy in stage III non-small cell lung cancer.

BACKGROUND: The cytotoxic effects of cisplatin and anthracyclins have been attributed to apoptosis induction, which has been recognized as a major function of the TP53 gene. The TP53 gene appears to be mutated in about 50% of cases of non-small cell lung cancer. A possible dependence of chemotherapy response on TP53 genotype was evaluated retrospectively in a group of patients with advanced non-small cell lung cancer and induction treatment. METHODS: Patients with complete or partial remission were compared with those with stable or progressive disease with respect to TP53 genotype and overall survival. Mutations in the TP53 gene were detected by complete direct sequencing (exons 2-11). RESULTS: A normal TP53 genotype proved to be significantly associated with major response to chemotherapy (P <.001). Overall, no association was found between p53 protein expression and TP53 genotype. A normal TP53 genotype was found to be highly sensitive in predicting response to treatment, whereas a mutant genotype was revealed to be specific in predicting lack of response. The difference in overall length of survival was significant between patients exhibiting a normal TP53 genotype (corresponding to those whose disease responded to chemotherapy) and patients showing mutant TP53 genotype (corresponding to those who had disease resistant to chemotherapy, P =.027). CONCLUSIONS: In a small cohort of patients with advanced non-small cell lung cancer we found a direct link between normal TP53 genotype and response to cisplatin-based induction treatment and also between mutant genotype and resistance to treatment, whereas p53 immunohistochemical result was predictive of neither.

Expression of the multidrug resistance protein (MRP1) in breast cancer.

BACKGROUND: The multidrug resistance protein (MRP1) is expressed in human breast carcinomas but its clinical significance remains unclear. The aim of the present study was to determine the clinical significance of MRP1 in breast cancer patients. MATERIALS AND METHODS: MRP1 expression of primary carcinomas from 100 breast cancer patients was immunohistochemically determined by means of the monoclonal antibodies QCRL-1/QCRL-3. RESULTS: MRP1 was negative in 20 (20%) and positive in 80 (80%) breast carcinomas. MRP1 expression was more frequent in both estrogen receptor-negative carcinomas and progesterone receptor-negative carcinomas (p = 0.1 in both cases), but was independent of tumor size and lymph node involvement. Patients with MRP1-negative carcinomas had prolongations of overall survival (p = 0.01 for death due to any cause, p = 0.04 for breast cancer-related death) and disease-free survival (p = 0.07) as compared to those with MRP1-positive carcinomas. Also in subsets of patients (negative lymph nodes; positive lymph nodes; positive estrogen receptor; T1/T2 tumors), overall survival was longer for patients with MRP1-negative carcinomas. In univariate Cox regression analyses, MRP1 positivity was associated with relative risks of 4.9 (95% CI 1.2-20.6; p = 0.03) for death due to any cause, 6.4 (95% CI 0.9-48.0; p = 0.07) for breast cancer-related death and 3.5 (95% CI 0.8-14.9; p = 0.09) for relapse. In multivariate Cox regression analyses, MRP1 positivity had relative risks of 5.1 (95% CI 1.2-21.7; p = 0.03) for death due to any cause, 6.5 (95% CI 0.8-50.1; p = 0.07) for breast cancer-related death and 3.4 (95% CI 0.8-15.1; p = 0.1) for relapse. CONCLUSIONS: Our results suggest that MRP1 might be an important factor in breast cancer indicating excellent prognosis for patients with MRP1-negative carcinomas.

RB growth control evasion in lung cancer.

We evaluated the expression of pRb by immunohistochemistry in 98 lung cancer specimens already characterized for their p16 and cyclin D1 status. We found the absence of pRb expression to be dependent upon the histological type, being more frequent in SCLCs than in NSCLCs (p < .00005). On the other hand, we failed to find any correlation between the expression of pRb and p16. In addition, we found a positive correlation between the expression of pRb and cyclin D1 (p = .0001). Therefore, we hypothesize that pRb growth control may be overcome by two different mechanisms in lung carcinogenesis: loss of pRb expression or overexpression of cyclin D1.