Peter Dohrmann

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.

Effective treatment of malignant pleural effusion by minimal invasive thoracic surgery: thoracoscopic talc pleurodesis and pleuroperitoneal shunts in 101 patients

BACKGROUND For effective palliation of patients with malignant pleural effusion due to advanced neoplastic disease, any proposed treatment should have low procedure-related mortality and morbidity. METHODS The clinical outcome of 119 thoracoscopies in 101 patients (56 women, 45 men), from 42 to 91 years of age (mean, 68 +/- 9 years) with malignant pleural effusions was evaluated in a retrospective study. Video-assisted thoracoscopy (VATS) talc pleurodesis was done in 105 instances, and a pleuroperitoneal shunt was performed 14 times as an alternative when complete expansion of the lung could not be achieved due to tumor implants on the visceral pleura. RESULTS The VATS talc pleurodesis resulted in clinically significant improvement of dyspnea in 92.2% of the patients. Thirty-day mortality was 2.8% and morbidity was 2.8%. The mean duration of postoperative survival was 6.7 months. Recurrent pleural effusion occurred in 5.7% of patients after a mean interval of 6 months. Clinical relief of dyspnea was obtained in 73% of the patients treated with pleuroperitoneal shunts. Thirty-day mortality in this group was 21% and morbidity was 14.3%. The mean duration of survival was 4.2 months. CONCLUSIONS The VATS talc pleurodesis is appropriate for palliation of patients with malignant pleural effusions and should be performed once the diagnosis has been confirmed. Patients with lungs trapped by visceral carcinomatosis may benefit from placement of a pleuroperitoneal shunt as an alternative.

Overexpression of phosphatidylinositol 3-kinase in human lung cancer

Abstract. Background: This study was conducted to investigate the expression of phosphatidylinositol 3-kinase (PI3K) and AKT2, a downstream effector, in primary human lung carcinomas of different histological type. Methods: Specimens from 105 human lung carcinomas and their corresponding lymph nodes and liver metastases were examined using immunohistochemistry and Northern-blot assays to study the PI3K p85 and p110 subunits and the AKT2-expression patterns. Results: The p85 and p110 subunits of PI3K were overexpressed at the protein level in 77% and 59% of 80 primary lung carcinomas, respectively, irrespective of the histological type. PI3K overexpression was correlated with tumor grading. In contrast, no overexpression of PI3K subunits was observed in normal lung tissue and benign lung tumors. Consistent with these findings, upregulation of p110 mRNA transcripts was restricted to primary lung carcinomas. Overexpression of AKT2 was observed in 10% of the investigated lung tumor specimens, but in none of the healthy lung sections. A profound increase of PI3K expression was uniformly observed in lung tissue specimens and in corresponding extra-pulmonary lymph-node and liver metastases with low-differentiation grades. Conclusion: PI3K appears to be associated with the process of tumor-cell transformation and proliferation. One of its major downstream effector molecules, AKT2, which contributes to apoptotic cell death, was not upregulated by PI3K overexpression in primary lung carcinomas.

Endoluminal ultrasound diagnosis and operative management of rectal endometriosis

PURPOSE: Endorectal ultrasound was performed in patients with endometriosis to evaluate the role of this technique for rectal wall involvement and to evaluate the position of preoperative diagnosis in the operative management of rectal endometriosis. METHODS: Sixteen patients with suspected fixation of endometriomas to the rectal wall during bimanual examination were included in the study. Endorectal ultrasound was performed using a real time unit with a 7.5 MHz endorectal transducer. The probe was introducedviaa rectoscope into the rectum up to the rectosigmoid. RESULTS: Endometriosis was confirmed histopathologically in all patients. In six patients rectal wall involvement was diagnosed, in two patients endometriomas were adjacent to the rectal wall, and in eight patients rectal wall involvement could be excluded. Preoperative diagnosis was confirmed in all patients during operation. Laparotomy was performed in those patients with preoperatively diagnosed rectal wall involvement, whereas the remaining patients were treated laparoscopically. Endometriomas with rectal wall involvement were treated in five of six patients with resection of the affected bowel predominantly by low anterior resection. CONCLUSIONS: Preoperative endorectal ultrasound is a reliable technique to visualize perirectal endometriomas and to assess rectal wall involvement. Based on preoperative endosonographic diagnosis, an operative management was established with laparotomy and resection of the affected bowel in cases of rectal wall involvement.

Combretastatin A-4 prodrug inhibits growth of human non-small cell lung cancer in a murine xenotransplant model.

BACKGROUND Combretastatin A-4 prodrug (CA-4PD) has been identified as a potent antivascular agent in various rodent tumor models. The aim of this study was to investigate the effect of CA-4PD on human non-small cell lung cancer (NSCLC). METHODS Cytostatic and cytotoxic effects of CA-4PD on selected NSCLC cells, Colo-699 and KNS-62, were studied in vitro. After subcutaneous xenotransplantation the effect of systemically administrated CA-4PD on tumor growth was investigated in vivo. A newly established orthotopic xenotransplant model was employed to estimate prolongation of survival after intrapulmonary tumor induction with secondary metastatic disease. RESULTS In vitro, CA-4PD displayed a time and dose dependent antiproliferative effect on human lung cancer cells. In vivo, CA-4PD significantly delayed growth of subcutaneously induced lung cancer. This growth delay was translated into a prolongation of survival in the metastasizing orthotopic xenotransplant model. CONCLUSIONS In vitro CA-4PD inhibits proliferation of NSCLC cells, most likely by disruption of microtubule assembly. In vivo, systemic treatment inhibits growth of subcutaneously xenotransplanted tumors by an antivascular effect. In the case of metastasizing human lung cancer this translated into a prolongation of survival.

New method of radiotherapy for anal cancer with three-dimensional tumor reconstruction based on endoanal ultrasound and ultrasound-guided afterloading therapy.

PURPOSE: Standard treatment of anal cancer is a protocol of combined chemotherapy and percutaneous radiotherapy. We developed a new endosonography-based radiation target simulation method, because endoanal sonography gives the best opportunity to stage the tumor accurately. Based on this method, an afterloading needle application procedure could be performed to optimize the radiation target geometry and to control the application of afterloading needles. In a prospective study, this new method was evaluated, with special regard for complications and tumor recurrence. METHODS: Anal cancer was restaged endosonographically six weeks after external beam radiation with 45 Gy. A computer-generated three-dimensional reconstruction of the tumor and radiation target simulation was performed based on endoanal sonographic imaging. By using a new type of applicator, which is permeable to ultrasound waves, the transperineal implantation procedure of afterloading needles could be controlled. Application needles were inserted into the target area according to the endoanal sonography-based dosimetry planing. The dose of the (high-dose rate) brachytherapy boost was started with two 6-Gy fractions, each within eight days. The fraction dose was reduced to 4 Gy to minimize side effects. Lymph node-positive tumors got additional chemotherapy (5-fluorouracil and mitomycin C). RESULTS: From January 1992 until August 1996, we performed 42 endosonography-guided afterloading procedures in 18 patients. One patient underwent percutaneous radiation two years before and was treated only by afterloading radiation. In every patient, we found complete tumor remission at the end of radiotherapy. Three patients with a high-dose rate of 2×6 Gy developed radiogenic proctitis, and two patients developed ulceration, which lead to reduction of the dose. After reduction to 4 Gy per fraction, no more side effects could be seen. In follow-up (median, 24 (range, 1–56) months), we detected two anal cancer recurrences (2/18 patients). CONCLUSION: The radiation target field can be optimized by individual endosonography-based three-dimensional tumor reconstruction and radiotherapy simulation. Endosonography-guided transperineal implantation of afterloading needles can be performed according to the computer-generated simulation by using a new type of applicator. We could achieve total primary tumor remission in every patient. After reduction of the afterloading dose to 2×4 Gy, no brachytherapy-related side effects could be seen.

Human endostatin inhibits growth of human non-small-cell lung cancer in a murine xenotransplant model.

Overall prognosis in human NSCLC remains poor. Antiangiogenic treatment has become a promising concept for the treatment of solid malignancies. Our purpose was to evaluate the efficacy of recombinant HSENDO for the treatment of human NSCLC in an orthotopic murine xenotransplantation model. The efficacy of HSENDO was tested in vitro in cell‐proliferation, cell‐migration and tube‐formation assays. In vivo, the effect of HSENDO on tumor growth was tested in s.c. xenotransplanted human NSCLC and on intrapulmonary induced human NSCLC. In vitro, HSENDO inhibited both human and rodent endothelial cell proliferation in a time‐ and dose‐dependent fashion. Endothelial cell migration was inhibited by 97%. Tube formation of murine endothelial cells was inhibited and preexisting tubes degenerated after HSENDO exposure. In vivo, HSENDO delayed growth of s.c. xenotransplanted tumors. Immunohistochemic staining demonstrated no change in microvessel density but a significant reduction of proliferating tumor cells and an increase in bFGF and VEGF expression, reflecting the antiangiogenic effect of HSENDO. Intrapulmonary tumor induction caused death subsequent to metastatic disease. Systemic HSENDO application extended survival significantly. HSENDO was demonstrated to inhibit endothelial cell proliferation, migration and tube formation effectively. In vivo growth of s.c. transplanted tumors was delayed and survival extended by 32% and 69%, respectively, after intrapulmonary NSCLC induction.

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

Abstract 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.

An improved orthotopic xenotransplant procedure for human lung cancer in SCID bg mice.

BACKGROUND Overall prognosis in human lung cancer is still poor. A highly reproducible, easy to perform in vivo model, which closely resembles the clinical features of advanced human lung cancer, is required for the evaluation of novel therapies. METHODS Tumor cells, originated from a human adenocarcinoma, a squamous cell carcinoma, and an undifferentiated large cell carcinoma, were xenotransplanted heterotopically by subcutaneous and intravenous injection and compared with orthotopic intrapleural and intrapulmonary xenotransplantation by a facilitated engraftment procedure into SCID bg mice. RESULTS Subcutaneous injection of tumor cells resulted in a 100% engraftment rate with establishment of solid tumors without clinically relevant metastases. Intravenous injection had poor engraftment rates by hematogenous spread. Depending on the cell line, a 80% to 100% engraftment rate in orthotopic xenotransplantation was achieved, resulting in a consistent pattern of mediastinal and bilateral pulmonary metastases. CONCLUSIONS The facilitated orthotopic xenotransplantation of human lung cancer is easy to perform and results in a reproducible in vivo model that closely resembles the clinical features of advanced human lung cancer. Consequently, this model appears suitable for in vivo evaluation of novel cancer therapies in preclinical tests.

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 μg/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 IIα (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.