Thursday, July 31, 2008
Involvement of Cyclooxygenase-2–Prostaglandin E2 Pathway in Interleukin-8 Production in Gastric Cancer Cells
Prostaglandin E2 (PGE2) is thought to play an important role in both inflammatory and anti-inflammatory effects. The effect of PGE2 on the proinflammatory chemokine interleukin-8 (IL-8) in the gastric epithelial cells has not been defined yet. A gastric cancer cell line (MKN45) and primary gastric fibroblasts were cocultured with Helicobacter pylori standard strain (NCTC11637). The expressions of IL-8 and cyclooxygenase 2 (COX-2) mRNA were examined by reverse transcription polymerase chain reaction (RT-PCR) amplification. The amount of IL-8 antigen secreted by the MKN45 cells and gastric fibroblasts was measured by enzyme-linked immunosorbent assay (ELISA). We examined the effects of H pylori stimulation on IL-8 and COX-2 expression levels and the effects of COX-2 inhibitor on H pylori-induced IL-8 production in the MKN45 cells and gastric fibroblasts. Furthermore, we examined the expressions of subtypes of PGE2 receptors, the effects of arachidonic acid and PGE2 on IL-8 production, and the effects of PGE2 on the total cellular cyclic adenosine monophosphate (cAMP) in MKN45 cells. MKN45 cells and gastric fibroblasts expressed IL-8 and COX-2 mRNA under stimulation with H pylori. The MKN45 cells produced IL-8 and PGE2 antigen into the culture medium with H pylori stimulation, and the production level of IL-8 and PGE2 antigen decreased significantly with COX-2 inhibitor pretreatment (concentration: 50 μM). On the other hand, the gastric fibroblasts strongly produced IL-8 antigen even in the unstimulated condition, and the amount of IL-8 antigen was not affected by H pylori stimulation and/or COX-2 inhibitor pretreatment. The MKN45 cells expressed IL-8 mRNA and released IL-8 antigen slightly, and the expression level of IL-8 mRNA and the amount of IL-8 antigen increased significantly with PGE2 treatment in a dose-dependent manner. PGE2-induced IL-8 production was inhibited by pretreatment with EP2 and EP4 antagonists. The MKN45 cells expressed EP2 and EP4 subtypes of PGE2 receptors, and these expression levels were not affected by H pylori stimulation or PGE2 treatment. The amount of IL-8 antigen increased slightly, but not significantly, with arachidonic acid treatment. PGE2 treatment for 15 minutes increased the total cellular cAMP in the MKN45 cells. These results suggest that the COX-2–PGE2 pathway may be involved in IL-8 production in gastric epithelial cells.
Results of an Aggressive Approach to Resection of Locally Recurrent Rectal Cancer
Abstract Background The value of resection for locally recurrent rectal cancer (LRRC) remains controversial. We analyzed outcomes of an aggressive approach to resection of LRRC.
Influence of mesna on the pharmacokinetics of cisplatin and carboplatin in pediatric cancer patients
Abstract Mesna, a reactive thiol, often encounters cisplatin and carboplatin in combination protocols involving oxazaphosphorines and platinum drugs. This co-administration might be unfavorable based on the inactivation of platinum drugs by thiol groups in vitro. We investigated whether mesna influences the pharmacokinetics of platinum drugs when co-administered with cisplatin or carboplatin. The pharmacokinetics of platinum drugs were investigated in 18 pediatric patients receiving either cisplatin or carboplatin in a combination with or without mesna. In cisplatin patients, a decrease in the distribution clearance of total platinum was observed when mesna was co-administered (CL d, 2.2±0.1 mL/min·kg; n=3), compared to cisplatin without mesna (CL d, 4.8±1.5 mL/min·kg; n=5) (p=0.029, t-test). This might have been caused by an influence of mesna in slowing down the protein binding of cisplatin since a trend (p=0.057) in prolonged distribution half-life of total platinum was also observed when mesna was present ({ie9-1}, 65±21 min; n=3) compared to cisplatin without mesna ({ie9-2}, 32±18 min; n=5). However, the impact of these changes on the area under the concentration time curve (AUC), total clearance (CL t), and volume of distribution (V) for total platinum and ultrafilterable platinum species was hardly noticeable. In carboplatin patients, when mesna was co-administered: AUC (2.5±0.4 mg·min/mL·400 mg/m2; n=5) CL t, (6.8±5.1 mL/min·kg; n=6), and V (0.7±0.4 L/kg; n=6) for ultrafilterable platinum species were not significantly different from when carboplatin were administered without mesna: AUC (2.3±1.3 mg·min/mL·400 mg/m2; n=4), CL t(5.8±4.6 mL/min·kg; n=5), and V (1.1±1.1 L/kg; n=5). Hence, mesna does not significantly influence the pharmacokinetics of cisplatin and carboplatin in pediatric cancer patients.
Microsomal glutathione S-transferase gene polymorphisms and colorectal cancer risk in a Han Chinese population
Abstract Background and aims Glutathione S-transferases (GSTs) are phase II detoxification enzymes. Human GSTs have been classified into cytosolic, mitochondrial, and microsomal families. Several studies reported the association of colorectal cancer (CRC) risk with the genetic polymorphisms of cytosolic GSTs. The microsomal GSTs are structurally distinct but functionally similar to cytosolic GSTs; their association with CRC has not been reported. In this report, we summarized the result of a case-control study aimed at investigating the association of MGST1 gene locus polymorphisms with CRC risk among Han Chinese.
Conservative treatment with transurethral resection, neoadjuvant chemotherapy followed by radiochemotherapy in stage T2-3 transitional bladder cancer
Abstract Purpose Organ preservation has been investigated in patients (p) with infiltrating transitional cell carcinoma (TCC) of the bladder over the past decade as an alternative to radical cystectomy. This is a trimodal schedule study, including transurethral resection of bladder tumor (TURB), neoadjuvant chemotherapy and concomitant radiochemotherapy (RTC).
Laparoscopic gastrectomy for early gastric cancer targeting as a less invasive procedure
Abstract Background Since only a few extensive reports are available on the less invasive nature of laparoscopic gastrectomy, we compared postoperative changes over time in vital signs and hematological parameters between this surgery and laparotomic gastrectomy.
A clinical study on global TCM therapy in treating senile advanced non-small cell lung cancer
Abstract Objective To assess the clinical efficacy of global traditional Chinese medicine (TCM) therapy in treating senile advanced non-small cell lung cancer (NSCLC), with the aim of seeking a standardized, rational and economical way to treat advanced NSCLC in old patients.
Community-based Preferences for Stool Cards versus Colonoscopy in Colorectal Cancer Screening
Summary Background In the United States, compliance with colorectal cancer (CRC) screening recommendations remains suboptimal. Professional organizations advocate use of shared decision making in screening test discussions, but strategies to facilitate informed choice in CRC screening have not been well elucidated.
Intraoperative fluoroscopy vs. intraoperative laparoscopic ultrasonography for early colorectal cancer localization in laparoscopic surgery
Abstract Background In colorectal cancer (CRC) surgery, precise tumor localization is important for oncologically correct surgery and adequate tumor and lymph node resection margins. During laparoscopic surgery it is difficult to localize early CRC. The aim of this study was to compare the usefulness of two tumor localization techniques; intraoperative fluoroscopy and intraoperative laparoscopic ultrasonography.
Pre-existing T-cell immunity against mucin-1 in breast cancer patients and healthy volunteers
Abstract Purpose: There is evidence that some tumor patients are able to generate tumor-associated antigen (TAA)-specific T-cell immunity spontaneously. However, little is understood about the existence and nature of self-reactive T-cells that recognize TAA in healthy donors (HD). Methods: Human mucin (MUC-1), a highly glycosylated transmembrane protein, is a well characterized TAA expressed by epithelial tumors. We compared endogenous MUC-1-specific T-cell immunity of breast cancer patients (BCP) and healthy volunteers using two MUC-1-derived HLA-A*0201-restricted peptides (MUC-1950–958, MUC-112–20). Antigen-dependent interferon (IFN)-γ and Granzyme B expression of T-cells were analysed by a reverse transcription-polymerase chain reaction (qRT-PCR)-based assay. Results: A 32% of BCP and 43% of healthy volunteers revealed pre-existent CD8+ T-cells specific for MUC-1950–958 but not for MUC-112–20. In patients, MUC-1-specific T-cells have been detected mainly in early stage disease prior adjuvant therapy. Those T-cells showed MUC-1-dependent IFN-γ production after short-term stimulation but no clear Granzyme B expression. However, after repetitive in vitro stimulations using peptide-pulsed CD40-stimulated B-cell lines as autologous antigen presenting cells (APC) T-cell lines exhibited lytic capacity against HLA-A*0201+/MUC-1+ tumor cells. Conclusion: MUC-1950–958 is a dominant tumor antigen against which CD8+ T-cells were found frequently in BCP as well as in HD. Until now, this was only known for MelanA/MART-1. In contrast to previous reports, MUC-1-specific immunity was not linked to gender or number of pregnancies in women. Whether MUC-1950–958-related immunity highlights a yet unknown cross-reactivity in HD remains unclear. The presence of MUC-1-specific T-cells in some BCP may reflect a balance between immune tolerance and immune defence during aetiopathology.
Combined use of zoledronic acid and 153Sm-EDTMP in hormone-refractory prostate cancer patients with bone metastases
Abstract Purpose 153Sm-ethylenediaminetetramethylenephosphonic acid (EDTMP; Quadramet?) is indicated for the treatment of painful bone metastases, whereas zoledronic acid (Zometa?) is indicated for the prevention of skeletal complications. Because of the different therapeutic effects, combining the treatments may be beneficial. Both, however, accumulate in areas with increased osteoblastic activity. Possible drug interactions were investigated.
Qualit?tssicherungsstudie zum Magenkarzinom in Deutschland
Zusammenfassung Die sich mit dem wissenschaftlichen Erkenntniszuwachs und den gesellschaftlichen Rahmenbedingungen st?ndig wandelnden Voraussetzungen für medizinische Behandlungsabl?ufe haben in den letzen Jahren das Interesse an der Ergebnisqualit?t dieser Prozesse unter klinischen Alltagsbedingungen verst?rkt. Im Hinblick auf die Entwicklung der chirurgischen Therapie des Magenkarzinoms liegen in Deutschland zwei prospektive multizentrische Beobachtungsstudien vor, die Deutsche Magenkarzinomstudie (GGCS ’92) und die Qualit?tssicherungsstudie der Ostdeutschen Arbeitsgruppe für Qualit?tssicherung und regionale Entwicklung in der Chirurgie e.V. (EGGCS ’02). Aufgrund des Studiendesigns sind die beiden Untersuchungen gut vergleichbar. Insgesamt konnte im Vergleich mit der GGCS ‘92 eine Verbesserung der peri- und frühpostoperativen Behandlungsqualit?t des Magenkarzinoms in den zwischen den Studien liegenden 12 Jahren konstatiert werden. Die onkologischen Langzeitergebnisse sind jedoch für das gesamte Patientenkollektiv mit einer Fünfjahresüberlebenswahrscheinlichkeit von ca. 40% nach wie vor unbefriedigend. In den letzten Jahren hat sich zunehmend die Erkenntnis durchgesetzt, dass auch beim Magenkarzinom eine multimodale Therapie ein Weg zur Verbesserung dieser Resultate sein kann. Diese Entwicklungen waren der Anlass, die neue Qualit?tssicherungsstudie für Magenkarzinome zu initiieren. Bei der überarbeitung der Erfassungsb?gen wurde besonderer Wert auf die gegenüber 2002 detaillierte Erfassung der multimodalen Therapiekonzepte gelegt. Mit Hilfe der im Januar 2007 beschlossenen Unterstützung der Studie durch den Konvent der leitenden Krankenhauschirurgen sollte ein hoher Erfassungsgrad der bundesweit behandelten Magenkarzinome m?glich sein.
Lymphknotendissektion beim papill?ren und follikul?ren Schilddrüsenkarzinom
Zusammenfassung Hintergrund Bezüglich des Umfangs der Lymphknotendissektion beim papill?ren (PTC) und follikul?ren (FTC) Schilddrüsenkarzinom besteht kein Konsens. Bislang gilt gem?? den Leitlinien ein für beide Tumoren gleiches Operationsausma?.
Estimating the number of rate limiting genomic changes for human breast cancer
Abstract We used multistage models that incorporate the age dependent dynamics of normal breast tissue, clonal expansion of intermediate cells and mutational events to fit data for the age-specific incidence of breast cancers in the surveillance, epidemiology, and end results (SEER) registry. Our results suggest that two or three rate limiting events occurring at rates characteristic of point mutation rates for normal mammalian cells set in motion a sequence of other genomic changes that lead with high probability to breast carcinoma.
Familial breast cancer: double heterozygosity for BRCA1 and BRCA2 mutations with differing phenotypes
Abstract The co-existence of mutations in the BRCA1 and BRCA2 genes is unusual, and to date almost all cases reported have had at least one of the Ashkenazi founder mutations. We report on a family in whom individuals are double heterozygotes for a mutation in BRCA1 and a novel splice site mutation in BRCA2. The phenotypes are discordant, where one sister has had multiple cancers in the BRCA spectrum, while the other is unaffected at 65 years of age. The utility of testing is discussed, and the completion of diagnostic testing despite the finding of a potentially causal mutation is validated.
Cancer de la prostate et relation conjugale : point de vue du patient et de sa conjointe. Résultats préliminaires
Résumé Notre étude s’est intéressé à l’ajustement à la maladie et à la relation conjugale chez 25 couples dont le mari est traité pour un cancer de la prostate. Les couples ont été rencontrés en début, milieu et fin de traitement où des questionnaires d’anxiété (STAI et MAS), de dépression (CESD), de qualité de vie (FACT-P, CQOLC et SF12) et de qualité de la relation conjugale (QRI) leur ont été proposés. L’analyse des résultats révèle que les patients ne présentent pas de troubles émotionnels importants, à l’inverse des conjointes qui sont plus anxieuses et dépressives que ces derniers. Ils jugent avoir une bonne qualité de vie malgré une diminution au cours du traitement chez le patient. Les patients sont satisfaits de la disponibilité et de l’intensité du soutien de leur conjointe alors que leurs conjointes per?oivent une diminution du soutien qu’elles re?oivent et une augmentation des conflits surtout au début du traitement.
Contribution of Radiotherapy to Function Preservation and Cancer Outcome in Primary Treatment of Nasopharyngeal Carcinoma
Abstract Development of primary treatment for nasopharyngeal carcinoma is summarized and the contribution of radiotherapy (RT) is reviewed. Accumulation of knowledge, together with technological advances, has led to significant improvement both for tumor control and organ preservation. With contemporary RT, it is possible to achieve a 10-year disease-specific survival of 47% with a severe late complication rate of 5%. Presenting stage is one of the most important prognostic factors, but unfortunately late presentation and delayed diagnosis remains a common problem. The average local control rate is 80% for tumor confined within the nasopharynx, but only 50% for those associated with erosion of the base of the skull or cranial nerve involvement. Nodal deposits from nasopharyngeal carcinoma are much more radiosensitive than those from other head and neck cancers. An average control rate of 75% can be achieved with RT alone, even in patients with nodes > 6 cm in diameter. Successful locoregional control is important, not only because it is crucial for survival but also because it is associated with a lower incidence of distant failure (29% versus 41%). Distant failure remains a sinister problem, especially for patients presenting with advanced T or N-stage cancers. Randomized trials exploring the value of additional chemotherapy are reviewed. The significant improvement in 3-year overall survival achieved by the addition of concurrent and adjuvant chemotherapy (78% versus 47%) recently reported is encouraging, but remaining uncertainties are also discussed.
5-Fluorouracil (5FU) treatment does not influence invasion and metastasis in microsatellite unstable (MSI-H) colorectal cancer
Abstract Microsatellite instability is a recognised pathway of colorectal carcinogenesis responsible for about 15% of all sporadic colorectal cancers. Recent evidence has suggested that these tumours may not have the same response as microsatellite stable colon cancers to 5-fluorouracil (5FU)-based chemotherapy. The response to 5FU in four microsatellite unstable (MSI-H) cell lines was examined by cell viability assays and invasion assays. Flow cytometry was used to assess the effect of 5FU on MSI-H cell lines. In vivo response to 5FU was assessed by intraperitoneal injection of 5FU or control to 80 nude mice that had received intrasplenic injections of an MSI-H cell line KM12C prior to commencing treatment. There was inhibition of cell growth in MSI-H cell lines when treated with 5FU. There was no difference in invasiveness in the MSI-H cell lines when treated with 5FU. Primary tumours formed in 27 of the untreated and 25 of the 5FU treated mice (p=NS). There was a 36% reduction in splenic weight in those mice treated with 5FU (p<0.03). Metastases formed in 5 of the untreated and 9 of the treated mice (p=0.12). 5FU treatment of MSI-H tumours results in a reduction in growth but does not result in a reduction in invasion or metastasis.
Thermosensitive mucoadhesive gel formulation loaded with 5-Fu: cyclodextrin complex for HPV-induced cervical cancer
Abstract Human Papilloma Virus (HPV) infections are the major cause of cervical cancers. To achieve a better therapeutic efficacy and patient compliance in the treatment for HPV-induced cervical cancers, anticancer agent 5-fluorouracil has been formulated in a vaginal gel using the thermosensitive polymer Pluronic? F127 together with alternative mucoadhesive polymers e.g., hyaluronic acid, Carbopol 934 and hydroxypropylmethylcellulose. To increase its aqueous solubility and to achieve the complete release of 5-FU from the gel, the drug was incorporated as its inclusion complex with 1:1 molar ratio with either β-cyclodextrin or hydroxypropyl-β-cyclodextrin. Following the characterization of drug:CD complexes, thermosensitive gel formulations containing different mucoadhesive polymers and the drug in free or complexed form were characterized in vitro by determining the gelation temperature and the rheological behavior of different formulations along with the in vitro release profiles of these formulations in pH 5.5 citrate buffer. It was observed that complexation with cyclodextrin accelerated the release of 5-FU with the exception of formulation containing Carbopol 934 as mucoadhesive polymer. As far as rheological properties are concerned, favorable thermosensitive in situ gelling properties were obtained with formulations containing HPMC as mucoadhesive polymer. Complete release of 5-FU from gels were obtained with both complexes of β-CD and HP-β-CD and cytotoxicity studies against HeLa human cervical carcinoma cells demonstrated that 1% 5-FU:CD complexes were equally effective as 1% free 5-FU indicating better therapeutic efficacy with lower dose.
Nuclear metallothionein expression correlates with cisplatin resistance of ovarian cancer cells and poor clinical outcome
Abstract Elevated metallothionein (MT) expression in ovarian cancers treated with cisplatin-based schemes represents an unfavorable prognostic index. MT expression is significantly higher in tumor samples obtained after chemotherapy. The present study aimed at examining MT expression in ovarian carcinoma cells sensitive (A2780) or resistant (A2780RCIS) against platinum drug treatment as well as examining effects of exposure to cisplatin on MT expression. Subcellular expression of MT was evaluated also in samples originating from 73 ovarian tumors. Cisplatin-resistant A2780RCIS cells were exposed to increasing cisplatin concentrations, and the subcellular expression of MT was determined by immunocytochemistry. The studies demonstrated that cisplatin-resistant A2780RCIS cells exposed to cisplatin typically manifested a nuclear MT expression. The study demonstrated also that exposure to cisplatin was paralleled by growing MT expression in cell nuclei. The nuclear expression of MT was also found to be specific for ovarian cancers of poor clinical outcome. No relationship could be demonstrated between cytoplasmic expression of MT and clinical variables. Nuclear MT expression is induced by cisplatin and seems to protect DNA in the cells from toxic effects of the drug.
Phase-II Study of Gemcitabine and Cisplatin in Patients with Metastatic Biliary and Gallbladder Cancer
Abstract There is no standard chemotherapy option for patients with biliary tract cancers. These patients present fairly ill and can have a rapid progression of disease. We conducted a multi-center, phase-II trial for patients with locally unresectable or metastatic bile duct or gallbladder adenocarcinomas using a modified regimen of gemcitabine and cisplatin to potentially improve tolerability. Patients received a 21-day treatment cycle of gemcitabine at 1,000 mg/m2 and cisplatin at 30 mg/m2 on days 1 and 8. To participate, 33 patients signed informed consent, and 30 patients received at least one dose of chemotherapy. By intention-to-treat analyses, 7 patients (21%) experienced a partial response and another 12 (36%) had stable disease for at least 12 weeks. The median progression-free survival was 6.3 months and median overall survival was 9.7 months. After 1 year, 39% of patients were alive. Most common grade 3–4 toxicities included neutropenia (33%), thrombocytopenia (23%), anemia (20%), nausea (20%), emesis (13%) and fatigue (10%). Of note, 52% of patients withdrew from study treatment, principally due to treatment-related adverse events. We concluded that this modified regimen appeared to have comparable activity to other gemcitabine and cisplatin regimens against advanced bile duct and gallbladder cancers, but there was still moderate toxicity in this patient population.
Preoperative selection of symptomatic breast cancer patients appropriate for lymphatic mapping and sentinel node biopsy
Abstract Background This study examines whether preoperative ultrasound-assessed tumour diameter and diagnostic core biopsy-determined grade can be used to select those most likely to benefit from SLNB (i.e. those that are “node negative”) before their definitive operation.
A phase I trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone in combination with gemcitabine for patients with advanced cancer
AbstractPurpose 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP), a new and potent inhibitor of ribonucleotide reductase (RR), increases the cellular uptake, DNA incorporation, and cytotoxicity of gemcitabine in tumor cell lines. A phase I trial was initiated to determine the safety profile and maximum tolerated doses of 3-AP and gemcitabine when used in combination in patients with advanced cancer.
Dihydropyrimidine dehydrogenase (DPD) rapidly regenerates after inactivation by eniluracil (GW776C85) in primary and metastatic colorectal cancer
AbstractPurpose Catabolism of 5-fluorouracil (5-FU) is primarily regulated by DPD. Inactivation of DPD using eniluracil is advantageous in that it renders 5-FU orally bioavailable with more predictable pharmacokinetics and blocks one of the major potential mechanisms of 5-FU chemoresistance. The purpose of this study was to initially document inactivation of DPD by eniluracil in primary and metastatic colorectal cancer (CRC) and then to assess the time-course of the regeneration of DPD activity in peripheral blood (and where possible, additional tissues).
Risikoadaptierte Hormontherapie des prim?r operablen Mammakarzinoms
Zusammenfassung St. Gallen 2005 hat 3 neue Risikokategorien für die adjuvante Therapie aufgestellt, das niedrige Risiko, das mittlere Risiko und das hohe Risiko. Innerhalb dieser Risikokonstellationen ist das endokrine Ansprechen (endocrine responsiveness) das Hauptkriterium, um Behandlungsempfehlungen für die adjuvante Systemtherapie zu treffen. Dieses endokrine Ansprechen wird in der vorliegenden Arbeit durch die Diskussion möglicher Faktoren und unterschiedlicher Steroidrezeptorkonstellationen differenziert dargestellt, um zusätzliche Entscheidungshilfen für Behandlungsempfehlungen zu schaffen. Gleichzeitig wurden die neuesten klinischen Daten der adjuvanten Hormonstudien des primär operablen Mammakarzinoms in die Behandlungsempfehlungen eingearbeitet. Tamoxifen ist heute nicht mehr allein Standard in der adjuvanten Therapie postmenopausaler Frauen. Die Aromatasehemmer führen zu höheren Ansprechraten und längeren Remissiondauern in der Therapie metastasierender Mammakarzinome und zu signifikant geringeren Rezidivraten in der adjuvanten Therapie. Aber auch zwischen den Aromatasehemmern bestehen Effektivitätsunterschiede in Abhängigkeit vom Risikoprofil, die in die Erarbeitung dieser Therapievorschläge eingeflossen sind. In der Initialtherapie können die Therapieempfehlungen anhand der Rezeptorkonstellation, des Nodalstatus, möglicher Kontraindikationen und bestehender Vorbehandlungen getroffen werden. In der Sequenztherapie ist nur noch der Nodalstatus, die Chemotherapie-Vorbehandlung, eine Tamoxifenunverträglichkeit und eine mögliche Therapiepause nach Tamoxifen für die Weiterbehandlung mit einem Aromatasehemmer entscheidend. Ein Aromatasehemmer kann als Initialtherapie signifikant mehr Frührezidive und als erweiterte Therapie signifikant mehr Spätrezidive verhindern. Eine frühe Sequenztherapie mit einem Aromatasehemmer nach 2–3 Jahren Tamoxifen kommt für die frühen Rezidive zu spät und erreicht aufgrund seiner kurzen Therapiedauer von 2–3 Jahren die Spätrezidive nicht.
Chirurgische Therapie des nichtkleinzelligen Bronchialkarzinoms
Zusammenfassung Jedem Patienten mit lokoregionär begrenztem nichtkleinzelligem Bronchialkarzinom (NSCLC) sollte die chirurgische Therapie angeboten werden. Bei Patienten mit ausreichender funktioneller Reserve sind Standardresektionsverfahren die Lobektomie, die Lobektomie mit bronchoplastischer und/oder angioplastischer Erweiterung, die Bilobektomie oder die Pneumonektomie. Nichtanatomische oder atypische Lungenresektionen kommen nur für Hochrisikopatienten infrage. Nichtbefallene Lungenlappen sollten erhalten und ggf. reanastomosiert werden. Eine Resektion, die über die radikale Entfernung des makroskopisch und mikroskopisch sichtbaren Tumors hinausgeht, bringt keinen Überlebensvorteil. Jede chirurgische Therapie mit kurativer Zielsetzung wird durch eine komplette ipsilaterale Lymphknotendissektion vervollständigt.Die Prognose nach Diagnosestellung eines NSCLC ist schlecht. Ein Jahr nach Diagnosestellung leben noch 45% der Patienten, nach 5 Jahren noch 14%. Betrachtet man die Untergruppe der kurativ operierten Patienten im Stadium IA, so findet man jedoch Überlebenswahrscheinlichkeiten von 93% nach 1 Jahr und von 70–80% nach 5 Jahren. Insofern bietet die Operation beim NSCLC im frühen Stadium eine begründete Aussicht auf Heilung. Eine zusätzliche adjuvante (postoperative) Chemotherapie nach kompletter Resektion kann die Überlebenswahrscheinlichkeit weiter um 4–15% verbessern (bei Stadium II). Generell sollte es einer sorgsam geführten, alle Faktoren der Tumorausdehnung und der individuellen Komorbidität berücksichtigenden interdiziplinären Beratung überlassen bleiben, die Indikation zur Operation zu stellen oder abzulehnen. Inoperabilität sollte nicht allein aufgrund der Papierform konstatiert werden, sondern nur unter Berücksichtigung aller indivuellen Patientenfaktoren.
Oral vinorelbine/paclitaxel combination treatment of metastatic breast cancer: a phase I study
Abstract Purpose Intravenous (i.v.) vinorelbine (VRL) generally given on days 1 and 8 of an every three-week cycle in combination with paclitaxel (PTX) is an effective option for the treatment of metastatic breast cancer (MBC). In an effort to improve both patient and chemotherapy unit convenience, oral VRL was used at equivalent doses of i.v. VRL.
Mitochondrial DNA Mutations in Differentiated Thyroid Cancer with Respect to the Age Factor
Abstract Introduction Increased numbers of mitochondria in differentiated thyroid cancer and, most strikingly, mutations in human mitochondrial DNA (mtDNA) in older people have led to speculation that mtDNA mutations might contribute to aging or accumulate in postmitotic tissues with age. Mutation analyses of mtDNA in papillary (PTCs) and follicular (FTCs) thyroid carcinomas have been limited to date. The significance and frequency of mtDNA mutations in PTC and FTC are therefore controversial, as is age dependence.
Ern?hrungsstatus krebskranker Kinder w?hrend Chemotherapie
ZusammenfassungHintergrund und Methode Bei Eltern und Ärzten besteht häufig die Befürchtung, dass krebskranke Kinder im Lauf der Chemotherapie Zeichen einer Mangelernährung entwickeln. Wir bestimmten deshalb bei 18 Kindern mit akuten Leukämien und 27 mit malignen soliden Tumoren (ausgenommen Gehirntumoren) Körperlänge, Körpergewicht, Body-Mass-Index, fettfreie Masse (bioelektrische Impedanzanalyse), Albumin und Präalbumin im 1. Monat wöchentlich, dann monatlich von der Diagnose bis zum Ende der intensiven Chemotherapie über einen mittleren Zeitraum von 104 Tagen (bis 357 Tage).
überleben mit h?matogen metastasierten HNO-Tumoren
Zusammenfassung Hintergrund Ein monozentrisches Kollektiv von 114 Patienten mit h?matogen metastasierten HNO-Tumoren wurde mit der Fragestellung untersucht, welche Parameter das überleben beeinflussten.
Low folate conditions may enhance the interaction of trifluorothymidine with antifolates in colon cancer cells
Abstract Purpose: Trifluorothymidine (TFT) is a fluoropyrimidine that is part of the novel combination metabolite TAS-102, in which TFT is combined with a potent thymidine phosphorylase inhibitor (TPI). TAS-102 is currently tested as an orally chemotherapeutic agent in different schedules in a phase I study. In its monophosphate form, TFT can inhibit thymidylate synthase (TS) activity after binding to the TS-nucleotide binding site leading to dTTP depletion, and in its triphosphate form TFT is incorporated into DNA, eventually leading to DNA damage. In this in vitro study, we investigated whether TFT could potentiate cytotoxicity of the antifolate-based TS inhibitors AG337 (Nolatrexed), ZD1694 (Raltitrexed) and GW1843; and whether increased TS inhibition or DNA damage would be related to this result. Methods: The drug combinations were studied in colon cancer cell lines either grown at low or high folate conditions. Multiple drug effect analysis was performed after measuring growth inhibition when the drugs were combined (MTT Assay) and expressed as Combination Index (CI), where CI<0.9 indicates synergism, CI=0.9–1.1 indicates additivity and CI>1.1 indicates antagonism. Drug target analysis was performed using the TS in situ inhibition assay and the FADU DNA-damage assay. Cells were exposed to either the drugs alone or in combination to determine the effect on TS activity and DNA damage induction, respectively. Results: Three experimental procedures were used to test the interaction of the drugs: either one of the drugs was kept at a constant concentration (IC25) or two drugs were added in a 1:1 IC50-based molar ratio. The combinations of TFT with one of the antifolates in which one of the drugs was kept at a constant concentration were synergistic for all antifolates in WiDr/F cells, which grow in low folate medium (CI=0.6–0.8), but only additive to antagonistic for the cell lines growing in high folate medium: TFT-AG337: CI=0.9–2.3; TFT-ZD1694: CI=0.9–1.3; TFT-GW1843: CI=0.8–1.7. The procedure in which the two drugs were added in a 1:1 IC50-based molar ratio showed antagonism for all three combinations in all cell lines (CI>2.7). TS inhibition (14.3%) and DNA damage (8%) were more pronounced than expected (P<0.05) when TFT was combined with GW1843 in WiDr/F cells, in contrast to AG337 and ZD1694, which showed inhibiting effects as expected (additive). Conclusions: The combination of TFT with the antifolates AG337, ZD1694 and GW1843 is mainly additive when the drugs are given simultaneously and this is mediated by an additive TS inhibition and DNA damage. The drug interaction may partly be dependent on the folate homeostasis since WiDr/F cells growing at low folate conditions show pronounced synergism in growth inhibition, two-sided TS inhibition and DNA damage, especially when TFT is combined with the tight-binding TS inhibitor GW1843.
Minimally invasive esophagectomy for cancer: laparoscopic transhiatal procedure or thoracoscopy in prone position followed by laparoscopy?
Abstract Background Minimally invasive esophagectomy is rapidly emerging as a suitable surgical alternative to the open technique. This retrospective comparative study aimed to compare two minimally invasive techniques for esophagectomy: transhiatal laparoscopy with intrathoracic or cervical anastomosis (group A) and right thoracoscopy in prone position followed by laparoscopy and left cervicotomy (group B) performed by the same surgeon (G.B.C.). The operative time, perioperative blood loss, intensive care and total hospital stays, peri- and postoperative morbidity, in-hospital mortality, number of lymph nodes dissected, and survival were the outcome measures.
How to reduce radiation-related toxicity in patients with cancer of the head and neck
Abstract Radiation for head and neck cancers is often curative, but high doses are used. Normal tissues, including mucosa, salivary glands, and muscles, are exposed to these high doses, resulting in severe mucositis, xerostomia, and dysphagia. Efforts to minimize toxicity have involved advances in radiation physics and development of pharmacologic agents. Radiation techniques include conformal and intensity-modulated therapy, which minimizes dose to normal tissues while delivering high doses to tumor targets. Drugs used to prevent mucositis have targeted infection, but recently interest has been shown in the use of growth factors. Cholinergic agonists and cytoprotective agents, specifically amifostine, can address xerostomia. Involvement of speech pathologists in evaluation and treatment of patients with dysphagia can minimize swallowing difficulties and identify the tissues most responsible for swallowing. Minimizing radiation dose to these tissues may lower the incidence of radiation-induced dysphagia.
Gene expression of gonadotropin-releasing hormone and its receptor in rat pancreatic cancer cell lines
Abstract The regression of experimental and clinical pancreatic cancers by treatment with gonadotropin-releasing hormone (GnRH) agonists or antagonists has been repeatedly reported and is usually presumed to result from the creation of a sex steroid deficiency. There are, however, indications that GnRH analogs can also suppress the growth of the tumor cells in vitro and that specific binding sites for GnRH are present on membranes of these cells. The regulatory role of GnRH in rat pancreatic adenocarcinoma was investigated by examining the gene for GnRH and GnRH receptor (GnRH-R) in two pancreatic tumor cell lines (AR42) and ARIP). Reverse transcriptase polymerase chain reaction and Southern blot analysis indicated both GnRH-mRNA and GnRH-R-mRNA transcripts in the two cell lines. This is the first report raising the possibility of an autocrine/paracrine role for GnRH in rodent malignant pancreas.
Traitement de l’anémie par injection hebdomadaire chez les patients atteints de cancer: analyse comparative des agents stimulants l’érythropo?èse
Résumé: L’anémie est fréquente chez les patients atteints d’un cancer, mais son impact est souvent sous-estimé. L’anémie dégrade la qualité de vie, et des données indiquent également qu’elle est associée à un mauvais résultat thérapeutique et à une réduction de la survie. L’introduction de l’érythropo?étine recombinante humaine (epoetin) a autorisé un traitement efficace de l’anémie sans les risques associés aux transfusions sanguines. Une récente étude randomisée menée chez des patients atteints d’une hémopathiemaligne amontré qu’une même dose hebdomadaire d’epoetin bêta était aussi efficace lorsqu’elle était administrée en une seule injection par semaine au lieu de trois injections par semaine. Cette administration hebdomadaire de l’epoetin bêta (NeoRecormon?) a été autorisée par les autorités réglementaires européennes pour le traitement des patients atteints d’une hémopathie lympho?de maligne, présentant une carence relative en érythropo?étine et recevant un traitement antitumoral. La darbepoetin alpha (Aranesp?) a également été autorisée en administration hebdomadaire pour le traitement de l’anémie chez les patients atteints d’une affection maligne non myélo?de traitée par chimiothérapie. La plus grande commodité et le moindre co?t d’administration du traitement hebdomadaire devraient permettre à un plus grand nombre de patients de bénéficier d’un traitement par epoetin.
Traitement de l’anémie par injection hebdomadaire chez les patients atteints de cancer: analyse comparative des agents stimulants l’érythropo?èse
Résumé: L’anémie est fréquente chez les patients atteints d’un cancer, mais son impact est souvent sous-estimé. L’anémie dégrade la qualité de vie, et des données indiquent également qu’elle est associée à un mauvais résultat thérapeutique et à une réduction de la survie. L’introduction de l’érythropo?étine recombinante humaine (epoetin) a autorisé un traitement efficace de l’anémie sans les risques associés aux transfusions sanguines. Une récente étude randomisée menée chez des patients atteints d’une hémopathiemaligne amontré qu’une même dose hebdomadaire d’epoetin bêta était aussi efficace lorsqu’elle était administrée en une seule injection par semaine au lieu de trois injections par semaine. Cette administration hebdomadaire de l’epoetin bêta (NeoRecormon?) a été autorisée par les autorités réglementaires européennes pour le traitement des patients atteints d’une hémopathie lympho?de maligne, présentant une carence relative en érythropo?étine et recevant un traitement antitumoral. La darbepoetin alpha (Aranesp?) a également été autorisée en administration hebdomadaire pour le traitement de l’anémie chez les patients atteints d’une affection maligne non myélo?de traitée par chimiothérapie. La plus grande commodité et le moindre co?t d’administration du traitement hebdomadaire devraient permettre à un plus grand nombre de patients de bénéficier d’un traitement par epoetin.
Technique and Long-Term Results of Intersphincteric Resection for Low Rectal Cancer
PURPOSE Intersphincteric resection of low rectal tumors is a surgical technique extending rectal resection into the intersphincteric space. This procedure is performed by a synchronous abdominoperineal approach with mesorectal excision and excision of the entire or part of the internal sphincter. This study was designed to evaluate the long-term results of this method focused on continence function and oncologic results.
Relation of the slow growth phenotype to neoplastic transformation: Possible significance for human cancer
Summary Deletions are widely distributed over the genome in the most frequently occurring human cancers and are the most abundant genetic lesion found there. Deletions are highly correlated with the slow growth phenotype of mutated animal and human cells and result in chromosomal transposition when the retained ends are joined. Transpositions are only a minor source of mutation in rapidly multiplying bacteria but are a major cause of mutations in stationary bacteria. The NIH 3T3 line of mouse cells undergoes neoplastic transformation during prolonged incubation in a stationary state and expresses the slow growth phenotype on serial subculture at low density, suggesting a relation between transformation and chromosomal deletions. To further explore the relation between neoplastic transformation and the slow growth phenotype as a surrogate for deletions, two sublines of the NIH 3T3 cells with differing competence for transformation were serially subcultured in the stationary state at confluence and tested at each subculture for transformation and growth rate. Cell death in a fraction of the population and a heritable slowdown in proliferation of most of the survivors became increasingly pronounced with successive rounds of confluence. The reduction in growth rate was not proportional to the degree of transformation of the cultures, but all of the transformed cultures were slow growers at low density. All of the discrete colonies from cloning transformed cultures developed at a lower initial rate than control colonies under optimal conditions for growth, but they continued to grow at later stages, forming multilayered colonies under conditions that inhibited the further growth of the control colonies. The results suggest that prolonged incubation of NIH 3T3 cells in the stationary state results in growth-impairing deletions over a wide range of sites in the genome, but more restricted subsets of such lesions are responsible for neoplastic transformation. These findings provide dynamic, functional support in culture for the histopathological evidence that the quiescent state of cells associated with atrophy and fibrosis plays a significant role in the origin of some cancers in experimental animals and human beings.
Hereditary medullary thyroid cancer in Slovenia – genotype-phenotype correlations
Zusammenfassung HINTERGRUND: Das medull?re Schilddrüsenkarzinom (MTC) ist ein seltener endokriner Tumor, der sporadisch oder vererbt als Teil von MEN 2A beziehungsweise MEN 2B, oder als famili?rer Tumor (FMTC) auftreten kann. Keimbahn-Punkt-Mutationen im RET-Proto-onkogen sind für die Tumorentstehung, die Vererbung und für die gro?e klinische Variabilit?t verantwortlich. Ziel dieser Studie war es, den Genotyp mit dem Ph?notyp (Alter bei Diagnoseerstellung, Geschlecht, TNM Klassifikation und Klinik) von Patienten mit vererbbarem MTC zu korrelieren. PATIENTEN: Von 1997 bis 2003 wurden bei 69 von 98 Patienten mit so genanntem "sporadischem" MTC Genanalysen durchgeführt. Es wurden 14 (20,2%) Mutationstr?ger (= Index-Patienten) gefunden. Bei 16 (51,6%) der 31 Verwandten dieser Index-Patienten wurde dieselbe Mutation festgestellt. Ein Patient mit MEN 2B (Mutation im Codon 918) wurde nicht in die Studie aufgenommen. METHODEN: Genomische DNS wurde aus den Leukozyten des peripheren Blutes isoliert. Die Exons 10, 11, 12, 13, 14, 15 und 16 des RET-Protoonkogens wurden in der Polymerase-Ketten-Reaktion (PCR) amplifiziert. Die Punktmutationen im RET-Gen wurden durch Single Strand Conformation Analyse (SSCA) und DNS Sequenzierung entdeckt. Die beobachteten Mutationen wurden durch Restriktions-Enzyme best?tigt. ERGEBNISSE: Mutationen im Codon 634 wurden bei 15 Patienten (50%; Alter: 18–76 Jahre; 6 Familien), im Codon 618 bei 9 Patienten (30%; Alter 12–65; 4 Familien) und im Codon 790 bei 5 Patienten (16,6%; Alter 16–74; 3 Familien) entdeckt. Der Median des Alters bei Diagnosestellung lag bei 31 ± 17,3 (Codon 618); bzw 33 ± 15,9 (Codon 634), bzw 36 ± 23,8 (Codon 790) Jahren. Frauen mit den Mutationen im Codon 618 und im Codon 634 hatten ein medianes Alter bei Diagnoseerstellung von 34,5 ± 15,6 verglichen mit 43,5 ± 22,9 bei den Patienten mit Mutation im Codon 790. Bei M?nnern war im Gegensatz dazu das Alter bei der Diagnose 26,5 ± 18 im Vergleich zu 16 Jahren bei der Mutation im Codon 790. Der Mann/Frau Quotient war 1:2 bei Patienten mit Ver?nderungen im Codon 618 und 634 und 1:4 bei Patienten mit Mutation im Codon 790. Ein Ph?ochromozytom (12/15 Patienten) bzw. ein prim?rer Hyperparathyreoidismus (6/15 Patienten) wurde nur bei Patienten mit einer Mutation im Codon 634 gefunden. Es wurde ein Patient mit einem FMTC und der Hirschsprung'schen Erkrankung in einer Familie mit Mutation im Codon 618 gefunden. SCHLUSSFOLGERUNGEN: Unsere limitierte Studie gibt Hinweise auf eine Korrelation des Genotyps mit der Tumorgr??e und dem MTC Tumorstadium vor allem bei Frauen mit einer Mutation im Codon 790. Der Umstand, dass diese Tumore sp?ter auftreten und einen weniger aggressiven Verlauf nehmen, sollte bei der Planung einer prophylaktischen Schilddrüsenentfernung Berücksichtigung finden. Das MEN 2A Syndrom wurde ausschlie?lich bei Patientne mit der Mutation im Codon 634 beobachtet.
Allelotype of ampulla of Vater cancer: highly frequent involvement of chromosome 11
AbstractPurpose To determine the genetic differences/similarities in ampulla of Vater cancers (AVC) with respect to other pancreatic tumor types.
Laparoscopic anterior resection and total mesorectal excision for rectal cancer: a prospective nonrandomized study
Abstract Background The purpose of this study was to present our experience of laparoscopic total mesorectal resection, including ultralow resection and coloanal anastomosis.
Stress-Induced Immune Dysregulation: Implications for Wound Healing, Infectious Disease and Cancer
Abstract The communication between the central nervous system and the immune system occurs via a complex network of bidirectional signals linking the nervous, endocrine and immune systems. The field of psychoneuroimmunology (PNI) has provided new insights to help understand the pathophysiological processes that are linked to the immune system. Work in this field has established that psychological stress disrupts the functional interaction between the nervous and immune systems. Stress-induced immune dysregulation has been shown to be significant enough to result in health consequences, including reducing the immune response to vaccines, slowing wound healing, reactivating latent herpesviruses, such as Epstein–Barr virus (EBV), and enhancing the risk for more severe infectious disease. Chronic stress/depression can increase the peripheral production of proinflammatory cytokines, such as interleukin (IL)-6. High serum levels of IL-6 have been linked to risks for several conditions, such as cardiovascular disease, type 2 diabetes, mental health complications, and some cancers. This overview will discuss the evidence that psychological stress promotes immune dysfunction that negatively impacts human health.
Value of the Sentinel Lymph Node Procedure in Patients With Large Size Breast Cancer
Abstract Background Widely used in routine for small breast cancers, the sentinel lymph node (SN) biopsy is still discussed in tumors ≥ 3 cm.
Saturday, July 26, 2008
Value of staining intensity in the interpretation of immunohistochemistry for tumor markers in colorectal cancer
Abstract The purpose of this study was to determine whether staining intensity in conjunction with the percentage of positive tumor cells should be used as an indicator of protein expression detected by immunohistochemistry. A tissue microarray of 1,197 colorectal cancers was immunostained for p53, Her2/neu, epidermal growth factor receptor (EGFR), adenomatosis polyposis coli (APC), and β-catenin. Immunoreactivity was described by the percentage of positive tumor cells (percent positivity) and by the staining intensity (weak, moderate, strong). The interobserver reproducibility of both was evaluated by two pathologists. The association of T stage, N stage, tumor grade, vascular invasion, and survival with percent positivity, staining intensity, and the combination of both was assessed. In univariate analysis, protein expression assessed by percent positivity resulted in 11 significant associations between the proteins and clinico-pathological features. Eight of these 11 were also demonstrated using only the degree of staining intensity. However, more than half of the associations identified by percent positivity alone were lost when staining intensity was also analyzed in combination with the percentage of positive tumor cells. A scoring method based on percent positivity, rather than on staining intensity, for p53, Her2/neu, EGFR, APC, and β-catenin is reproducible and appears to be sufficient for establishing associations of the selected tumor markers with most clinico-pathological features.
RECK—a newly discovered inhibitor of metastasis with prognostic significance in multiple forms of cancer
Abstract The RECK (reversion-inducing cysteine rich protein with Kazal motifs) protein was initially discovered by its ability to induce reversion in ras-activated fibroblasts. The key action of RECK is to inhibit matrix metalloproteinases (MMPs) involved in breakdown of the extracellular matrix (ECM), and angiogenesis—namely MMP-2, MMP-9 and MTP-1. To this effect, it plays important physiological roles in embryogenesis and vasculogenesis. Additionally, it has a significant effect on tumorigenesis by limiting angiogenesis and invasion of tumours through the ECM. RECK has been studied in the context of a number of human tumours including colorectal, breast, pancreas, gastric, hepatocellular, prostate, and non-small cell lung carcinoma. In many of these tumours, RECK is down-regulated most likely as a result of inhibition at the Sp1 promoter site. MMP-2 and MMP-9 generally show an inverse association with RECK expression, but there are exceptions to this rule. Likewise, a reduction in tumour microvascular density (MVD) and VEGF have also been correlated with increased RECK levels, although more studies are required to define this effect. The predominant finding across all human tumour studies is a significantly improved prognosis (due to decreased invasion and metastasis) in tumours with preserved RECK expression. Although further research is required, RECK is a promising prognostic marker and potential therapeutic agent in multiple cancers.
p53 and HLA class-I expression are not down-regulated in colorectal cancer liver metastases
Abstract p53 overexpression occurs in more than 50% of colorectal carcinomas, which makes it an interesting target for immunotherapy. HLA class I expression on tumor cells is required for the presentation of p53 peptides and an effective T-cell mediated-immune response to ensue. To analyze to which extent p53 and HLA-I expression in a primary tumor reflects expression in liver metastases, we investigated p53, HLA-A and HLA-B/C expression in 82 colorectal carcinomas and 143 associated liver metastases of 82 patients. We used the monoclonal antibodies DO-7 (p53), HCA2 (HLA-A) and HC-10 (HLA-B/C) on formalin-fixed, paraffin embedded tissue. The percentage of expressing cells was estimated. P53 was overexpressed in 73% of the colorectal carcinomas and 66% of liver metastases. HLA-A was expressed in 98% and 96% and HLA-B/C in 100% and 94% of colorectal cancers and liver metastases respectively. There were no significant differences between the primary tumors and the liver metastases for each marker. The concordance was also very high in those cases in which more than one metastasis was available. Discordant cases consisted of tumors in which expression of p53 or HLA-A was lost in the liver metastases, whereas it was present in only a few tumor cells in the primary tumor. The combined analysis of p53 and HLA-I expression in liver metastases demonstrated that both molecules were expressed in 63% of the cases. P53 and HLA-I were expressed in the majority of primary tumors and their associated liver metastases. This allows to select patients for p53-immunotherapy on the basis of p53 and HLA-I expression in the primary tumor.
Scintimammography with 99mTc-MIBI and magnetic resonance imaging in the evaluation of breast cancer
Abstract This study was performed to evaluate the sensitivity and specificity of technetium-99m methoxyisobutylisonitrile (99mTc-MIBI) scintimammography (SMM) and contrast-enhanced magnetic resonance imaging (MRI) in patients with breast masses, using the histological findings as the gold standard. Forty-five consecutive patients with a breast lesion, detected by self-examination, physical examination or screening mammography, underwent SMM and MRI. In 38 cases (84.5%), the histopathology was malignant; the breast cancers ranged from 3 to 100 mm in diameter (mean 22 mm). In the overall patient group, MRI showed a slightly higher sensitivity than SMM (92% vs 84%), but SMM showed a better specificity: 71% vs 42%. The accuracy was 82% and 84% for SMM and MRI respectively. To evaluate the influence of lesion size on the results, patients with lesions 20 mm and 15 mm were examined. In patients with lesions 20 mm, the sensitivity of SMM and MRI decreased to 64% and 82% respectively, while SMM again displayed considerably better specificity: 83% vs 50% for MRI. The accuracy of SMM and MRI was 64% and 82% respectively. In patients with lesions 15 mm, SMM again showed better specificity (75% vs 50%), while MRI displayed better sensitivity and accuracy (sensitivity, 81% vs 62%; accuracy, 75% vs 65%). In this study the specificity of SMM in patients with breast lesions was thus superior to that of MRI. The combination of SMM and MRI may be used in those patients with equivocal findings at mammography and ultrasound to reduce the number of unnecessary surgical biopsies.
Aromatasehemmer in der endokrinen Therapie des Mammakarzinoms
Zusammenfassung Aromatasehemmer wurden in klinischen Studien als Ersatz und als Additivum der Standardtherapie mit Tamoxifen untersucht. In prospektiv-randomisierten Studien konnte für Anastrozol, Letrozol und Exemestan eine Steigerung der Ansprechraten, eine signifikante Verlängerung des progressionsfreien Intervalls und eine Verbesserung der Gesamtüberlebensrate bei postmenopausalen Patientinnen mit metastasiertem Mammakarzinom nachgewiesen werden. In den letzten Jahren wurde versucht, diese Therapeutika in die adjuvante Phase einzuführen. Die ATAC-Studie zeigte, dass Anastrozol bei Frauen mit steroidrezeptorpositiven Tumoren gegenüber Tamoxifen die Rate an Lokal- und an Fernrezidiven signifikant senken kann. Zwei weitere Studien haben den sequenziellen Einsatz von Tamoxifen und Letrozol bzw. Exemestan untersucht. Nach 2,4 Jahren Nachbeobachtungszeit zeigte sich ein signifikanter Vorteil für Letrozol bezüglich des rezidivfreien Überlebens. Auch in einem sequenziellen Therapieansatz mit Tamoxifen und Exemestan konnte eine Reduktion an Lokal- und Fernrezidiven sowie kontralateralen Mammakarzinomen nachgewiesen werden. Im Gesamtüberleben wiesen diese Studien keine Unterschiede zwischen den Therapiearmen auf.
Prognostic Groups in 1,676 Patients with T3 Rectal Cancer Treated without Preoperative Radiotherapy
Purpose The use of preoperative radiotherapy in patients with T3 tumors shows considerable variation among countries and institutions. The Norwegian guidelines have been very restrictive, limiting the indication to T4. This study was designed to identify subgroups of patients with T3 tumors with presumed high risks on adverse outcome and to use these results to reevaluate the national guidelines for preoperative radiotherapy.
P53/MDM2 overexpression in metastatic endometrial cancer: correlation with clinicopathological features and patient outcome
Abstract Several studies have reported that p53/mdm2 distortions play a pivotal role in the development and progression of various human malignancies. However, the number of reports having evaluated simultaneously the components of the P53-pathway alterations in advanced-stage human endometrial carcinomas (EC) is low. In this study, we examined the expression of P53/MDM2 proteins in primary and metastatic ECs, and analyzed the clinicopathological characteristics as well as the survival outcome of patients in relation to P53/MDM2 overexpression. The study group comprised 36 patients with advanced EC, whose primary and metastatic tumor slides were sufficient for analysis. Immunohistochemical assessment was made by applying anti-human P53 and MDM2 antibodies and a highly sensitive EnVision+/HPR visualization system. Nuclear P53 overexpression was seen in 11 (31%) primary ECs and 12 (33%) metastatic tumors. There was a significant correlation between P53 overexpression (in primary cancers and metastatic tumors) and MDM2 overexpression in metastatic tumors. Nuclear MDM2 overexpression was noted in 42% (15/36) of primary carcinomas and in 47% (17/36) of metastatic tumors. A significant association existed between MDM2 overexpression and histological grading (G1 + G2 versus G3, P = 0.043). P53/MDM2 overexpression occurred simultaneously in 7 out of 36 (19%) primary ECs and in 9 out of 36 (25%) metastatic lesions. Concomitant overexpression of these proteins was reported in 7 out of 36 (19%) cases and tended to be higher in tumors showing VSI compared to neoplasms lacking vascular space invasion (P = 0.051). P53 overexpression, either in primary ECs (P < 0.0001) or metastatic lesions (P < 0.0001), was significantly associated with poor survival in univariate analysis. Moreover, the log-rank test demonstrated that simultaneous P53/MDM2 overexpression was also correlated with decreased length of survival. There was no correlation between MDM2 overexpression and patient survival. Multivariate Cox regression analysis revealed that only P53 overexpression is an independent predictor of survival. In conclusion, our data support the view that patients with P53 overexpression are significantly associated with an unfavorable outcome, whereas MDM2 overexpression is not related to decreased survival length in women operated on for advanced-stage EC.
Isolierte Tumorzellen in Knochenmark und Blut von Patientinnen mit prim?rem Mammakarzinom – Klinische Relevanz
Zusammenfassung Trotz wesentlicher Fortschritte in der systemischen Therapie des Mammkarzinoms sind Rezidive nach oft langer Latenzzeit charakteristisch. Ausgangspunkt für eine Fernmetastasierung sind in der Regel isolierte Tumorzellen, die bereits früh im Verlauf der Erkrankung h?matogen disseminieren. Der Nachweis dieser minimalen Tumorresiduen („minimal residual disease“, MRD) ist mit konventionellen bildgebenden Verfahren nicht m?glich; die dafür am besten etablierte Methode ist der immunzytochemische Nachweis isolierter Tumorzellen im Knochenmark (KM). Die daraus gewonnenen Informationen über Pr?valenz und Ph?notyp der Tumorzellen lassen Rückschlüsse auf Tumorbiologie und individuelle Prognose zu und k?nnten in der adjuvanten Situation eine Therapieoptimierung erm?glichen. Die immunzytochemische KM-Untersuchung k?nnte die Antwort auf die Frage nach dem individuellen Erfolg adjuvanter Therapien erleichtern und Grundlage für die Einleitung einer sekund?r-adjuvanten Therapie sein. Au?erhalb klinischer Studien sollte der Nachweis isolierter Tumorzellen derzeit nicht als alleinige Grundlage für eine Therapieentscheidung herangezogen werden.
Polymorphisms in genes related to activation or detoxification of carcinogens might interact with smoking to increase renal cancer risk: results from The Netherlands Cohort Study on diet and cancer
Abstract Metabolic gene polymorphisms have previously been suggested as risk factors for renal cell carcinoma (RCC). These polymorphisms are involved in activation or detoxification of carcinogens in cigarette smoke which is another RCC risk factor. We evaluated gene–environment interactions between CYP1A1, GSTμ1 and smoking in a large population-based RCC case group. The Netherlands Cohort Study on diet and cancer (NLCS) comprises 120,852 persons who completed a questionnaire on smoking and other risk factors at baseline. After 11.3 years of follow-up, 337 incident RCC cases were identified. DNA was collected for 245 cases. In a case-only analysis, interaction-odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using logistic regression. We observed a moderate, not statistically significant, interaction between current smoking and CYP1A1*2C (OR 1.42; 95% CI 0.70–2.89) and GSTμ1 null (OR 1.35; 95% CI 0.65–2.79). For current smokers with both a variant (heterozygous or homozygous) in CYP1A1 and GSTμ1 null, risk was also increased (OR 1.63; 95% CI 0.63–4.24). No interaction was observed between ever smokers, smoking duration (increments of 10 smoking years) or amount (increments of 5 cigarettes/day) and CYP1A or GSTμ1. Our results show a modest trend towards a statistically significant gene–environment interaction between CYP1A1, GSTμ1 and smoking in RCC. This could indicate that RCC risk among smokers might be more increased with the CYP1A1*2C genotype, GSTμ1 null, or both a CYP1A1 variant and GSTμ1 null.
Thomsen-Friedenreich (TF) antigen as a target for prostate cancer vaccine: clinical trial results with TF cluster (c)-KLH plus QS21 conjugate vaccine in patients with biochemically relapsed prostate cancer
Abstract The differential overexpression of self-antigens on tumor cells is a prime feature of malignant transformation. Thomsen-Friedenreich (TF), a core disaccharide of O-glycosylated complex glycoproteins, is one of many self antigens expressed on malignantly transformed cells that has served as a target for immune recognition and attack. Previously, we conducted clinical trials with a series of synthetic glycolipid, peptide and carbohydrate antigens conjugated to the immunological carrier keyhole limpet hemocyanin (KLH) mixed with the immunological saponin adjuvant, QS21. These trials resulted in the generation of high-titer IgM and IgG antibody responses specific for the individual antigens, and, in several cases, the capacity of those antibodies to mediate complement lysis. Four groups of five patients who had evidence of a biochemical relapse defined as rising prostate-specific antigens (PSAs) following primary therapy for prostate cancer with either prostatectomy or radiation were treated with escalating doses of 1, 3, 10 and 30 g of synthetic TF in a clustered formation (c) which was conjugated to KLH and given with 100 g of QS21. Patients received a total of five subcutaneous vaccines over 6 months and were monitored expectantly with scans every 3–4 months. Serum samples were obtained at weeks 1, 2, 3, 7, 9, 13, 19, 26, 50 and every 3 months. Antibody titers were monitored by ELISA and antibody binding to the cell surface of prostate cell lines was performed by flow cytometry. Complement-dependent cytotoxicity was performed on selected patients. Twenty evaluable patients were accrued to the study, of whom only one did not receive all six vaccinations. All patients developed maximum IgM and IgG antibody titers by week 9. The median IgM antibody titer by week 7 was 1/1,280 at 10 g, 1/320 at 30 g, 1/1,280 at 3 g and 1/1,280 at 1 g dose groups. The IgM titers from all groups remained greater than 1/320 by week 32 and beyond through week 50. We report here the results of a dose-escalating trial of a TF(c)-KLH conjugate vaccine in patients in the clinical state of a rising PSA in the absence of radiographic disease. For the first time, a synthetically made TF trimer or cluster (c) was made with three TF disaccharides attached to three sequential threonines on a peptide backbone. TF(c) doses of 1, 3, 10 and 30 g were conjugated to KLH and administered with QS21. All doses induced high-titer IgM and IgG antibodies against TF. Unlike our findings in previous dose-escalating phase I trials, there did not appear to be increased antibody production with increasing doses of vaccine; higher titers of IgM and IgG antibodies developed at the lowest dose level (1 g). An anti-tumor effect in the form of a change in post-treatment versus pretreatment logPSA slopes was also observed. The results justify the inclusion of TF(c) at a dose of 1 g as a relevant antigenic target in a multivalent phase II vaccine trial in patients in the high-risk minimal disease state.
Local interleukin 2 therapy is most effective against cancer when injected intratumourally
Abstract Local interleukin 2 (IL-2) therapy is more effective against systemic tumours than systemic IL-2 therapy, but it remains unclear whether IL-2 should be injected intratumourally or peritumourally. To investigate this question, we treated DBA/2 mice bearing a large subcutaneous syngeneic SL2 lymphoma with either intra or peritumoural IL-2 therapy. Both applications enhanced survival, but intratumourally injected IL-2 was more effective than peritumourally injected IL-2. Tumours started to regress 4 days after IL-2 injection. Tumour cells died at the IL-2 injection site, although IL-2 is not directly cytotoxic for SL2 cells in vitro. Tumour cell death correlated well with oedema and extravascular erythrocytes, but less with leukocyte infiltrates. In mice bearing two s.c. tumours, intratumoural application therapy of IL-2 in one tumour caused decrease in size of both tumours in 4–9 days after therapy. However, the IL-2 treated tumours regressed more strongly than the untreated tumours. We conclude that vascular leakage and/or tissue destruction inside the tumour may contribute to the enhanced effect of intratumoural IL-2 therapy compared to peritumoural IL-2 therapy. Hence, we recommend applying of intratumoural rather than peritumoural IL-2 therapy.
Bone cancer risk in mice exposed to 224Ra: protraction effects from promotion
Abstract This paper analyzes data for the osteosarcoma incidence in life-time experiments of 224Ra injected mice with respect to the importance of initiating and promoting action of ionizing high LET-radiation. This was done with the biologically motivated two step clonal expansion (TSCE) model of tumor induction. Experimentally derived osteosarcoma incidence in 1,194 mice following exposure to 224Ra with different total radiation doses and different fractionation patterns were analyzed together with incidence data from 1,710 unirradiated control animals. Effects of radiation on the initiating event and on the clonal expansion rate, i.e. on promotion were found to be necessary to explain the observed patterns with this model. The data show a distinct inverse protraction effect at high doses, whereas at lower doses this effect becomes insignificant. Such a behavior is well reproduced in the proposed model: At dose rates above 6 mGy/day a longer exposure produces higher ERR per dose, while for lower rates the reverse is the case. The TSCE model permits the deduction of several kinetic parameters of a postulated two-step bone tumorigenesis process. Mean exposure rates of 0.13 mGy/day are found to double the baseline initiation rate. At rates above 100 mGy/day, the initiation rate decreases. The clonal expansion rate is doubled at 8 mGy/day, and it levels out at rates beyond 100 mGy/day.
Photodynamic Therapy for Cancer Cells Using a Flash Wave Light Xenon Lamp
Abstract We determined photodynamic therapy (PDT) efficacy using a flash wave (FW) and a continuous wave (CW) light, of which the fluence rate was 70 W/cm2, for murine thymic lymphoma cells (EL-4) cultivated in vitro. The irradiation frequency and the pulse width of the FW light were in the range of 1–32 Hz and less than one millisecond, respectively. 5-Aminolevulinic acid-induced protoporphyrin IX (ALA-PpIX) was used as a photosensitizer. When EL-4 with ALA administration was irradiated by the light for 4 h (irradiation fluence: 1.0J/cm2), the survival rate of EL-4 by the FW light was lower than that by the CW light, except for the FW light with irradiation frequency of 32 Hz, and decreased gradually with decreasing irradiation frequency. Moreover, the FW light, especially at lower irradiation frequency, was superior to the CW light for the generation of singlet oxygen in an aqueous PpIX solution. Therefore, thehigher PDT efficacy for EL-4 of the FW light would be caused by the greater generation of singlet oxygen in the cells.
Selection and validation of differentially expressed genes in head and neck cancer
Abstract We applied a robust combinatorial (multi-test) approach to microarray data to identify genes consistently up- or down-regulated in head and neck squamous cell carcinoma (HNSCC). RNA was extracted from 22 paired samples of HNSCC and normal tissue from the same donors and hybridized to the Affymetrix U95A chip. Forty-two differentially expressed probe sets (representing 38 genes and one expressed sequence tag) satisfied all statistical tests of significance and were selected for further validation. Selected probe sets were validated by hierarchical clustering, multiple probe set concordance, and target-subunit agreement. In addition, real-time PCR analysis of 8 representative (randomly selected from 38) genes performed on both microarray-tested and independently obtained samples correlated well with the microarray data. The genes identified and validated by this method were in comparatively good agreement with other rigorous HNSCC microarray studies. From this study, we conclude that combinatorial analysis of microarray data is a promising technique for identifying differentially expressed genes with few false positives.
Phase I dose escalation trial of feverfew with standardized doses of parthenolide in patients with cancer
Abstract Purpose: Feverfew is a botanical product that contains parthenolide. Parthenolide has in vitro and in vivo anti-tumor and anti-angiogenic activity. Feverfew has been used extensively without any formal pharmacokinetic analysis. A Phase I trial was conducted to evaluate the pharmacokinetics and toxicity of parthenolide given as a component of feverfew. Patients and methods: Feverfew (Tanacet) was administered as a daily oral tablet in a 28-day cycle. A starting dose of 1 mg per day was explored with subsequent dose escalations to 2, 3, and 4 mg. Assessment of plasma pharmacokinetics was performed on patients accrued to the trial. Solid phase extraction and mass spectroscopy were used to evaluate parthenolide plasma concentrations. The limit of detection for parthenolide in plasma was 0.5 ng/ml. Patients were evaluated for response after every two cycles. Results: Feverfew given on this schedule had no significant toxicity, and the maximum tolerated dose was not reached. When parthenolide was administered at doses up to 4 mg as a daily oral capsule in the feverfew preparation, there was not detectable concentration in the plasma. Because of this, parthenolide pharmacokinetics were not able to be completed. Conclusion: Feverfew, with up to 4 mg of parthenolide, given daily as an oral tablet is well tolerated without dose-limiting toxicity, but does not provide detectable plasma concentrations. Purification of parthenolide for administration of higher doses will be needed.
Cellular and molecular effects of protons: Apoptosis induction and potential implications for cancer therapy
Abstract Due to their ballistic precision, apoptosis induction by protons could be a strategy to specifically eliminate neoplastic cells. To characterize the cellular and molecular effects of these hadrons, we performed dose-response and time-course experiments by exposing different cell lines (PC3, Ca301D, MCF7) to increasing doses of protons and examining them with FACS, RT-PCR, and electron spin resonance (ESR). Irradiation with a dose of 10 Gy of a 26,7 Mev proton beam altered cell structures such as membranes, caused DNA double strand breaks, and significantly increased intracellular levels of hydroxyl ions, are active oxygen species (ROS). This modified the transcriptome of irradiated cells, activated the mitochondrial (intrinsic) pathway of apoptosis, and resulted in cycle arrest at the G2/M boundary. The number of necrotic cells within the irradiated cell population did not significantly increase with respect to the controls. The effects of irradiation with 20 Gy were qualitatively as well as quantitatively similar, but exposure to 40 Gy caused massive necrosis. Similar experiments with photons demonstrated that they induce apoptosis in a significantly lower number of cells and in a temporally delayed manner. These data advance our knowledge on the cellular and molecular effects of proton irradiation and could be useful for improving current hadrontherapy protocols.
Human metabolism of [14C]indisulam following i.v. infusion in cancer patients
Abstract Indisulam is a new anticancer drug with a unique mechanism of action, arresting the cell cycle at the G1/S transition. The major excretory pathway of indisulam is via the urine, accounting for 63% of the radioactive dose ([14C]indisulam) administered in a human mass balance study. Radiochromatographic profiling of urine samples resulted in the detection of several radioactive peaks. The purpose of the present investigation was to elucidate the chemical structures of these observed indisulam metabolites. We collected fractions after chromatographic separation of the urine samples. These fractions were analysed using tandem mass spectrometry. We propose the chemical structure of 15 indisulam metabolites in urine. The metabolism of indisulam is very complex, consisting of oxidative dechlorination, hydroxylation, hydrolysis, acetylation, sulphation and glucuronidation. The clinical relevance of the observed indisulam metabolites needs further investigation.
Life course breast cancer risk factors and adult breast density (United Kingdom)
Abstract Objective To determine whether risk factors in childhood and early adulthood affect later mammographic breast density. Methods: Subjects were 628 women who attended a medical examination at the University of Glasgow Student Health Service (1948–1968), responded to a questionnaire (2001) and had a screening mammogram in Scotland (1989–2002). Mammograms (median age of 59years) were classified using a six category classification (SCC) of breast density percent. Logistic regression was used to determine associations between risk factors and having a high-risk mammogram (25 dense). Results: In multi-variable analyses, high-risk mammograms were associated with parity (adjusted odds ratio (OR) per child: 0.77 (95 confidence interval (CI) 0.61–0.99)), age at first birth, OR per year: 1.05 (0.99–1.11), smoking at university, OR smokers versus non-smokers: 0.58 (0.36–0.92) and body mass index (BMI) while at university, OR per 1kg/m20.75 (0.69–0.82). No associations with SCC were found for age at menarche, birth weight, oral contraceptive (OC) use, height, leg length or exercise at age 20. Conclusions: We confirm previous findings that breast density is affected by reproductive events and some anthropometric measures, however most of the risk factors acting throughout the life course which we examined were not closely related to adult breast density.
Requirement of cyclooxygenase-2 expression and prostaglandins for human prostate cancer cell invasion
Abstract The PC-3 Low Invasive cells and the PC-3 High Invasive cells were used to investigate the correlation of the COX-2 expression and its arachidonic acid metabolites, prostaglandins, with their invasiveness through Matrigel? using a Boyden chamber assay. The COX-2 expression in PC-3 High Invasive cells was approximately 3-fold higher than in PC-3 Low Invasive cells while the COX-1 expression was similar in both cell sublines. When incubated with arachidonic acid, PGE2 was the major prostaglandin produced by these cells. PC-3 High Invasive cells produced PGE2 approximately 2.5-fold higher than PC-3 Low Invasive cells. PGD2 was the second most abundant prostaglandin produced by these cells. Both indomethacin (a nonspecific COX inhibitor) and NS-398 (a specific COX-2 inhibitor) inhibited the production of prostaglandins and the cell invasion. PGE2 alone did not induce the cell invasion of PC-3 Low Invasive cells. However, PGE2 reversed the inhibition of cell invasion by NS-398 and enhanced the cell invasion of the PC-3 High Invasive cells. In contrast, PGD2 slightly inhibited the cell invasion. These results suggest that in the PC-3 Low Invasive cells, COX-2-derived PGE2 may not be sufficient to induce cell invasion while in the PC-3 High Invasive cells, PGE2 may be sufficient to act as an enhancer for the cell invasion. Further, PGD2 may represent a weak inhibitor and counteracts the effect of PGE2 in the cell invasion.
Local and systemic chemotherapy with taurolidine and taurolidine/heparin in colon cancer-bearing rats undergoing laparotomy
Abstract Experimental studies in the therapy of malignant abdominal tumors have shown that different cytotoxic agents suppress the intraperitoneal tumor growth. Nevertheless, a general accepted approach to prevent tumor recurrences does not exist. Following subcutaneous and intraperitoneal injection of 104 colon adenocarcinoma cells (DHD/K12/TRb), the influences of both taurolidine or taurolidine/heparin on intraperitoneal and subcutaneous tumor growth was investigated in 105 rats undergoing midline laparotomy. The animals were randomized into 7 groups and operated on during 30 min. To investigate the intraperitoneal (local) influence of either taurolidine or heparin on tumor growth, the substances were applied intraperitoneally. Systemic and intraperitoneal effects were evaluated after intravenous injection of the substances. Both application forms were also combined to analyze synergistic effects. Tumor weights, as well as the incidence of abdominal wound metastases, were determined four weeks after the intervention. In order to evaluate the effects of the agents, blood was taken to determine the peripheral leukocytes counts. Intraperitoneal tumor growth in rats receiving intraperitoneal application of taurolidine (median 7.0 mg, P=0.05) and of taurolidine/heparin (median 0 mg, P=0.02) was significantly reduced when compared to the control group (median 185 mg). The simultaneous instillation of both agents also reduced the intraperitoneal tumor growth (median 4 mg, P=0.04), while the intravenous injection of the substances caused no local effect. In contrast, the subcutaneous tumor growth did not differ among all groups. In all groups, abdominal wound recurrences were rare and did not differ. Independent of the agents and the application form, the operation itself caused a slight leukopenia shortly after the operation and a leukocytosis in the following course. Intraperitoneal therapy of either taurolidine or in combination with heparin inhibits local tumor growth and abdominal wound recurrences in rats undergoing midline laparotomy. Neither the intraperitoneal nor the intravenous application or the combination of the two agents influenced the subcutaneous tumor growth. The substances did not alter the changes of peripheral leukocytes.
Evaluation of Residual Stomach Motility After Proximal Gastrectomy for Gastric Cancer by Electrogastrography
Abstract The relationship between the motility and the size of the residual stomach after proximal gastrectomy was evaluated using electrogastrography (EGG). Based on fast Fourier transformation, recorded slow waves could be analyzed to obtain the following parameters: dominant frequency (DF), percentage normal frequency (% 3 cycles per minute [cpm]), and power ratio (PR). EGG parameters, the length of the greater curvature of the residual stomach (LGC), were recorded in 18 gastrectomized patients. Compared to 12 healthy controls, the gastrectomized patients had abdominal EGG parameters including lower %3cpm (43 ± 21% vs 83 ± 7%; P < 0.05), DF (2.2 ± 0.4 vs 3.0 ± 0.2 cpm; P < 0.05), and PR (1.5 ± 0.8 vs 2.5± 0.8; P < 0.05). In relation to LGC and parameters, there was no difference between the patients whose LGC was > 20 cm and controls in PR (2.3± 0.9 vs 2.5± 0.8; n.s.). In conclusion, the motility of the residual stomach would be equal to that of the nonresected stomach as if the volume of the residual stomach was more than half.
How Accurate is Magnetic Resonance Imaging in Restaging Rectal Cancer in Patients Receiving Preoperative Combined Chemoradiotherapy?
PURPOSE Preoperative combined chemoradiotherapy is currently the main neoadjuvant therapy used to treat locally advanced middle and low rectal adenocarcinoma. A restaging work-up with magnetic resonance imaging was hoped to provide information about the effects related to combined chemoradiotherapy. The goal was to evaluate the correlation between pathologically verified tumor stages and clinical stages predicted by magnetic resonance imaging after combined chemoradiotherapy.
Wednesday, July 23, 2008
Inhalative Immuntherapie beim pulmonal metastasierten Nierenzellkarzinom
Zusammenfassung Studien zur inhalativen Immuntherapie mit Interleukin-2 (IL-2) beim pulmonal metastasierten Nierenzellkarzinom berichten über objektive Remissionen von 11%. Ziel der vorliegenden Untersuchung war es Wirksamkeit, Nebenwirkungsspektrum und Lebensqualität unter der inhalativen Immuntherapie zu untersuchen.Patienten mit pulmonal metastastasiertem Nierenzellkarzinom erhielten Interferon- (IFN-) 3×106 IU/m2 s.c. an den Tagen 1, 3 und 5 und inhalierten 2-mal täglich 9×106 IU IL-2 an den Tagen 1–5. Ein Therapiezyklus entsprach 4 Wochen und nach einer 2-wöchigen Pause schloss sich ein 2. Zyklus an. Anschließend erfolgte eine Reevaluierung, bei Ansprechen wurde die Therapie um weitere 2 Zyklen fortgesetzt. Die Patienten wurden vor, während und nach der Therapie zur Lebensqualität befragt (QLQ-C30-Fragebögen).
Stellenwert der systemische Chemotherapie des Harnblasenkarzinoms
Zusammenfassung Die Hälfte der Patienten mit einem muskelinvasiven Harnblasenkarzinom hat zum Zeitpunkt der initialen Diagnose bereits okkulte regionale oder Fernmetastasen. Die systemische Erkrankung hat mit weniger als 10% Langzeit-Überlebensrate eine ungünstige Prognose. Mit der systemischen Chemotherapie versucht man, den weiteren Verlauf einer lokal fortgeschrittenen oder metastasierten Erkrankung günstig zu beeinflussen. Ein Überlebensvorteil von 5% einer neoadjuvanten und 9–11% einer adjuvanten Chemotherapie ist im ersten Fall minimal, für die adjuvante Situation schon eher beachtenswert. Als induktive Chemotherapie sind das MVAC-Schema und die Kombination Gemcitabin/Cisplatin als Standardschemata anzusehen. Dennoch sind die 5-Jahres-Überlebensraten mit 15 bzw. 13% enttäuschend. Von besonderer Bedeutung sind in diesem Zusammenhang prognostische Faktoren, bei deren Berücksichtigung deutliche Unterschiede im Überleben bestehen. Hoffnungen werden in eine neue Substanzgruppe, die sog. target-spezifischen Medikamente, gesetzt, die gezielt in die Kaskade der Tumorgenese eingreifen.
High-dose-rate-Brachytherapie beim Risikoprostatakarzinom
Zusammenfassung Beim Prostatakarzinom ist zur Einschätzung des Therapieerfolgs hinsichtlich der rezidivfreien Zeit die Gruppierung in Niedrig-, Intermediär- und Hochrisikokarzinome sinnvoll. Die Trias PSA 10, Gleason-Score 7 und die klinische Tumorkategorie cT3 (extrakapsuläres Tumorwachstum) sind bei der Einteilung hilfreich und einfach.Das Phänomen des posttherapeutischen biochemischen Rezidivs könnte eine Folge der zzt. noch zu ungenauen Bildgebung in der Erkennung von Lymphknoten- oder Knochenmetastasen sein, sodass bereits zum Diagnosezeitpunkt eine Metastasierung nicht erkannt und eine lokale Therapie eingeleitet wird. Andererseits sind Karzinome der Hochrisikogruppe durch biologische Tumoreigenschaften gekennzeichnet, die auch sekundär zu einer fortschreitenden Erkrankung führen. Hierbei ist eine risikoadaptierte Therapie von immenser Wichtigkeit. In der Strahlentherapie spielt die applizierte Strahlendosis eine wichtige Rolle. Das Auftreten des biochemischen Lokalrezidivs korreliert mit den Risikofaktoren und der Strahlendosis. Vor diesem Hintergrund kann bei einem selektionierten Patientengut eine initiale 3D-konformale perkutane Strahlentherapie und HDR-Brachytherapie einen Vorteil bringen.
Genetic pathways and new progression markers for prostate cancer defined by microsatellite allelotyping
Abstract A prospective study was carried out on a large cohort of males undergoing radical retropubic prostatectomy in order to identify genetic marker regions significantly associated with tumor formation. By comprehensive allotyping of chromosomes known to be associated with prostate carcinogenesis, an algorithm could be formulated for the genetic pathway and a method of discrimination between aggressive and less aggressive forms could be identified.
A skin tumor as a marker for a hereditary cancer syndrome: Muir-Torre syndrome
Abstract If after excision of a skin tumor, the diagnosis of the pathologist is an epithelioma, adenoma, or carcinoma of sebaceous origin, one should be alert for Muir-Torre syndrome (MTS). In its simplest description, this syndrome is the association of sebaceous gland neoplasm with internal malignancy in the same patient. The sebaceous gland tumor may precede, appear concurrently, or follow the diagnosis of the patients internal malignancy. The sebaceous tumor occurs prior to or concurrent with an internal malignancy in 44% to 63% of the MTS patients [3, 7]. The sebaceous skin tumor can therefore be used as a marker for internal malignancies. This fact is important because internal malignancies in MTS tend to be less aggressive compared to sporadic malignancies. This article describes the incidence of MTS in a cohort of patients diagnosed as suffering from a sebaceous gland neoplasm, who visited our Department of Plastic and Reconstructive Surgery, in collaboration with the Department of Dermatology.
PET/CT with intravenous contrast can be used for PET attenuation correction in cancer patients
AbstractPurpose If the CT scan of a combined PET/CT study is performed as a full diagnostic quality CT scan including intravenous (IV) contrast agent, the quality of the joint PET/CT procedure is improved and a separate diagnostic CT scan can be avoided. CT with IV contrast can be used for PET attenuation correction, but this may result in a bias in the attenuation factors. The clinical significance of this bias has not been established. Our aim was to perform a prospective clinical study where each patient had CT performed with and without IV contrast agent to establish whether PET/CT with IV contrast can be used for PET attenuation without reducing the clinical value of the PET scan.
Mechanistic and antineoplastic evaluation of taurolidine in the DU145 model of human prostate cancer
Abstract Taurolidine (TRD) was designed in the 1970s as a broad-spectrum antibiotic and is used clinically at high doses without systemic toxicity. We have found that this agent possesses cytotoxic activity in human tumor cell lines and antineoplastic activity in mice bearing i.p. human tumor xenografts. We now report the mechanism by which TRD induces cell death in DU145 human prostate tumor cells. The IC50 (3 days) of TRD in this model was 16.8±1.1 M. Cytotoxicity was associated with DNA debris and increased membrane phosphatidylserine externalization, both suggesting the induction of apoptosis. This was confirmed by the ability of TRD to induce PARP cleavage in these cells, an effect prevented by coexposure to the pan-caspase inhibitor zVAD-FMK. TRD exposure also resulted in the appearance of cytochrome c in the cytoplasm, procaspase 9 activation within 2 h of drug exposure and procaspase 8 activation 4 h after exposure. Parallel experiments revealed that cytochrome cappearance in the cytoplasm was not blocked by preexposure to zVAD-FMK, while activation of both procaspase 9 and procaspase 8 was prevented. Finally, antineoplastic activity was assessed in mice bearing subcutaneous xenografts of DU145 cells. Initial studies quantitated the toxicity of three i.p. injections of TRD, administered as one injection on three alternate days per week, at doses ranging from 500 to 700 mg/kg per injection. The 500 mg/kg dose produced about 7% mortality after three cycles and effectively inhibited tumor growth. Thus, TRD induced mitochondrial-mediated apoptosis in DU145 human prostate tumor cells and this effect could be exploited for therapeutic advantage.
Pharmacokinetically guided dosing of carboplatin in paediatric cancer patients with bilateral nephrectomy
Abstract An approach to carboplatin dosing in children with bilateral nephrectomy using a renal function-based dosing formula with a glomerular filtration rate of zero was investigated in the current study. Carboplatin exposure was determined in a total of nine courses of chemotherapy in four patients with Wilms tumour. Carboplatin exposures following initial dosing were less than 50% of the defined target area under the plasma concentration-time curve (AUC) in all four patients studied, with actual AUC values of between 31% and 45% of the target exposures. The use of real-time pharmacokinetic monitoring to guide dosing within a course of carboplatin treatment resulted in exposures within 15% of the target AUC in all patients. Using this information to guide dosing on additional courses of treatment in the same patient resulted in consistent exposures without the need for further monitoring or dose adjustment. These results indicate that real-time pharmacokinetic monitoring of carboplatin treatment plays a key role in ensuring that an appropriate exposure to carboplatin is achieved in children with bilateral nephrectomy. Carboplatin dosing based on patient body weight, or use of a fixed dose of carboplatin, would both be predicted to result in individual patients receiving unsatisfactory drug exposures. Further studies are warranted to further elucidate the relationship between non-renal clearance of carboplatin and patient body weight in this and other patient subpopulations where there remains concern about the optimal way to use this anticancer drug.
Update on management of infections in cancer and stem cell transplant patients
Abstract Infections are the most important causes of morbidity and mortality in patients with aggressive malignancies and those undergoing allogeneic stem cell transplantation. The introduction of new therapeutic approaches including the use of nucleoside analogs and of monoclonal antibodies to CD20 and CD52 and the increased use of matched unrelated stem cell donors has resulted in new challenges with regard to systemic viral and fungal infections. In patients with bacterial infections, emergence of resistance to formerly widely used antibiotics as well as a shift of causative pathogens towards a predominance of multi-resistant gram-positive cocci has to be taken into consideration. In high-risk neutropenic patients with fever of unknown origin, prompt empiric monotherapy with piperacillin–tazobactam, cefepime, ceftazidime, or a carbapenem is mandatory. In patients with lung infiltrates, early preemptive intervention with an antifungal active against aspergilli is recommended, whereas in patients with catheter-related, skin or soft tissue infections, preemptive addition of a glycopeptide shows a high response rate. The prompt preemptive use of ganciclovir or foscarnet in allogeneic stem cell transplant recipients can reliably be guided by serial monitoring of cytomegalovirus antigen and polymerase chain reaction monitoring.
In vitro sequence-dependent interaction between nedaplatin and paclitaxel in human cancer cell lines
AbstractPurpose To define the most effective combination schedule of paclitaxel and nedaplatin, a new platinum derivative, we investigated the in vitro interaction between these drugs in AZ-521 and NUGC-4 gastric adenocarcinoma and KSE-1 esophageal squamous carcinoma cell lines.
The cardiovascular safety of high-dose intravenous granisetron in cancer patients receiving highly emetogenic chemotherapy
AbstractObjectives To assess the cardiovascular safety, tolerability and efficacy of high doses of granisetron for the treatment of nausea and vomiting in patients undergoing highly emetogenic chemotherapy.
MR imaging of gastric cancer in vitro: accuracy of invasion depth diagnosis
Abstract The purpose of this study was to evaluate the accuracy of grading cancerous invasion of the gastric wall in vitro using magnetic resonance (MR) imaging. Twelve specimens of gastric carcinoma were examined at 1.5-T using a small, loop surface coil. They were imaged within 2 days of fixation in formalin. The field of view was 30 mm; the matrix size was 256×256, and the section thickness was 2 mm. T1-weighted, T2-weighted and short inversion time inversion recovery (STIR) images were obtained. Two radiologists evaluated the MR images independently, and in discrepant cases, consensus was obtained through discussion. Findings on MR images were compared with histopathologic findings. All T1-weighted, T2-weighted and STIR images depicted the normal gastric wall as consisting of six layers. STIR images depicted normal six layers most clearly. Histologically, the cancerous invasion was found to extend into the mucosa in 4 of the 12 specimens, the submucosa in 3, the muscularis propria in 2, the subserosa in 2 and the serosa in 1. The grading by MR imaging matched the histopathologic findings for all 12 tumors. The overall accuracy was 100%. Thus, MR imaging in vitro was sufficiently accurate for grading cancerous invasion of the gastric wall.
Sacral nerve stimulation for faecal incontinence following a rectosigmoid resection for colorectal cancer
AbstractIntroduction Following recto-sigmoid resection some patients may become faecally incontinent and remain so despite conservative treatment. This multicentre prospective study assessed the use of sacral nerve stimulation (SNS) in this group.
Functional expression of the interleukin-11 receptor alpha-chain in normal colonic epithelium and colon cancer
AbstractBackground Interleukin-11 (IL-11) has been evaluated as an anti-inflammatory and mucosa-protective therapeutic agent in inflammatory bowel diseases (IBDs). Activity of IL-11 requires binding to the α receptor subunit (IL-11Rα) that provides ligand specificity. Recently, we showed that in the intestinal mucosa, IL-11Rα is mainly present on epithelial cells mediating antiapoptotic effects. The aim of this study was to investigate the expression profiling of IL-11Rα and its downstream signaling cascade in colonic adenoma and carcinoma.
Molecular interactions of B-CAM (basal-cell adhesion molecule) and laminin in epithelial skin cancer
Abstract Molecular events underlying the progression of malignant tumors through the surrounding tissue are largely mediated by membrane-bound adhesion molecules. Basal-cell adhesion molecule (B-CAM), a 90-kDa laminin receptor of the immunoglobulin superfamily, is induced in some epithelial malignancies. Its function in these tumors, however, still remains obscure. We demonstrated that expression of B-CAM is very weak, if detectable at all, in normal epidermis but is strongly induced in both basal cell carcinomas and squamous cell carcinomas of the skin, and most pronounced at the basal surface of the tumor nests. Interestingly, the only known B-CAM ligand, laminin, was markedly upregulated within corresponding microanatomical sites surrounding the tumor nests, suggesting that both molecules may interact there. Consistent with this hypothesis, we were able to directly demonstrate binding of a B-CAM/Fc chimeric molecule to the peritumoral stroma in situ. Finally, in proof-of-principle experiments, human B-CAM was overexpressed both in murine and in human fibroblasts. The haptotactic migration of these novel B-CAM+ cell populations on a laminin matrix was significantly increased (P=0.02) as compared to mock-transfected cells when integrin-mediated adhesion was blocked by chelation of divalent cations. Thus, our findings provide the first direct experimental evidence that interactions of B-CAM and laminin may be involved in progression of epithelial skin tumors.
Base of the tongue metastatic cancer from hepatocellular carcinoma: a case report
Abstract Although hepatocellular carcinoma (HCC) is a common malignancy in Taiwan, metastasis to the head and neck area is extremely rare. In this report, we document a case of HCC metastasis to the base of the tongue. The patient involved had been treated for HCC with chemoembolization and radiotherapy 3 years prior to being diagnosed with tongue base metastasis. Symptoms of the metastasis included frequent oozing from the tongue base tumor. The patient died 3 months after a palliative resection of the tongue. To our knowledge, this is the first clinical presentation of HCC metastasis to the tongue base documented in the English language. We also believe that this particular case is important because we predict that the advancement in HCC treatment modalities will allow enough survival time in patients to cause occult extrahepatic metastatic lesion to develop into a field of clinical significance.
The inverse dose-rate effect for radon induced lung cancer: a modified approach for risk modelling
Abstract One of the features of high LET α-ray exposure due to radon inhalation is the well-known inverse dose-rate effect. The longer a given dose is delivered to the lung, the higher is its carcinogenic effect. This introduces the problem of risk extrapolation from high levels of radon exposure typical for uranium miners, down to low levels of radon exposure typical for the general population. An analytical model is presented that accounts for dose-rate effects over the entire exposure range. In accordance with radiobiological considerations and microdosimetric implications, the model provides an adequate description of the inverse dose-rate effect in the higher dose range. At the same time, a linear slope at low exposures that is independent of the dose-rate of exposure is attained.
Genomic screening of head and neck cancer and its implications for therapy planning
Abstract Despite great technical improvements in radiotherapy and surgery, survival for patients with squamous cell carcinoma of the head and neck (SCCHN) has still not improved significantly over the last decades. Management of SCCHN has mainly been based on the TNM staging and site over this time period, even though we know that there are individual differences independent of the TNM status. Individual patients with small tumors might have a poor outcome, and patients with large tumors may end up with a favorable prognosis, despite their respective TNM classification. Recent molecular studies indicate that underlying genetic abnormalities may reflect such individual differences independently of TNM status. Individualization of treatment based on such biological properties of the tumors might result in less over as well as under treatment. However, the optimal panel of biomarkers to be used for the individualization of treatment is yet to be defined. A variety of laboratory techniques have been used in studies that investigate the individual biological features, spanning from methods that screen the genome for chromosomal and genetic abnormalities, e.g., cytogenetics, CGH, SKY and cDNA micro array, to detailed studies of specific aberrations. The purpose of this review of the literature is to summarize what has been studied so far by methods for genetic screening and to relate these results to the prediction of the clinical outcome. We conclude that it is time to focus future prospective studies on how treatment can be individualized based on biomarkers in combination with the macroscopic features of SCCHN.
Genetic basis of human testicular germ cell cancer: insights from the fruitfly and mouse
Abstract The prevalence of tumours of the germ line is increasing in the male population. This complex disease has a complex aetiology. We examine the contribution of genetic mutations to the development of germ line tumours in this review. In particular, we concentrate on fly and mouse experimental systems in order to demonstrate that mutations in some conserved genes cause pathologies typical of certain human germ cell tumours, whereas other mutations elicit phenotypes that are unique to the experimental model. Despite these experimental systems being imperfect, we show that they are useful models of human testicular germ cell tumourigenesis.
Early satiety in cancer patients: a common and important but underrecognized symptom
AbstractIntroduction The severity of anorexia correlates with the presence of early satiety. The sense of fullness limits nutritional intake. The symptom is poorly understood because most assessment questionnaires do not include early satiety.
From oncology pharmacy to pharmaceutical care: new contributions to multidisciplinary cancer care
Abstract In recent years a paradigm shift towards a patient-focused rather than a disease-focused approach occurred in many health care systems. The pharmacy profession experienced an accordant development. The traditional drug-oriented services expanded towards patient-oriented services. In oncology, pharmacists established central services for compounding of cytotoxic drugs and offered therapeutic drug monitoring for critical substances. Pharmaceutical care concepts are now being introduced to optimize individual drug therapy. Pharmaceutical care aims at improving safety and therapeutic outcomes and consequently, the patients quality of life. These objectives imply a close relationship to supportive care. To achieve this, a multidisciplinary approach seems to be beneficial.
Inhalative Immuntherapie des pulmonal metastasierten Nierenzellkarzinoms
Zusammenfassung Die Inhalation von Interleukin-2 verhindert mehrheitlich und langfristig Ersticken durch pulmonalen oder mediastinalen Progress. Die Therapie ist ausgesprochen gut verträglich, ambulant und erlaubt Berufstätigkeit oder Familienbetreuung. Zuverlässig reproduzierbar entsteht eine dosisabhängige Immunmodulation in der Lunge. Immunzellen, Aktivierungsmarker, IL-5-Produktion und Stickstoffmonoxid nehmen zu. Wesentliche Nebenwirkung ist Husten und Müdigkeit. IL-2 Aerosoltherapien induzieren die längsten progressionsfreien Überlebenszeiten. Eine israelische Studie berichtet median 8,7 Monate bei 40 zuvor progredienten Patienten, die systemisch nicht behandelt werden konnten. Erstmals wird bei Hochrisikopatienten ohne Therapiealternative von Langzeitüberleben berichtet. In einer deutschen Studie überlebte die Inhalationsgruppe (INH, n=94) doppelt solange wie die systemisch (SYST, n=103) therapierte (12 vs. 6,3 Monate). Fünfjahresüberleben war 21% (INH) bzw. 0% (SYST) Gruppe. Die Aerosol-Interleukin-2-Therapie ist gut verträglich, praktikabel und vorteilhaft für Patienten, die an ihrem metastasierenden Nierenzellkarzinom zu ersticken drohen.
Zweitlinientherapie des kleinzelligen Lungenkarzinoms (SCLC)
Zusammenfassung Bei 70% aller Patienten mit kleinzelligem Lungenkarzinom im Stadium I–III und bei >90% im Stadium IV tritt ein Rezidiv nach der Erstlinientherapie auf, sodass eine Zweitlinientherapie ein medizinisch relevantes Problem darstellt. Im Gegensatz zum nichtkleinzelligen Lungenkarzinom, bei dem es durch Phase-III-Studien abgesicherte Daten und für diese Indikation zugelassene Substanzen gibt, ist die Datenlage beim rezidivierten kleinzelligen Lungenkarzinom unbefriedigend. Prognostisch ist beim SCLC das primär refraktäre (therapiefreie Zeit 90 Tage) zu differenzieren. Bei sensiblen Rezidiven ist eine Wiederholung (Rechallenge) der Erstlinientherapie prinzipiell möglich. In dieser Situation kommen auch Monotherapien mit Topotecan oder Kombinationstherapien wie bei refraktären Rezidiven in Betracht. Bei refraktären Rezidiven sollten nichtkreuzresistente Substanzen eingesetzt werden. Eine Platinhaltige Therapie führt zu höheren Remissionsraten als eine Anthrazyklinhaltige Zweitlinientherapie. Neuere, überwiegend Phase-II-Studien belegen eine hohe Aktivität — auch bei refraktären Rezidiven — für CPT11-, Topotecan- und Paclitaxel-Kombinationstherapien. Problematisch bei den Empfehlungen ist die fehlende Absicherung unterschiedlicher Therapiestrategien durch Phase-III-Studien, sodass die definitive Therapieentscheidung immer eine Einzelfallentscheidung bleibt, die die Toxizität der Vortherapie, den Allgemeinzustand, Komorbiditäten und das Therapieziel berücksichtigen muss.
Subscribe to:
Posts (Atom)