Clinical outcomes and health-related quality of life after thoracoscopic talc pleurodesis.

OBJECTIVES: Thoracoscopic pleurodesis is a safe and effective method of palliative care for patients suffering from malignant pleural effusion. Health-related quality of life (QOL) is an important factor in palliative therapy; however, we are not aware of any studies that have examined the QOL of patients following thoracoscopic pleurodesis. METHODS: A total of 123 patients underwent thoracoscopic pleurodesis between January 2006 and February 2009. A total of 45 patients agreed to take part at the QOL assessment and were enrolled in our prospective study. In addition to clinical outcome, the patients' QOL data were assessed prior to thoracoscopic pleurodesis and for 12 months after surgery using the European Organization for Research and Treatment of Cancer (EORTC) QLQ C-30 questionnaire. We compared the patients' QOL scores at each time point with their preoperative scores and analyzed these data relative to the scores of a healthy age-matched population. RESULTS: Due to the advanced clinical status of the patients in our study, the overall median survival time was 7.5 months versus 10.2 months for patients' QOL data. Following discharge from the hospital, most functional scales (with exception of emotional function, p=0.035) did not significantly differ from preoperative scores. Throughout the study period, patients experienced statistically and clinically significant improvements in functional scales. Global health values increased after surgery throughout the entire study period. There was a clear decline in dyspnea upon discharge, followed by a continuous remote increase throughout the subsequent months. QOL of the study population remained lower than that of the healthy cohort. CONCLUSIONS: Our data are consistent with clinical findings that pleurodesis decreases respiratory symptoms, but does not alleviate impairments in the patient's general condition.

Age-related impairment of quality of life after lung resection for non-small cell lung cancer.

BACKGROUND: Health-related quality of life (QOL) after resection of non-small cell lung cancer (NSCLC) is of primary interest to clinicians, secondary to clinical outcome. However, few studies have explored QOL following lung resection and, to our knowledge, no studies have specifically examined the QOL of elderly patients. METHODS: A total of 131 patients with NSCLC underwent surgical resection (lobectomy or bilobectomy) between January 1998 and December 2004 and were enrolled in our prospective study. The patients' QOL and clinical data were assessed prior to resection and for up to 24 months after surgery using the EORTC QLQ C-30 questionnaire and the lung-specific questionnaire, QLQ-LC13. Quality of life was then calculated and the QOL of patients younger than 70 years was compared with that of patients aged 70 years or older. RESULTS: The overall 5-year survival rate was 47%, and the rate of complications did not differ significantly between the groups. Overall, most QOL indicators, including physical function (p<0.001), pain (p=0.025), and dyspnea (p<0.001) were significantly impaired after surgery and remained so for up to 24 months. Elderly patients survived for an average of 39 months, while younger patients survived for an average of 49 months (p=0.18). The QOL of younger patients returned to preoperative levels significantly faster than did the QOL of elderly patients. CONCLUSIONS: Elderly patients who underwent lung resection for NSCLC failed to make a complete recovery. They showed a decreased tendency to achieve the preoperative level of QOL compared to younger patients.

The extent of lung parenchyma resection significantly impacts long-term quality of life in patients with non-small cell lung cancer.

BACKGROUND: Secondary to clinical outcome, health-related quality of life (QOL) after resection of non-small cell lung cancer (NSCLC) is of particular interest. However, few studies have explored QOL following lung resection. METHODS: Between January 1998 and December 2004, a total of 159 patients with NSCLC underwent surgical resection and were enrolled in this prospective study. QOL and clinical data were assessed prior to resection and for up to 24 months after surgery by applying the European Organization for Research and Treatment of Cancer core questionnaire and the lung-specific questionnaire, the European Organization for Research and Treatment of Cancer lung-specific module. QOL was calculated, and QOL following bilobectomy/lobectomy was compared with QOL after pneumonectomy. RESULTS: Overall, the 5-year survival rate was 42%. Mean survival of the pneumonectomy group was slightly lower than that of the bilobectomy/lobectomy group, although the difference was not statistically significant (p = 0.058). The rate of complications was not significantly different between the two groups. After a postoperative drop, most QOL indicators remained near baseline for up to 24 months, with the exception of physical function (p < 0.001), pain (p = 0.034), and dyspnoea (p < 0.001), which remained significantly impaired. QOL was significantly better (difference > 10 points) after bilobectomy/lobectomy than after pneumonectomy. However, differences were statistically significant only with regards to physical function (at 3 months), social function (at 3 and 6 months), role function (at 3, 6, and 12 months), global health (at 3 and 6 months), and pain (at 6 months). CONCLUSIONS: Patients who underwent lung resection for NSCLC failed to make a complete recovery after 24 months. Patients who underwent pneumonectomy had significantly worse QOL values and a decreased tendency to recover, compared with patients who underwent bilobectomy/lobectomy. Therefore, major lung resection has a much more serious impact on the QOL of affected patients than does major visceral surgery.

Activated coagulation factors in human malignant effusions and their contribution to cancer cell metastasis and therapy.

We have shown that the thrombin G-protein coupled receptors (GPCR) designated as protease-activated receptors (PAR-1) are expressed in primary cancer cells isolated from peritoneal and pleural malignant effusions. Here, our main goal was to evaluate several coagulation and thrombin activation effectors and markers in a series of 136 malignant effusions from cancer patients with gastrointestinal, lung and mammary carcinomas. All these patients present a highly activated coagulation system in blood and their malignant effusions, as indicated by high levels of prothrombin F1.2 fragments and D-dimers. Notably, we detected in the effusions all the coagulation factors of the tissue factor pathway inducing thrombin activation, namely factors VII, V, X and II, as well as high VEGF levels and IGF-II in mature and precursor forms. Fibrin clot formation also correlated with higher levels of free ionized calcium (iCa), suggesting that iCa and its binding protein albumin are regulatory factors for fibrinogenesis in effusions. Consequently, thrombin, VEGF and IGFII appear to converge in the promotion of survival and invasivity of the metastatic cancer cells from blood to the malignant effusions. Thus, we add new insights on the interconnections between blood coagulation disorders in cancer patients and thrombin activation in malignant effusions, including their functional interaction with PAR in metastatic cancer cells. Based on these data we propose to counteract the metastatic cascades by targeted invalidation of key effectors of the coagulation system. Therefore, potential therapeutic approaches include the application of thrombin protease inhibitors, VEGF-blocking antibodies, and drugs targeting the VEGF and thrombin signaling pathways, such as tyrosine kinase or GPCR inhibitors.

Combination phenylbutyrate/gemcitabine therapy effectively inhibits in vitro and in vivo growth of NSCLC by intrinsic apoptotic pathways.

BACKGROUND: Standard chemotherapy protocols in NSCLC are of limited clinical benefit. Histone deacetylase (HDAC) inhibitors represent a new strategy in human cancer therapy. In this study the combination of the HDAC inhibitor phenylbutyrate (PB) and the nucleoside analogue gemcitabine (GEM) was evaluated and the mechanisms underlying increased cell death were analyzed. METHODS: Dose escalation studies evaluating the cytotoxicity of PB (0.01-100 mM), GEM (0.01-100 microg/ml) and a combination of the two were performed on two NSCLC cell lines (BEN and KNS62). Apoptotic cell death was quantified. The involvement of caspase-dependent cell death and MAP-kinase activation was analyzed. Additionally, mitochondrial damage was determined. In an orthotopic animal model the combined effect of PB and GEM on therapy was analyzed. RESULTS: Applied as a single drug both GEM and PB revealed limited potential to induce apoptosis in KNS62 and Ben cells. Combination therapy was 50-80% (p = 0.012) more effective than either agent alone. On the caspase level, combination therapy significantly increased cleavage of the pro-forms compared to single chemotherapy. The broad spectrum caspase-inhibitor zVAD was able to inhibit caspase cleavage completely, but reduced the frequency of apoptotic cells only by 30%. Combination therapy significantly increased changes in MTP and the release of cyto-c, AIF and Smac/Diabolo into the cytoplasm. Furthermore, the inhibitors of apoptosis c-IAP1 and c-IAP2 were downregulated and it was shown that in combination therapy JNK activation contributed significantly to induction of apoptosis. The size of the primary tumors growing orthotopically in SCID mice treated for 4 weeks with GEM and PB was significantly reduced (2.2-2.7 fold) compared to GEM therapy alone. The Ki-67 (KNS62: p = 0.015; Ben: p = 0.093) and topoisomerase IIalpha (KNS62: p = 0.008; Ben: p = 0.064) proliferation indices were clearly reduced in tumors treated by combination therapy, whereas the apoptotic index was comparably low in all groups. CONCLUSION: Therapy combining GEM and the HDAC inhibitor PB initiates a spectrum of apoptosis-inducing mitochondrial and further JNK-dependent events, thereby overcoming the therapeutic resistance of NSCLC tumor cells. In vivo, the combination therapy substantially reduced tumor cell proliferation, suggesting that the well tolerated PB is a useful supplemental therapeutic agent in NSCLC.

Case report: successful interdisciplinary treatment of cerebrally disseminated invasive pulmonal aspergillosis in a child with acute myeloid leukemia.

Invasive pulmonary aspergillosis (IPA) is a life-threatening infection in immunocompromised patients. Mortality rates of cerebrally disseminated IPA approach 100%. We report on a case of a 9-year-old girl with acute myeloid leukemia, who acquired cerebrally disseminated IPA during chemotherapy-induced leukopenia. Longtime survival was achieved by left pneumonectomy and neurosurgical resection of the intracerebral lesion combined with systemic application of itraconazole and liposomal amphotericin B. A review of literature revealed 7 other cases of cerebrally disseminated IPA with survival of more than 12 months.

Resistance developing after long-term ganciclovir prodrug treatment in a preclinical model of NSCLC.

BACKGROUND: We recently demonstrated a 100% increase in the survival period with ganciclovir (GCV) therapy in mice hearing orthotopic HSV-TK-positive non-small cell lung cancer (NSCLC) tumors. However, long-term survival was not achieved. The aim of the present study was to evaluate tumor growth during extended GCV therapy and to monitor the herpes simplex virus thymidine kinase (HSV-TK) gene and protein in tumors at different time points. MATERIALS AND METHODS: The human NSCLC cell line KNS 62 was retrovirally transduced with the HSV-TK30 gene. Cell suspensions in which 100% or 25% of the cells were TK30-positive were inoculated subcutaneously in SCID bg mice. Tumor growth was evaluated during GCV therapy and HSV-TK DNA, RNA and protein were analyzed at different time points using PCR, RT-PCR and immunoblotting. RESULTS: HSV-TK DNA, RNA and TK30 protein were demonstrated in the tumors 21 days after subcutaneous tumor inoculation. TK-positive tumors regressed during GCV therapy and tumors in which 25% of the cells were TK-positive grew significantly more slowly than control tumors did. After 4 weeks of GCV therapy, HSV-TK DNA, RNA and TK protein were not detectable in the remaining tumors, which were therefore resistant to further GCV therapy. CONCLUSION: Prodrug therapy of the NSCLC cell line KNS 62, including bystander effects, is sufficient. Nevertheless, GCV-resistant tumors develop after functional loss of the TK gene. In the clinical context, further studies will need to evaluate immunological bystander effects or combinations with other drugs.

Retroviral endostatin gene transfer inhibits growth of human lung cancer in a murine orthotopic xenotransplant model.

BACKGROUND AND AIMS: The administration of endostatin, a potent anti-angiogenic agent, will be required for extended periods of time as a cancer treatment. The aim of the present study was to induce endogenous endostatin secretion in a continuous fashion, based on retroviral gene transfer. The tumor response was evaluated in an orthotopic murine tumor model of human lung cancer. MATERIALS AND METHODS: Human non-small-cell lung cancer cells (KNS 62) were retrovirally transduced with the human endostatin gene. An orthotopic murine xenotransplant model was used to investigate tumor growth, metastases and survival. After 4 weeks of subcutaneous growth, endostatin expression was measured by immunoblot analysis in tumor lysates. RESULTS: The growth of the subcutaneous tumors was significantly delayed, and orthotopic tumor growth and pleural metastases were significantly reduced in endostatin-transduced KNS 62 tumors. Prolongation of survival subsequent to orthotopic tumor induction was demonstrated. Strong endostatin expression was found in subcutaneous tumors after 4 weeks. CONCLUSION: Retroviral transduction of the human endostatin gene is capable of achieving long-term endostatin expression. Endostatin transduction provides significant anti-tumor effects with regard to local tumor growth, metastases and survival.

Wortmannin inhibits growth of human non-small-cell lung cancer in vitro and in vivo.

BACKGROUND AND AIMS: Recently we demonstrated that phosphatidylinositol 3-kinase (PI3K) is overexpressed in human lung cancer. This study evaluated whether the PI3K inhibiting agent wortmannin affects proliferation of human lung cancer cells in vitro and in vivo. METHODS: Effects of exposure of human non-small-cell lung cancer (NSCLC) cells (KNS-62, Colo-699) to wortmannin were investigated in vitro by proliferation, cytotoxicity, and DNA fragmentation assays. In vivo we examined the effects of blocking PI3K by wortmannin prior to xenotransplantation of human NSCLC cells into SCID-bg mice and the effect of systemic wortmannin administration following intrapulmonary xenotransplantation of human NSCLC. RESULTS: Exposure of KNS-62 and Colo-699 lung cancer cells to wortmannin inhibited proliferation in correlation to concentration in vitro. In vivo the blocking of PI3K by wortmannin prior to xenotransplantation caused a significant delay in the growth of subcutaneously induced tumors. Systemic wortmannin administration increased mean survival after intrapulmonary xenotransplantation of human NSCLC significantly by 38% and 47%. CONCLUSIONS: These data suggest inhibition of PI3K activity as a potential target for treatment of human NSCLC. Systemic toxicity of wortmannin requires development of improved PI3K inhibitors with favorable pharmacological properties.

Ganciclovir prodrug therapy is effective in a murine xenotransplant model of human lung cancer.

BACKGROUND: Therapy failures have been reported for retroviral gene transfer of herpes simplex virus thymidine kinase (HSV-TK) gene followed by systemic ganciclovir application in human lung cancer. Use of the HSV-TK mutant TK30 in combination with a VSV-G pseudotyped retroviral vector was found to enhance the efficacy of prodrug therapy. The present study evaluated this therapeutic strategy in human non-small cell lung cancer cell lines in a preclinical murine xenotransplant model. METHODS: Intrathoracally induced by HSV-TK30 transduced non-small cell lung cancer cell lines Colo 699 (adenocarcinoma) and KNS 62 (squamous cell carcinoma) were monitored for local tumor growth, survival, and metastases. So-called bystander effects were investigated in tumors consisting of as little as 25% TK30 transfected cells and by analysis of gap junctional protein connexin-43 expression. RESULTS: Survival was significantly prolonged, and tumor growth and pleural metastases were reduced in HSV-TK30-positive tumors of both cell lines. A significant therapeutic effect in bystander experiments was observed in squamous cell carcinoma. This was correlated with higher expression of connexin-43. CONCLUSIONS: Delivery of HSV-TK30 in a VSV-G pseudotyped retroviral vector and subsequent ganciclovir application provided therapeutic efficacy. Despite of low transduction rates achievable in gene transfer in situ, prodrug therapy appears to be feasible in tumor cells with efficient bystander effects.