Studies in health technology and informatics, 2014
Healthcare innovations are crucial for enhancing patient treatment and a high-quality healthcare ... more Healthcare innovations are crucial for enhancing patient treatment and a high-quality healthcare system. However, bringing new technologies, methods and procedures into the healthcare market is challenging. Enormous amounts of financial, personnel and organizational resources are required with no upfront certainty for the medical and economic benefit. A new and innovative approach uses interdisciplinary medical, technical and economic expertise to forecast effects of healthcare innovations already at the early research and concept phase of an idea and before major investments are made. A process model framework was developed to operationalize this structured assessment of healthcare innovations. The Visionary Iterative Tailored Approach (VITA) is based on conceptual modeling, simulation and health economics evaluation. Its application for the prospective assessment of an innovative prostate cancer screening is presented.
Second in incidence behind breast cancer, lung cancer causes by far the highest death toll worldw... more Second in incidence behind breast cancer, lung cancer causes by far the highest death toll worldwide. Recent progress in systemic treatment with the introduction of targeted therapy and immunotherapy lead to encouraging improvement in long term survival. However, the overall prognosis remains still poor. This can be attributed to the fact, that lung cancer remains clinically silent for a long period of time and is therefore diagnosed at advanced stages which limits the curative options. Cigarette smoking is accountable for 80-90% of all lung cancers and it is estimated that more than one in five adults in the world smoke tobacco. These two aspects advocate for two streams of lung cancer prevention: (I) primary prevention with smoking prevention and cessation and (II) secondary prevention with early disease detection through low dose chest computed tomography. Evidence from randomized controlled trails could prove that low-dose chest CT based screening of patients at risk is able to reduce lung cancer related mortality. This led to the recommendation for lung cancer screening with low dose CT in the United States. Individuals are enrolled in the program based on their smoking history and age. Still, the optimal selection of screening candidates is a matter of debate. Recently the United States Preventive Task Force adapted the eligibility criteria for screening from ≥30 to ≥20 PY as it became obvious that current smokers of 20-29 PY have a similar risk compared to former smokers of ≥30 PY who quit smoking within 15 years (a second eligibility criterium for screening). In his contribution to this series, Pilz discusses in more detail how to enhance the selection of a screening population based on independent risk factors integrated into a risk model. This might be a way to increase the effectiveness of a lung cancer screening program. Lung cancer screening CTs are currently conducted on an annual basis in the US. This adds an additional burden to the radiologists and requires an accurate longitudinal measurement of lesions if follow-up CTs, e.g., after 3 months were conducted to catch the lesion's growth dynamic. Measurements of small pulmonary nodules therefore must be highly accurate to avoid wrong conclusions. In their work, Sartorio and colleagues discuss the value of volumetric measurements compared to diameter as an option to increase the precision of nodule measurement as a prerequisite for follow-up. In addition to semiautomated volume measurement, it is reported by Yang et al. in this series, that new tools such as radiomics or neural network based deep learning approaches will help to increase the accuracy of classification. This will improve risk stratification of lung nodules detected by screening. Once a lung nodule is detected and the indication for a biopsy is set, the impact of underlying tumor heterogeneity on the efficacy of a core needle biopsy to allow a histopathological and molecular diagnostic characterization of a tumor needs to be considered. As an important contribution to this lung cancer screening series, the chance of detecting different histopathological and molecular features from a tumor specimen gained by a core needle biopsy is discussed by Binder et al. As lung cancer screening is conducted as serial chest CT examinations e.g., on an annual basis, the aspect of cumulative radiation dose exposure is of high relevance. Several techniques have been developed to reduce the dose exposure to the patient and one of these-namely iterative reconstruction is discussed by Köng et al. in this series. We know through other screening programs that screening can cause psychological distress. Apparently, it is important to consider psychological factors associated with lung cancer screening as well. In their work, Garcia et al. discuss the impact of false positive findings or indeterminate nodules and stigmatization of the individual by screening for lung cancer. This special series in Shanghai Chest on lung cancer screening provides insights form renowned experts in their field to important aspects of lung cancer screening going beyond just scanning persons at risk.
Incidence of febrile neutropenia following cytotoxic treatment of tumor patients can be reduced b... more Incidence of febrile neutropenia following cytotoxic treatment of tumor patients can be reduced by prophylactic G-CSF treatment. We report results of a prospective open non-interventional multicenter observational trial in 2233 patients on lenograstim, a recombinant glycoprotein (rHuG-CSF) expressed and glycosylated in Chinese hamster ovary cells. In total 10 846 courses of chemotherapy followed by G-CSF treatment have been documented for either hematologic or oncologic malignancies (breast and ovarian cancer 4207 courses, Hodgkin’s disease and Non Hodgkin’s lymphoma 4381 courses, lung cancer 780 courses, other malignancies 1478 courses, respectively). Lenogratim was administered either interventionally or to less amount for prophylaxis of granulocytopenia; the mean daily dosage was 263 micrograms subcutaneously. A significant number of patients were treated for stage III or IV disease. Almost 1/3 of the patients (34,2%) were elderly aged at least 65 years old. The patients had not ...
Purpose of review This review highlights the status and developments of PET imaging in oncology, ... more Purpose of review This review highlights the status and developments of PET imaging in oncology, with particular emphasis on lung cancer. We discuss the significance of PET for diagnosis, staging, decision-making, monitoring of treatment response, and drug development. The PET key advantage, the noninvasive assessment of functional and molecular tumor characteristics including tumor heterogeneity, as well as PET trends relevant to cancer care are exemplified. Recent findings Advances of PET and radiotracer technology are encouraging for multiple fields of oncological research and clinical application, including in-depth assessment of PET images by texture analysis (radiomics). Whole body PET imaging and novel PET tracers allow assessing characteristics of most types of cancer. However, only few PET tracers in addition to 18F-fluorodeoxyglucose have sufficiently been validated, approved, and are reimbursed for a limited number of indications. Therefore, validation and standardization of PET parameters including tracer dosage, image acquisition, post processing, and reading are required to expand PET imaging as clinically applicable approach. Summary Considering the potential of PET imaging for precision medicine and drug development in lung and other types of cancer, increasing efforts are warranted to standardize PET technology and to provide evidence for PET imaging as a guiding biomarker in nearly all areas of cancer treatment.
In a previous study, we found that treatment of HCT-8 cells with ZD1694, a specific antifolate-ba... more In a previous study, we found that treatment of HCT-8 cells with ZD1694, a specific antifolate-based thymidylate synthase inhibitor, resulted in DNA fragmentation. In this study, we have demonstrated the dose-and time-dependent induction of DNA fragmentation accompanied by elevation of p53 and WAF1 protein expression by ZD1694. WAF1 mRNA showed a timedependent increase, whereas p53 mRNA was not found to be significantly overexpressed. The initial increase in WAF1 mRNA was detected at 4 hr, but increased WAF1 protein expression was detected 8-24 hr after a 2-hr exposure. The amount of total and hypophosphorylated pRb seems to be rising greatly after ZD1694 exposure. The effects of ZD1694 on the expression of E2F1 and formation of the E2F1-Rb complex were investigated after a 2-hr drug exposure (IC 90). The results showed a time-dependent decrease in E2F1 mRNA and protein Supported in part by Project Grants CA65761 and CA56890 from the National Cancer Institute.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, Jan 26, 2017
Although the effectiveness of screening for lung cancer remains controversial, it is a fact that ... more Although the effectiveness of screening for lung cancer remains controversial, it is a fact that the majority of lung cancers are diagnosed at an advanced stage outside of lung cancer screening programs. In 2013, the U.S. Preventive Services Task Force (USPSTF) revised its lung cancer screening recommendation, now supporting lung cancer screening by low-dose computed tomography (LDCT) in patients at high risk. This is also endorsed by many major medical societies and advocacy group stakeholders, however with different eligibility criteria. In Europe, population-based lung cancer screening has so far not been recommended or implemented, as some important issues remain unresolved. Among them remains the open question on how enlarging pulmonary nodules (PNs) detected in lung cancer screening should be managed. This article comprises two parts: a review of the current lung cancer screening approaches, as well as the potential therapeutic options for enlarging PNs, followed by a meeting ...
Thyroid cancer accounts for approximately only 1% of all reported malignancies, but is the most c... more Thyroid cancer accounts for approximately only 1% of all reported malignancies, but is the most common endocrine malignancy. 1 It is of either follicular cell origin with well-differentiated papillary thyroid cancer and follicular thyroid cancer, poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC), or of parafollicular C-cell origin with medullary thyroid cancer (MTC). 2 ATC, one of the most aggressive malignancies in humans, accounts for approximately 2-5% and MTC for approximately 3-5% of all thyroid cancers. 2 Owing to their distinct clinical and molecular characteristics, different multimodal treatment strategies have to be pursued.
Background: Multidisciplinary care of prostate cancer is increasingly offered in specialised canc... more Background: Multidisciplinary care of prostate cancer is increasingly offered in specialised cancer centres. It requires the optimisation of medical and operational processes and the integration of the different medical and non-medical stakeholders. Objective: To develop a standardised operational process assessment tool basing on the capability maturity model integration (CMMI) able to implement multidisciplinary care and improve process quality and efficiency. Design, Setting, and Participants: Information for model development was derived from medical experts, clinical guidelines, best practice elements of renowned cancer centres, and scientific literature. Data were organised in a hierarchically structured model, consisting of 5 categories, 30 key process areas, 172 requirements, and more than 1500 criteria. Compliance with requirements was assessed through structured on-site surveys covering all relevant clinical and management processes. Comparison with best practice standards allowed to recommend improvements. 'Act On Oncology'(AoO) was applied in a pilot study on a prostate cancer unit in Europe. Results and Limitations: Several best practice elements such as multidisciplinary clinics or advanced organisational measures for patient scheduling were observed. Substantial opportunities were found in other areas such as centre management and infrastructure. As first improvements the evaluated centre administration described and formalised the organisation of the prostate cancer unit with defined personnel assignments and clinical activities and a formal agreement is being worked on to have structured access to First-Aid Posts. Conclusions: In the pilot study, the AoO approach was feasible to identify opportunities for process improvements. Measures were derived that might increase the operational process quality and efficiency.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2015
Modern imaging techniques that can provide functional information on tumor vascularization, metab... more Modern imaging techniques that can provide functional information on tumor vascularization, metabolic activity, or cellularity have seen significant improvements over the past decade. However, most of these techniques are currently not broadly utilized neither in clinical trials nor in clinical routine, although there is a large agreement on the fact that conventional approaches for therapy response assessment such as Response Evaluation Criteria in Solid Tumors or World Health Organization criteria-that exclusively focus on the change in tumor size-are of less value for response assessment in modern thoracic oncology. The aim of this article comprises two parts: a short review of the most promising state-of-the-art imaging techniques that have the potential to play a larger role in thoracic oncology within the near future followed by a meeting report including recommendations of an interdisciplinary expert panel that discussed the potential of the different techniques during the Dr...
Journal of Hematotherapy & Stem Cell Research, 2002
TRANSMISSION OF DONOR CELL NEOPLASIA to recipients of allogeneic stem cell transplantation has be... more TRANSMISSION OF DONOR CELL NEOPLASIA to recipients of allogeneic stem cell transplantation has been reported twice. Niederwieser described the first case in 1990, in which an acute myeloid leukemia was transplanted with marrow graft (1). Recently Berg et al. described manifestations of donor cell-type non-Hodgkin’s lymphoma 3 years after transplantation (2). Information about the donor’s bone marrow state pre-donation was not given. We have evaluated a 65-year-old male sibling for stem cell donation for his HLA-identical sister suffering from chronic myeloid leukemia. The man’s history did not give any hint of a hematological malignancy. B signs were not reported. The ultrasonic-measured spleen size was 1023 36.8 mm. Routine parameters of clinical chemistry and automated and microscopy blood cell examination gave normal results. Diagnostic bone marrow examination was done despite it not being required in routine donor evaluation, neither by literature nor by the National Marrow Donor Program (NMDP) in the United States or by the German Bone Marrow Donor Registry (DKMS) (3,4). The picture by microscopy of the marrow smear was normal; however, using fluorescence-activated cell sorting (FACS) analysis, a mature B cell population with co-expression of CD5 and CD23 monoclonal for k-light chains was detected (5). Four weeks later, a slight lymphocytosis of 45% was seen in peripheral blood, and immunohistological bone marrow examination confirmed slight infiltration of the marrow by chronic lymphocytic leukemia. The man was withdrawn from stem cell donation and a search for an unrelated donor was initiated. We conclude that there is a potential risk of transmission of donor cell neoplasia in early stages by stem cell transplantation. In the described case, the standard procedures of stem cell donor evaluation were not sufficient to detect occult chronic lymphocytic leukemia. Although the detection of an occult lymphoma in potential stem cell donors is a rare event, marrow puncture for cytological examination and flow cytometry should be considered in preharvest evaluation of the potential donor, at least in elderly people. The more painful biopsy of marrow for histological examination should only be performed in case of suspicious results obtained by cytology or cytometry.
tetrahydro-2H-pyran-2-yloxy)R 1)R 2-diamminedichloroplatinum(II) complexes (1-12) consisting of C... more tetrahydro-2H-pyran-2-yloxy)R 1)R 2-diamminedichloroplatinum(II) complexes (1-12) consisting of CDDP linked to THP via aliphatic CH 2-spacers were tested in two TGCT cell lines. The most promising compound, 2-(4-(tetrahydro-2H-pyran-2-yloxy)-undecyl)-propane-1,3-diamminedichloroplatinum(II) (12), completely overcame CDDP resistance of 1411HP cells, correlating with increased and accelerated cellular platinum uptake and much faster initiation of apoptotic cell kill. At equitoxic IC 90 concentrations, 12 induced accelerated DNA fragmentation and caspase-3 and PARP cleavages. In contrast, DNA platination rate was much lower as compared to CDDP and no upregulation of p53 as well as no initiation of cell cycle arrest were observed. Apoptosis induction by 12 could not be inhibited by pretreatment with caspase-specific inhibitor Z-VAD-Fmk and was accompanied by strong calcium release and generation of reactive oxygen species. To summarize, 12 overcomes CDDP resistance and induces programmed cell death with molecular features different from CDDP, suggesting that both drugs induce apoptosis through different initial pathways.
6-Aminomethylnicotinate)dichloridoplatinum(II) complexes 4 esterified with terpene alcohols were ... more 6-Aminomethylnicotinate)dichloridoplatinum(II) complexes 4 esterified with terpene alcohols were tested on a panel of five human tumor cell lines. While they were accumulated in all cell lines more readily than cisplatin (CDDP), their cytotoxicities were tumor-specific and structure-dependent. Cell lines known to feature elevated levels of antiapoptotic, ion-channel-affecting proteins or otherwise impaired caspase-9 activation responded better to 4 than to CDDP, e.g., the HL-60 leukemia to the fenchyl and bornyl derivatives 4a,b at an IC 90 e 10 µM. The (-)-menthyl complex 4g was far better accumulated and more efficacious in CDDP-resistant 1411HP male germ cell tumor cells than in the congenerous CDDP-sensitive H12.1 cell line. 4g also broke the CDDP resistance of 518A2 melanoma cells. Cell decay in each case was apoptotic as to TUNEL and Annexin V fluorescence assays. Some complexes 4 seem to positively modulate the permeability of the cell membrane and of blocked mitochondrial anion channels.
Journal of Cancer Research and Clinical Oncology, 2004
To evaluate the ability of D-saccharic acid 1.4-lactone (SAL), a b-glucuronidase inhibitor, to pr... more To evaluate the ability of D-saccharic acid 1.4-lactone (SAL), a b-glucuronidase inhibitor, to prevent irinotecan hydrochloride (CPT-11) from inducing mucosal damage as a cause of diarrhea in rats. Methods: Wistar rats were divided into six groups of three animals each, administered 1.0 ml isotonic solution intraperitoneally once daily for up to three consecutive days, respectively for up to six days. The series were as follows: (1) On days 1-3: saline; (2). On days 1-3: 200 mg CPT-11/m 2 ; (3) On days)3 to)1 relative to the first administration of CPT-11: 10 mg/ml SAL; on days 1-3: 200 mg CPT-11/m 2 ; (4) On days)3 to +3 relative to the first administration of CPT-11: 10 mg/ml SAL, and on days 1-3: additional 200 mg CPT-11/m 2 ; (5) On days 1-3: 200 mg CPT-11/m 2 (0.5 ml) + 10 mg/0.5 ml SAL; (6) On days)3 to)1 relative to the first administration of CPT-11: 3 mg/ml SAL, and on days 1-3: 200 mg CPT-11/m 2. Luminal mucosa damage of the small intestine was detected by histology 24 h after the last intraperitoneal application. Peptidase activities of the proximal jejunum were measured by using an in situ perfusion model. Results: Following intraperitoneal CPT-11 treatment, using conventional histology of paraffin sections, we observed severe mucosal damage. This was reflected by a decrease of the villi/crypt ratio, an increase of apoptotic cells, as well as an increase of mitotic figures in the crypt region. There was a concomitant increased lymphatic infiltration in mucosa of CPT-11 treated rats. This damage pattern could be clearly reduced by co-treatment with the b-glucuronidase inhibitor, SAL, independent of the treatment schedule. In contrast to our expectations based on previous reports, the intraperitoneal application of CPT-11 alone or in combination with SAL did not cause significant differences in luminal enzyme liberation in comparison with controls in the in situ perfusion assay. Conclusions: The b-glucuronidase inhibitor SAL is able to significantly reduce CPT-11-induced mucosal damage in the small intestine of rats. This observation might soon have a clinical impact for the treatment of patients with CPT-11.
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1998
The newly synthesized calcium channel blocker, Ro44-5912, significantly potentiates doxorubicin D... more The newly synthesized calcium channel blocker, Ro44-5912, significantly potentiates doxorubicin Dox-induced cytotoxicity at non-cytotoxic concentrations in Dox-resistant human ovarian cell line, A2780rDX5, overexpressing Ž. Ž. P170-glycoprotein Pgp. Induction of DNA single-and double-strand breaks ssbs and dsbs was measured using alkaline Ž. elution and constant-field gel electrophoresis CFGE assays. The results indicate that potentiation of the cytotoxicity of Dox by Ro44-5912 was accompanied by significant increases in both, Dox-induced DNA ssbs and dsbs in the resistant Ž. cells. Pulsed-field gel electrophoresis PFGE analysis showed that Dox induced DNA fragments in the 50-800 kilobase Ž. Ž. kb and 0.8-5.7 megabase Mb ranges. The majority of the newly synthesized DNA fragments were in the 50-800 kb range. Ro44-5912 treatment resulted in significant potentiation of DNA fragmentation in the 50-800 kb range with a minor increase in 0.8-5.7 Mb DNA fragments, suggesting that the modulator functions by potentiating nascent DNA fragmentation in the resistant cells. Exposure to Dox with Ro44-5912 was associated with a prolonged blockage of cells in the Ž. S-phase. In contrast, exposure to Dox alone resulted in temporary blockage of cells in G rM phase ; 24 h followed by 2 restoration of cell proliferation and normal DNA histograms at 48 h after 2 h drug exposure. Incorporation of BrdUrd by flow cytometric analysis was inhibited by Dox in the presence of Ro44-5912, showing that there is a block of DNA replication. An increased damage in newly synthesized DNA could concur with a blocked DNA replication. Moreover, slowing progression through the S-phase in cells exposed to Dox in combination with Ro44-5912 is accompanied by increased sensitivity of Dox poisons, indicating a correlation of specific S-phase perturbation with the reversal of Dox resistance by Ro44-5912 in cells expressing Pgp. The results suggest that drug-induced augmentation of nascent DNA fragmentation and specific cell-cycle perturbation are potentially important molecular determinants for reversal of multidrug resistance in addition to restoration of intracellular drug retention. q 1998 Elsevier Science B.V.
Although the majority of testicular germ cell tumors (TGCTs) are curable by cisplatin-based chemo... more Although the majority of testicular germ cell tumors (TGCTs) are curable by cisplatin-based chemotherapy, in a few cases, the occurrence of cisplatin resistance results in a poor outcome. The biological basis of this differential cisplatin sensitivity in TGCTs remains largely unexplained. Embryonal carcinoma (EC) cells represent the presumptive tumor stem cells in nonseminomatous TGCTs and are known to express the embryonal transcription factor Oct-3/4 and to be hypersensitive to cisplatin. In the present study, we analyzed TGCT cell lines and nude mouse xenografts showing differential cisplatin sensitivity. Here we demonstrate that a lack of expression of Oct-3/4 in TGCT cells is associated with a higher apoptotic threshold and cisplatin resistance which is accompanied by an impaired caspase-9 activation, reduced caspase-3 activity and altered p53 accumulation. We were able to induce loss of Oct-3/4 in a cisplatin-sensitive EC cell line resulting in a secondary cisplatin-resistant cell type with retained EC cell characteristics and changes in apoptotic signaling identical to those in primary resistant cells. Furthermore, we show that EC cells are retained in their undifferentiated state by Oct-3/4 and that a complete and ultimate loss of Oct-3/4 followed by an early differentiation step is necessary to establish the cisplatin-resistant state. Our data suggest that loss of Oct-3/4 expression leads to induction of a higher apoptotic threshold and to cisplatin resistance in EC cells of nonseminomatous TGCTs. We hypothesize that in refractory TGCTs the original tumor stem cell population of Oct-3/4-positive, cisplatin-sensitive EC cells could be replaced by an Oct-3/4-negative, resistant population in a selection process. In contrast, the presence of the Oct-3/4-positive, highly sensitive EC cells as the tumor stem cell component in most TGCTs could explain the general high chemosensitivity and curability of these tumors.
Studies in health technology and informatics, 2014
Healthcare innovations are crucial for enhancing patient treatment and a high-quality healthcare ... more Healthcare innovations are crucial for enhancing patient treatment and a high-quality healthcare system. However, bringing new technologies, methods and procedures into the healthcare market is challenging. Enormous amounts of financial, personnel and organizational resources are required with no upfront certainty for the medical and economic benefit. A new and innovative approach uses interdisciplinary medical, technical and economic expertise to forecast effects of healthcare innovations already at the early research and concept phase of an idea and before major investments are made. A process model framework was developed to operationalize this structured assessment of healthcare innovations. The Visionary Iterative Tailored Approach (VITA) is based on conceptual modeling, simulation and health economics evaluation. Its application for the prospective assessment of an innovative prostate cancer screening is presented.
Second in incidence behind breast cancer, lung cancer causes by far the highest death toll worldw... more Second in incidence behind breast cancer, lung cancer causes by far the highest death toll worldwide. Recent progress in systemic treatment with the introduction of targeted therapy and immunotherapy lead to encouraging improvement in long term survival. However, the overall prognosis remains still poor. This can be attributed to the fact, that lung cancer remains clinically silent for a long period of time and is therefore diagnosed at advanced stages which limits the curative options. Cigarette smoking is accountable for 80-90% of all lung cancers and it is estimated that more than one in five adults in the world smoke tobacco. These two aspects advocate for two streams of lung cancer prevention: (I) primary prevention with smoking prevention and cessation and (II) secondary prevention with early disease detection through low dose chest computed tomography. Evidence from randomized controlled trails could prove that low-dose chest CT based screening of patients at risk is able to reduce lung cancer related mortality. This led to the recommendation for lung cancer screening with low dose CT in the United States. Individuals are enrolled in the program based on their smoking history and age. Still, the optimal selection of screening candidates is a matter of debate. Recently the United States Preventive Task Force adapted the eligibility criteria for screening from ≥30 to ≥20 PY as it became obvious that current smokers of 20-29 PY have a similar risk compared to former smokers of ≥30 PY who quit smoking within 15 years (a second eligibility criterium for screening). In his contribution to this series, Pilz discusses in more detail how to enhance the selection of a screening population based on independent risk factors integrated into a risk model. This might be a way to increase the effectiveness of a lung cancer screening program. Lung cancer screening CTs are currently conducted on an annual basis in the US. This adds an additional burden to the radiologists and requires an accurate longitudinal measurement of lesions if follow-up CTs, e.g., after 3 months were conducted to catch the lesion's growth dynamic. Measurements of small pulmonary nodules therefore must be highly accurate to avoid wrong conclusions. In their work, Sartorio and colleagues discuss the value of volumetric measurements compared to diameter as an option to increase the precision of nodule measurement as a prerequisite for follow-up. In addition to semiautomated volume measurement, it is reported by Yang et al. in this series, that new tools such as radiomics or neural network based deep learning approaches will help to increase the accuracy of classification. This will improve risk stratification of lung nodules detected by screening. Once a lung nodule is detected and the indication for a biopsy is set, the impact of underlying tumor heterogeneity on the efficacy of a core needle biopsy to allow a histopathological and molecular diagnostic characterization of a tumor needs to be considered. As an important contribution to this lung cancer screening series, the chance of detecting different histopathological and molecular features from a tumor specimen gained by a core needle biopsy is discussed by Binder et al. As lung cancer screening is conducted as serial chest CT examinations e.g., on an annual basis, the aspect of cumulative radiation dose exposure is of high relevance. Several techniques have been developed to reduce the dose exposure to the patient and one of these-namely iterative reconstruction is discussed by Köng et al. in this series. We know through other screening programs that screening can cause psychological distress. Apparently, it is important to consider psychological factors associated with lung cancer screening as well. In their work, Garcia et al. discuss the impact of false positive findings or indeterminate nodules and stigmatization of the individual by screening for lung cancer. This special series in Shanghai Chest on lung cancer screening provides insights form renowned experts in their field to important aspects of lung cancer screening going beyond just scanning persons at risk.
Incidence of febrile neutropenia following cytotoxic treatment of tumor patients can be reduced b... more Incidence of febrile neutropenia following cytotoxic treatment of tumor patients can be reduced by prophylactic G-CSF treatment. We report results of a prospective open non-interventional multicenter observational trial in 2233 patients on lenograstim, a recombinant glycoprotein (rHuG-CSF) expressed and glycosylated in Chinese hamster ovary cells. In total 10 846 courses of chemotherapy followed by G-CSF treatment have been documented for either hematologic or oncologic malignancies (breast and ovarian cancer 4207 courses, Hodgkin’s disease and Non Hodgkin’s lymphoma 4381 courses, lung cancer 780 courses, other malignancies 1478 courses, respectively). Lenogratim was administered either interventionally or to less amount for prophylaxis of granulocytopenia; the mean daily dosage was 263 micrograms subcutaneously. A significant number of patients were treated for stage III or IV disease. Almost 1/3 of the patients (34,2%) were elderly aged at least 65 years old. The patients had not ...
Purpose of review This review highlights the status and developments of PET imaging in oncology, ... more Purpose of review This review highlights the status and developments of PET imaging in oncology, with particular emphasis on lung cancer. We discuss the significance of PET for diagnosis, staging, decision-making, monitoring of treatment response, and drug development. The PET key advantage, the noninvasive assessment of functional and molecular tumor characteristics including tumor heterogeneity, as well as PET trends relevant to cancer care are exemplified. Recent findings Advances of PET and radiotracer technology are encouraging for multiple fields of oncological research and clinical application, including in-depth assessment of PET images by texture analysis (radiomics). Whole body PET imaging and novel PET tracers allow assessing characteristics of most types of cancer. However, only few PET tracers in addition to 18F-fluorodeoxyglucose have sufficiently been validated, approved, and are reimbursed for a limited number of indications. Therefore, validation and standardization of PET parameters including tracer dosage, image acquisition, post processing, and reading are required to expand PET imaging as clinically applicable approach. Summary Considering the potential of PET imaging for precision medicine and drug development in lung and other types of cancer, increasing efforts are warranted to standardize PET technology and to provide evidence for PET imaging as a guiding biomarker in nearly all areas of cancer treatment.
In a previous study, we found that treatment of HCT-8 cells with ZD1694, a specific antifolate-ba... more In a previous study, we found that treatment of HCT-8 cells with ZD1694, a specific antifolate-based thymidylate synthase inhibitor, resulted in DNA fragmentation. In this study, we have demonstrated the dose-and time-dependent induction of DNA fragmentation accompanied by elevation of p53 and WAF1 protein expression by ZD1694. WAF1 mRNA showed a timedependent increase, whereas p53 mRNA was not found to be significantly overexpressed. The initial increase in WAF1 mRNA was detected at 4 hr, but increased WAF1 protein expression was detected 8-24 hr after a 2-hr exposure. The amount of total and hypophosphorylated pRb seems to be rising greatly after ZD1694 exposure. The effects of ZD1694 on the expression of E2F1 and formation of the E2F1-Rb complex were investigated after a 2-hr drug exposure (IC 90). The results showed a time-dependent decrease in E2F1 mRNA and protein Supported in part by Project Grants CA65761 and CA56890 from the National Cancer Institute.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, Jan 26, 2017
Although the effectiveness of screening for lung cancer remains controversial, it is a fact that ... more Although the effectiveness of screening for lung cancer remains controversial, it is a fact that the majority of lung cancers are diagnosed at an advanced stage outside of lung cancer screening programs. In 2013, the U.S. Preventive Services Task Force (USPSTF) revised its lung cancer screening recommendation, now supporting lung cancer screening by low-dose computed tomography (LDCT) in patients at high risk. This is also endorsed by many major medical societies and advocacy group stakeholders, however with different eligibility criteria. In Europe, population-based lung cancer screening has so far not been recommended or implemented, as some important issues remain unresolved. Among them remains the open question on how enlarging pulmonary nodules (PNs) detected in lung cancer screening should be managed. This article comprises two parts: a review of the current lung cancer screening approaches, as well as the potential therapeutic options for enlarging PNs, followed by a meeting ...
Thyroid cancer accounts for approximately only 1% of all reported malignancies, but is the most c... more Thyroid cancer accounts for approximately only 1% of all reported malignancies, but is the most common endocrine malignancy. 1 It is of either follicular cell origin with well-differentiated papillary thyroid cancer and follicular thyroid cancer, poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC), or of parafollicular C-cell origin with medullary thyroid cancer (MTC). 2 ATC, one of the most aggressive malignancies in humans, accounts for approximately 2-5% and MTC for approximately 3-5% of all thyroid cancers. 2 Owing to their distinct clinical and molecular characteristics, different multimodal treatment strategies have to be pursued.
Background: Multidisciplinary care of prostate cancer is increasingly offered in specialised canc... more Background: Multidisciplinary care of prostate cancer is increasingly offered in specialised cancer centres. It requires the optimisation of medical and operational processes and the integration of the different medical and non-medical stakeholders. Objective: To develop a standardised operational process assessment tool basing on the capability maturity model integration (CMMI) able to implement multidisciplinary care and improve process quality and efficiency. Design, Setting, and Participants: Information for model development was derived from medical experts, clinical guidelines, best practice elements of renowned cancer centres, and scientific literature. Data were organised in a hierarchically structured model, consisting of 5 categories, 30 key process areas, 172 requirements, and more than 1500 criteria. Compliance with requirements was assessed through structured on-site surveys covering all relevant clinical and management processes. Comparison with best practice standards allowed to recommend improvements. 'Act On Oncology'(AoO) was applied in a pilot study on a prostate cancer unit in Europe. Results and Limitations: Several best practice elements such as multidisciplinary clinics or advanced organisational measures for patient scheduling were observed. Substantial opportunities were found in other areas such as centre management and infrastructure. As first improvements the evaluated centre administration described and formalised the organisation of the prostate cancer unit with defined personnel assignments and clinical activities and a formal agreement is being worked on to have structured access to First-Aid Posts. Conclusions: In the pilot study, the AoO approach was feasible to identify opportunities for process improvements. Measures were derived that might increase the operational process quality and efficiency.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2015
Modern imaging techniques that can provide functional information on tumor vascularization, metab... more Modern imaging techniques that can provide functional information on tumor vascularization, metabolic activity, or cellularity have seen significant improvements over the past decade. However, most of these techniques are currently not broadly utilized neither in clinical trials nor in clinical routine, although there is a large agreement on the fact that conventional approaches for therapy response assessment such as Response Evaluation Criteria in Solid Tumors or World Health Organization criteria-that exclusively focus on the change in tumor size-are of less value for response assessment in modern thoracic oncology. The aim of this article comprises two parts: a short review of the most promising state-of-the-art imaging techniques that have the potential to play a larger role in thoracic oncology within the near future followed by a meeting report including recommendations of an interdisciplinary expert panel that discussed the potential of the different techniques during the Dr...
Journal of Hematotherapy & Stem Cell Research, 2002
TRANSMISSION OF DONOR CELL NEOPLASIA to recipients of allogeneic stem cell transplantation has be... more TRANSMISSION OF DONOR CELL NEOPLASIA to recipients of allogeneic stem cell transplantation has been reported twice. Niederwieser described the first case in 1990, in which an acute myeloid leukemia was transplanted with marrow graft (1). Recently Berg et al. described manifestations of donor cell-type non-Hodgkin’s lymphoma 3 years after transplantation (2). Information about the donor’s bone marrow state pre-donation was not given. We have evaluated a 65-year-old male sibling for stem cell donation for his HLA-identical sister suffering from chronic myeloid leukemia. The man’s history did not give any hint of a hematological malignancy. B signs were not reported. The ultrasonic-measured spleen size was 1023 36.8 mm. Routine parameters of clinical chemistry and automated and microscopy blood cell examination gave normal results. Diagnostic bone marrow examination was done despite it not being required in routine donor evaluation, neither by literature nor by the National Marrow Donor Program (NMDP) in the United States or by the German Bone Marrow Donor Registry (DKMS) (3,4). The picture by microscopy of the marrow smear was normal; however, using fluorescence-activated cell sorting (FACS) analysis, a mature B cell population with co-expression of CD5 and CD23 monoclonal for k-light chains was detected (5). Four weeks later, a slight lymphocytosis of 45% was seen in peripheral blood, and immunohistological bone marrow examination confirmed slight infiltration of the marrow by chronic lymphocytic leukemia. The man was withdrawn from stem cell donation and a search for an unrelated donor was initiated. We conclude that there is a potential risk of transmission of donor cell neoplasia in early stages by stem cell transplantation. In the described case, the standard procedures of stem cell donor evaluation were not sufficient to detect occult chronic lymphocytic leukemia. Although the detection of an occult lymphoma in potential stem cell donors is a rare event, marrow puncture for cytological examination and flow cytometry should be considered in preharvest evaluation of the potential donor, at least in elderly people. The more painful biopsy of marrow for histological examination should only be performed in case of suspicious results obtained by cytology or cytometry.
tetrahydro-2H-pyran-2-yloxy)R 1)R 2-diamminedichloroplatinum(II) complexes (1-12) consisting of C... more tetrahydro-2H-pyran-2-yloxy)R 1)R 2-diamminedichloroplatinum(II) complexes (1-12) consisting of CDDP linked to THP via aliphatic CH 2-spacers were tested in two TGCT cell lines. The most promising compound, 2-(4-(tetrahydro-2H-pyran-2-yloxy)-undecyl)-propane-1,3-diamminedichloroplatinum(II) (12), completely overcame CDDP resistance of 1411HP cells, correlating with increased and accelerated cellular platinum uptake and much faster initiation of apoptotic cell kill. At equitoxic IC 90 concentrations, 12 induced accelerated DNA fragmentation and caspase-3 and PARP cleavages. In contrast, DNA platination rate was much lower as compared to CDDP and no upregulation of p53 as well as no initiation of cell cycle arrest were observed. Apoptosis induction by 12 could not be inhibited by pretreatment with caspase-specific inhibitor Z-VAD-Fmk and was accompanied by strong calcium release and generation of reactive oxygen species. To summarize, 12 overcomes CDDP resistance and induces programmed cell death with molecular features different from CDDP, suggesting that both drugs induce apoptosis through different initial pathways.
6-Aminomethylnicotinate)dichloridoplatinum(II) complexes 4 esterified with terpene alcohols were ... more 6-Aminomethylnicotinate)dichloridoplatinum(II) complexes 4 esterified with terpene alcohols were tested on a panel of five human tumor cell lines. While they were accumulated in all cell lines more readily than cisplatin (CDDP), their cytotoxicities were tumor-specific and structure-dependent. Cell lines known to feature elevated levels of antiapoptotic, ion-channel-affecting proteins or otherwise impaired caspase-9 activation responded better to 4 than to CDDP, e.g., the HL-60 leukemia to the fenchyl and bornyl derivatives 4a,b at an IC 90 e 10 µM. The (-)-menthyl complex 4g was far better accumulated and more efficacious in CDDP-resistant 1411HP male germ cell tumor cells than in the congenerous CDDP-sensitive H12.1 cell line. 4g also broke the CDDP resistance of 518A2 melanoma cells. Cell decay in each case was apoptotic as to TUNEL and Annexin V fluorescence assays. Some complexes 4 seem to positively modulate the permeability of the cell membrane and of blocked mitochondrial anion channels.
Journal of Cancer Research and Clinical Oncology, 2004
To evaluate the ability of D-saccharic acid 1.4-lactone (SAL), a b-glucuronidase inhibitor, to pr... more To evaluate the ability of D-saccharic acid 1.4-lactone (SAL), a b-glucuronidase inhibitor, to prevent irinotecan hydrochloride (CPT-11) from inducing mucosal damage as a cause of diarrhea in rats. Methods: Wistar rats were divided into six groups of three animals each, administered 1.0 ml isotonic solution intraperitoneally once daily for up to three consecutive days, respectively for up to six days. The series were as follows: (1) On days 1-3: saline; (2). On days 1-3: 200 mg CPT-11/m 2 ; (3) On days)3 to)1 relative to the first administration of CPT-11: 10 mg/ml SAL; on days 1-3: 200 mg CPT-11/m 2 ; (4) On days)3 to +3 relative to the first administration of CPT-11: 10 mg/ml SAL, and on days 1-3: additional 200 mg CPT-11/m 2 ; (5) On days 1-3: 200 mg CPT-11/m 2 (0.5 ml) + 10 mg/0.5 ml SAL; (6) On days)3 to)1 relative to the first administration of CPT-11: 3 mg/ml SAL, and on days 1-3: 200 mg CPT-11/m 2. Luminal mucosa damage of the small intestine was detected by histology 24 h after the last intraperitoneal application. Peptidase activities of the proximal jejunum were measured by using an in situ perfusion model. Results: Following intraperitoneal CPT-11 treatment, using conventional histology of paraffin sections, we observed severe mucosal damage. This was reflected by a decrease of the villi/crypt ratio, an increase of apoptotic cells, as well as an increase of mitotic figures in the crypt region. There was a concomitant increased lymphatic infiltration in mucosa of CPT-11 treated rats. This damage pattern could be clearly reduced by co-treatment with the b-glucuronidase inhibitor, SAL, independent of the treatment schedule. In contrast to our expectations based on previous reports, the intraperitoneal application of CPT-11 alone or in combination with SAL did not cause significant differences in luminal enzyme liberation in comparison with controls in the in situ perfusion assay. Conclusions: The b-glucuronidase inhibitor SAL is able to significantly reduce CPT-11-induced mucosal damage in the small intestine of rats. This observation might soon have a clinical impact for the treatment of patients with CPT-11.
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1998
The newly synthesized calcium channel blocker, Ro44-5912, significantly potentiates doxorubicin D... more The newly synthesized calcium channel blocker, Ro44-5912, significantly potentiates doxorubicin Dox-induced cytotoxicity at non-cytotoxic concentrations in Dox-resistant human ovarian cell line, A2780rDX5, overexpressing Ž. Ž. P170-glycoprotein Pgp. Induction of DNA single-and double-strand breaks ssbs and dsbs was measured using alkaline Ž. elution and constant-field gel electrophoresis CFGE assays. The results indicate that potentiation of the cytotoxicity of Dox by Ro44-5912 was accompanied by significant increases in both, Dox-induced DNA ssbs and dsbs in the resistant Ž. cells. Pulsed-field gel electrophoresis PFGE analysis showed that Dox induced DNA fragments in the 50-800 kilobase Ž. Ž. kb and 0.8-5.7 megabase Mb ranges. The majority of the newly synthesized DNA fragments were in the 50-800 kb range. Ro44-5912 treatment resulted in significant potentiation of DNA fragmentation in the 50-800 kb range with a minor increase in 0.8-5.7 Mb DNA fragments, suggesting that the modulator functions by potentiating nascent DNA fragmentation in the resistant cells. Exposure to Dox with Ro44-5912 was associated with a prolonged blockage of cells in the Ž. S-phase. In contrast, exposure to Dox alone resulted in temporary blockage of cells in G rM phase ; 24 h followed by 2 restoration of cell proliferation and normal DNA histograms at 48 h after 2 h drug exposure. Incorporation of BrdUrd by flow cytometric analysis was inhibited by Dox in the presence of Ro44-5912, showing that there is a block of DNA replication. An increased damage in newly synthesized DNA could concur with a blocked DNA replication. Moreover, slowing progression through the S-phase in cells exposed to Dox in combination with Ro44-5912 is accompanied by increased sensitivity of Dox poisons, indicating a correlation of specific S-phase perturbation with the reversal of Dox resistance by Ro44-5912 in cells expressing Pgp. The results suggest that drug-induced augmentation of nascent DNA fragmentation and specific cell-cycle perturbation are potentially important molecular determinants for reversal of multidrug resistance in addition to restoration of intracellular drug retention. q 1998 Elsevier Science B.V.
Although the majority of testicular germ cell tumors (TGCTs) are curable by cisplatin-based chemo... more Although the majority of testicular germ cell tumors (TGCTs) are curable by cisplatin-based chemotherapy, in a few cases, the occurrence of cisplatin resistance results in a poor outcome. The biological basis of this differential cisplatin sensitivity in TGCTs remains largely unexplained. Embryonal carcinoma (EC) cells represent the presumptive tumor stem cells in nonseminomatous TGCTs and are known to express the embryonal transcription factor Oct-3/4 and to be hypersensitive to cisplatin. In the present study, we analyzed TGCT cell lines and nude mouse xenografts showing differential cisplatin sensitivity. Here we demonstrate that a lack of expression of Oct-3/4 in TGCT cells is associated with a higher apoptotic threshold and cisplatin resistance which is accompanied by an impaired caspase-9 activation, reduced caspase-3 activity and altered p53 accumulation. We were able to induce loss of Oct-3/4 in a cisplatin-sensitive EC cell line resulting in a secondary cisplatin-resistant cell type with retained EC cell characteristics and changes in apoptotic signaling identical to those in primary resistant cells. Furthermore, we show that EC cells are retained in their undifferentiated state by Oct-3/4 and that a complete and ultimate loss of Oct-3/4 followed by an early differentiation step is necessary to establish the cisplatin-resistant state. Our data suggest that loss of Oct-3/4 expression leads to induction of a higher apoptotic threshold and to cisplatin resistance in EC cells of nonseminomatous TGCTs. We hypothesize that in refractory TGCTs the original tumor stem cell population of Oct-3/4-positive, cisplatin-sensitive EC cells could be replaced by an Oct-3/4-negative, resistant population in a selection process. In contrast, the presence of the Oct-3/4-positive, highly sensitive EC cells as the tumor stem cell component in most TGCTs could explain the general high chemosensitivity and curability of these tumors.
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Papers by Wieland Voigt