Drug Prescribing for Patients with Chronic Kidney Disease in General Practice: a Cross-Sectional Study

Patienten mit lokal fortgeschrittenen nichtkleinzelligen Lungenkarzinomen (NSCLC) werden zunehmend häufig einer neoadjuvanten Therapie zugeführt. Dabei zeigen Patienten mit einer ausgeprägten therapieinduzierten Tumorregression (weniger als 10% vitales Tumorgewebe) signifikant längere Überlebenszeiten. Hinsichtlich der Frage, ob aus einer kompletten therapieinduzierten Tumorregression (Regressionsgrad III) gegenüber einer subtotalen Tumorregression (Regressionsgrad IIb) ein zusätzlicher Überlebensvorteil resultiert, wurden 212 Resektionspräparate der Münsteraner Phase III-Studie (GLCCG-Studie) morphologisch analysiert und die ermittelten Regressionsgrade (RG) mit der Überlebenszeit (ÜLZ) korreliert. Dies ergab die folgenden Resultate: RG I (keine therapieinduzierte Tumorregression): mediane ÜLZ 18 Mon., 5J-Überlebensrate (5J-ÜLR) 16,4%; RG IIa (>10% vitales Tumorgewebe): mediane ÜLZ 27 Mon., 5J-ÜLR 27%; RG IIb (<10% vitales Tumorgewebe): mediane ÜLZ 50 Mon., 5J-ÜLR 43%; RG III (komplette therapieinduzierte Tumorregression): mediane ÜLZ 25 Mon., 5J-ÜLR 36,3%. Dabei konnte die prognostische Relevanz des angewandten Regressionsgradings bestätigt werden (RG I/IIa vs. RG IIb/III, mediane ÜLZ 23 Mon. vs. 45 Mon., Log-Rank-Test, p=0,0023). Signifikant unterschiedliche Überlebenszeiten konnten dagegen bei einer kompletten gegenüber einer subtotalen therapieinduzierten Tumorregression nicht nachgewiesen werden (RG IIb vs. RG III, Log-Rank-Test, p=0,168), sodass aus einer kompletten morphologisch fassbaren Tumorregression kein zusätzlicher Überlebensvorteil resultiert.

To evaluate the impact of palliative high dose rate brachytherapy on survival and a pattern of failure, we performed a matched pair study. 94 patients with tumor recurrence after external beam radiation received endobronchial brachytherapy. They were followed prospectively and matched retrospectively with 94 comparable patients who had not received brachytherapy. Matched parameters were age, gender, smoking behaviour, histology, tumor stage, EBRT-dose and fractionation. The leading cause of death in both groups was generalized tumor growth. In the combined therapy group, fatal hemorrage was 27.7 %, two and a half times higher than in the EBRT group with 10.6 %, whereas respiratory insufficiency in the brachytherapy group was 6.4 % and 11.7 % in the EBRT group. A complete remission after brachytherapy yielded a 10.5 months longer mean survival. Patients dying from fatal hemorrhage after endobronchial brachytherapy lived on average 10.2 months longer than matched EBRT patients dying from the same cause. Analyzing the time-course of fatal hemorrage in the brachytherapy group we conclude that - because of its early onset in the first 10 months after induction of therapy roughly 20 % of the deaths can be attributed to a radiation damage. In those patients who died after 10 months the major cause of fatal hemorrhage was the natural course of sqamous cell carcinoma with prolonged survival.

Purpose: The objective of this trial was to compare two vinorelbine-based doublets with carboplatin (CBDCA-VC) or with gemcitabine (VG) in patients with stage IIIB-IV non-small cell lung cancer (NSCLC).Patients and Methods: A total of 316 patients with advanced NSCLC previously untreated were randomized to either vinorelbine 30 mg/m(2) D1,8 with carboplatin AUC 5 D1 (VC) or vinorelbine 25 mg/m(2) with gemcitabine (VG) 1000 mg/m(2) both given D1,8 every 3 weeks. The primary endpoint was response rate with secondary parameters being survival (OS), progression-free survival (PFS), tolerance and clinical benefit.Results The median number of cycles was four in each arm with a total of 1268 cycles. The objective response (OR) on intent-to-treat was 20.8% in VC and 28% in VG (p = 0.15). Median PFS was 3.9 months in VC and 4.4 months (mo) in VG (p = 0.18). Median survival was significantly longer (p = 0.01) for VG with 11.5 mo compared to 8.6 mo in VC with 1 year survival at 48.9 and 34.4%, respectively. Tolerance was better in the VG arm as compared to the VC patients. Four toxic deaths were recorded in the VC group. Clinical benefit response rate was 32.4% compared to 40.9% in 111 and 110 evaluable patients in VC and VG, respectively. Conclusion: VG compared to VC resulted in a similar overall response rate, favourable median survival and a better toxicity profile. For non-cisplatin-based chemotherapy, VG is a useful alternative. (C) 2005 Elsevier Ireland Ltd. All rights reserved.

To evaluate the impact of palliative high dose rate brachytherapy on survival and a pattern of failure, we performed a matched pair study. 94 patients with tumor recurrence after external beam radiation received endobronchial brachytherapy. They were followed prospectively and matched retrospectively with 94 comparable patients who had not received brachytherapy. Matched parameters were age, gender, smoking behaviour, histology, tumor stage, EBRT-dose and fractionation. The leading cause of death in both groups was generalized tumor growth. In the combined therapy group, fatal hemorrage was 27.7 %, two and a half times higher than in the EBRT group with 10.6 %, whereas respiratory insufficiency in the brachytherapy group was 6.4 % and 11.7 % in the EBRT group. A complete remission after brachytherapy yielded a 10.5 months longer mean survival. Patients dying from fatal hemorrhage after endobronchial brachytherapy lived on average 10.2 months longer than matched EBRT patients dying from the same cause. Analyzing the time-course of fatal hemorrage in the brachytherapy group we conclude that - because of its early onset in the first 10 months after induction of therapy roughly 20 % of the deaths can be attributed to a radiation damage. In those patients who died after 10 months the major cause of fatal hemorrhage was the natural course of sqamous cell carcinoma with prolonged survival.

Hämoptysen sind potenziell lebensbedrohliche Komplikationen unterschiedlichster Krankheiten. Häufigste Ursachen sind entzündliche und infektiöse Erkrankungen, gefolgt von Neoplasmen, Lungenembolien, Herzklappenfehlern, Gerinnungsstörungen und zahlreichen Systemerkrankungen. Routineuntersuchungen sind: Thoraxröntgenbild, (Angio-)CT und Bronchoskopie sowie evtl. eine Kontrastdarstellung der Bronchialarterien. Gefährdet ist der Patient durch Verschlüsse der Atemwege mit Koageln. Die wichtigsten Maßnahmen bei Hämoptoe sind daher Sauerstoffgabe, Lagerung auf die blutende Seite, bronchoskopische Absaugung von Blut und Gerinnseln. Gerinnungsstörungen müssen ausgeglichen werden. Kurzfristig helfen vasokonstriktive Medikamente. Bei zentralen Prozessen kann man über das Bronchoskop mit dem Argon-Plasma-Beamer oder dem Laser koagulieren. Bei schweren Blutungen aus der Peripherie muss eine Ballon- oder Tubustamponade durchgeführt werden. Je nach Ursache und Schweregrad der Hämoptoe folgt eine antientzündliche Behandlung, eine hämostyptische Strahlentherapie, eine Bronchialarterienembolisation oder eine Operation.

BACKGROUND:Expression and amplification of the HER2/neu protooncogene was analyzed in locally advanced NSCLC in a multimodality therapy approach in order to obtain information on the predictive value of HER2/neu for success or failure of neoadjuvant therapy.METHODS:In the scope of a prospective randomized phase III-trial, tumor tissue of pre-therapeutically obtained mediastinal lymph node biopsies (n=105) and corresponding post-surgical resection specimens (n=44) was analyzed by means of immunohistochemistry (DAKO-Hercep-Test) and fluorescence in situ hybridization (FISH). In 58 of 105 patients with metastatic mediastinal lymph node disease the extent of therapy-induced tumor regression could be established.RESULTS:Concerning HER2/neu expression, 16 lymph node biopsies (15.2%) showed 1+, 2+, or 3+ results. Five of these cases revealed amplification in FISH analysis (4.8%). In 44 corresponding resection specimens, Hercep-Test showed 1+, 2+, or 3+ results in 13 tumors (29.5%). Two of these patients revealed HER2/neu amplification in FISH analysis (4.5%). In patients with HER2/neu expressing tumors a trend towards a less extensive therapy-induced tumor regression could be demonstrated. When comparing pre-therapy and post-surgical results, there was a weak trend towards a selection of HER2/neu expressing tumor tissue in the course of neoadjuvant therapy.CONCLUSIONS:Only a limited subcollective of locally advanced NSCLC meets the biological requirements for anti-HER2/neu therapy. HER2/neu positive tumors appeared to be relatively resistant to chemotherapy and radiation treatment, none of these cases having a pathological complete or at least subtotal response in the corresponding resection specimens. This observation requires confirmation in large randomized controlled studies.

To evaluate the impact of preoperative simultaneous hyperfractionated (hf)RTCT plus surgery compared to surgery plus postoperative radiotherapy, both after neoadjuvant chemotherapy, on resectability, tumor control, survival and toxicity. After stratification according to center and stage (IIIA vs IIIB, mediastinoscopy obligatory) all patients had 3 cycles Cisplatin/Etoposide (PE). In arm A, PE was followed by hfRT (45 Gy, 2 × 1.5 Gy/d) with concurrent Carboplatin/Vindesin (d 1, 8, 15), then surgery and, if no or R1/2 resection, additional hfRT (24 Gy, 2 × 1.5 Gy/d) was given. In arm B, PE was followed by surgery and postoperative RT (54 Gy or, if no or R1/2 resection, 68.4 Gy, 1.8 Gy/d). From 10/95 to 8/03 558 patients were randomized; 33 (6%) were ineligible. Patient characteristics (arm A/arm B): male 83/83.1%, female 17/16.9%; age (median) 59/59 yrs; PS 0 86.6/87.2%; PS 1 13.4/12.8%; stage IIIA 31/35%, stage IIIB 69/65%; squamous cell carcinoma 57/61%; adenocarcinoma 30/30%. After a median follow-up of 52 months, 3year rates for overall survival (OS) and progression -free survival (PFS) (arm A/arm B) were 26.2/ 24.6% and 17.8/19.9% (n.s.). Complete and partial remission rates (CR/PR), R0-resection rates, median OS and PFS are shown in table 1. Grade 3/4 esophagites was more frequent in arm A (19% in arm A vs. 3% in arm B, p = 0.0001) whereas the incidence of pneumonitis grade 3/4 was higher in arm B (1% in arm A vs. 6% in arm B, p = 0.004). There was no difference in treatment-related mortality (arm A 5.8% vs. arm B 5.1%). After neoadjuvant chemotherapy, no advantage for either preoperative simultaneous hfRTCT plus surgery or surgery plus postoperative radiotherapy concerning PFS and OS could be shown, with different toxicity-patterns in both arms.

Patienten mit lokal fortgeschrittenen nicht-kleinzelligen Lungenkarzinomen (NSCLC) werden zunehmend häufig einer neoadjuvanten Therapie zugeführt. Dabei erlangt das Ausmaß der erzielten therapieinduzierten Tumorregression prognostische Bedeutung. Zur Bestimmung des Regressionsgrades werden die Befunde nach einem standardisierten Regressionsgrading klassifiziert. Patienten mit einer ausgeprägten therapieinduzierten Tumorregression (weniger als 10% vitales Tumorgewebe) zeigen signifikant längere Überlebenszeiten. Bei gesonderter Betrachtung der Tumorregression in Primärtumor (PT) und Lymphknoten (LK) ergibt sich ein heterogenes Bild. Hinsichtlich der Qualität der therapieinduzierten Tumorregression konnten keine Unterschiede festgestellt werden. Während quantitativ morphologische Zeichen einer therapieinduzierten Tumorregression häufiger im PT als in den LK–Metastasen nachzuweisen sind, wird eine Tumorfreiheit häufiger in den LK–Metastasen erzielt. Bei einer ausgeprägten therapieinduzierten Tumorregression findet sich der Resttumor häufiger in der Lunge als in den LK. Diese Befunde können durch eine schnellere und daher zum Zeitpunkt der Resektion weiter fortgeschrittene Resorption der therapieinduzierten Nekrosen in den LK-Metastasen erklärt werden. Dies kann auf das dort i. a. geringere Tumorvolumen mit Ausbildung kleinerer therapieinduzierter Nekrosen in den LK zurückgeführt werden.

The German Lung Cancer Cooperative Group (GLCCG) is assessing the impact of chemoradiation in addition to chemotherapy in the neoadjuvant treatment of stage III NSCLC. After three cycles of cisplatin/etoposide patients receive either hyperfractionated radiotherapy (RT) with concurrent carboplatin/vindesine and then surgery (arm A) versus surgery and then conventional RT (arm B). Quality of life (QL) was assessed throughout therapy using the EORTC QLQ-C30 and EORTC QLQ-LC 13. Of 126 eligible patients, 54 completed treatment. For patients in both treatment arms physical functioning decreased, whereas dyspnoea, fatigue and pain increased from beginning to the end of treatment. For self-assessed QL no statistically significant effect was found in or between the two treatment arms. The combined modality approach with preoperative radio/chemotherapy proves to be feasible in treating locally advanced NSCLC patients without decreasing their subjective QL.

Hemoptysis is a potentially life-threatening complication of various diseases. The most common causes are infectious and inflammatory processes, followed by neoplasms, pulmonary embolisms, mitral stenoses, coagulopathies, and multiple systemic disorders. Primary examinations include a chest x-ray, an angio CT and a bronchoscopy. Sometimes, a bronchial artery angiogram is required. The patient is at risk of suffocation because blood and clots can severely obstruct his airways. Thus, the most important measures are: supplemental oxygen, positioning the patient with the bleeding side down, bronchoscopical suctioning and removal of blood and clots. Coagulopathies have to be corrected. Application of vasoactive drugs may help temporarily. In cases of bleeding from central lesions, coagulation with laser or argon-plasma-coagulator is feasible. Heavy bleeding from the periphery requires a balloon or tube tamponade. Depending on the cause and the severity of the bleeding either anti-inflammatory medical treatment, hemostyptic radiation therapy, bronchial artery embolisation or a surgical procedure must follow.

BACKGROUND:Bulky endobronchial tumours in patients with lung cancer are difficult to treat. Brachytherapy and photodynamic therapy (PDT) are variably effective, and the combination of these treatments is not often recommended. However, cell culture studies and animal studies indicate a possible synergistic effect of combining PDT with ionising radiation. We assessed the safety and effectiveness of combined brachytherapy and PDT in patients with bulky endobronchial lung cancer.METHODS:Patients with histologically proven non-small cell bronchogenic carcinoma and bulky endobronchial tumours were treated using a combination of PDT (Photofrin, 2 mg/kg) and brachytherapy. Six weeks after PDT, brachytherapy was applied with five fractions of 4 Gy at weekly intervals. Follow up was performed with standard and autofluorescence bronchoscopy and tissue biopsies every 3 months.RESULTS:Thirty two patients were treated. Tumours were extensive with lengths ranging from 10 to 60 mm along the bronchus and estimated volumes ranging from 40 to 3500 mm3. At a mean follow up of 24 months, 26 patients were free of residual tumour and local recurrence. The remaining patients received a second treatment with PDT, brachytherapy, Nd:YAG laser coagulation, or external beam radiation. Distant metastases (lung, lymph node) developed in two of the six patients. Currently, all 32 patients are well. There is no evidence of residual or local recurrent endobronchial cancer in 28 patients and none had severe complications.CONCLUSION:The combination of PDT and brachytherapy for treating patients with lung cancer and extensive endobronchial tumour is safe and, in this study, had excellent therapeutic efficacy.

7004 Background: In the neoadjuvant treatment setting of stage III NSCLC the additional impact of hfRT/CT after preoperative CT on resectability and survival is open to conjecture. Methods: In a phase III trial patients [pts] with stage III NSCLC (invasive mediastinal staging obligatory) were stratified (center; stage, IIIA vs IIIB) and then randomized to (arm A) 3 cycles P 55 mg/m2 (d 1+4) / E 100 mg/m2 (d 1–4), followed by hfRT (45 Gy; 2 x 1.5 Gy/d) with concurrent Carboplatin 100 mg/m2 / Vindesin 3 mg (d 1, 8, 15), then surgery and, if no or R1/2-resection, additional hfRT (24 Gy; 2 x 1.5 Gy/d) versus (arm B) 3 cycles of PE followed by surgery and then RT (1.8 Gy/d) with 54 Gy or, if no or R1/2-resection, 68.4 Gy. The primary (secondary) study endpoint was progression free survival [PFS] (survival [S]). With 500 pts. evaluable an improvement of median PFS (S) from 10 to 14 (17 to 23) months [mo]; 3 y.-rate from 8 to 17 (23 to 34) % could be detected. Results: 558 pts. were randomized (10/95–07/03); 32 (6%) were ineligible. On december 1st, 2003 median follow up was 46 mo with outcome data available for 481 pts. Patient characteristics were well balanced between arm A (245 pts.) and arm B (236 pts): male 82%/83%, female 18%/17%; PS 0 86%/87%; PS 1 14%/13%; age 59/59 ys. [median]; stage IIIA 31%/34%; stage IIIB 69%/66%. Whilst the rate of grade 3/4-esophagitis was significantly different between treatment arms (15%/4%, p < 0.001), there was no significant difference for the response rate after induction (52%/47%; p = 0.35), the proportion of patients with complete tumor resection (111/245, 45% /118/236, 50%; p = 0.30), the treatment related mortality rate (5,6%/5,3%), nor for PFS (median, 10/10 mo; 3 y.-rate, 17%/18%; p = 0.37, log-rank) or S (median, 15/17 mo; 3 y.-rate, 24%/23%; p = 0.89, log-rank). Conclusions: In this trial the addition of hfRT/CT to PE prior to planned surgery had no impact on PFS or S but contributed to significantly higher rates of grade 3/4 esophagitis. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly

Fallbeschreibungen: Bei einer 78-jährigen Frau mit intrinsic Asthma erfolgte zur Klärung mehrerer Rundherde eine offene Lungenbiopsie. Histologisch handelte es sich um eine bronchozentrische Granulomatose mit Aspergillennachweis im Bronchiallumen sowie eine chronisch interstitielle Pneumonie mit herdförmiger Ausbildung von Tumorlets. Die Rundherde bildeten sich unter einer Steroidtherapie zurück.

Fallbeschreibung: Bei der 35-jährigen Frau traten 8 Wochen vor stationärer Aufnahme Thoraxschmerzen, Dyspnoe, Leistungsabnahme und Fieber bis 39.5°C auf.

Cardiotoxin III (CTX III), a basic polypeptide isolated from Naja naja atra venom, has been shown to exhibit anticancer activity. Epidermal growth factor (EGF) and its receptor, EGFR, play roles in cancer metastasis in various tumors. We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of CTX III on cell migration. CTX III inhibited the EGF-induced activation of matrix metalloproteinase-9 (MMP-9), and further suppressed cell invasion and migration without obvious cellular cytotoxicity. CTX III suppressed EGF-induced nuclear factor-kappaB (NF-κB) nuclear translocation and also abrogated the EGF-induced phosphorylation of EGFR, phosphatidylinositol 3-kinase (PI3K)/Akt, and extracellular regulated kinase (ERK)1/2. In addition, CTX III similar to wortmannin (a PI3K inhibitor) and U0126 (an up-stream kinase regulating ERK1/2 inhibitor) attenuated cell migration and invasion induced by EGF. Furthermore, the EGFR inhibitor AG1478 inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of ERK1/2 and PI3K/Akt, suggesting that ERK1/2 and PI3K/Akt activation occur downstream of EGFR activation. These findings suggest that CTX III inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt, ERK1/2, and NF-κB signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of CTX III as a potent anti-metastatic agent in MDA-MB-231 cells.

BACKGROUND:Paclitaxel administered in combination with a topoisomerase-II inhibitor (such as etoposide) and carboplatin is an effective and safe first-line treatment for patients with small-cell lung cancer (SCLC). We conducted a randomized phase III multicenter trial to determine whether paclitaxel plus etoposide plus carboplatin improves the outcome of patients with primary SCLC relative to standard chemotherapy (carboplatin, etoposide, and vincristine).METHODS:Between January 1998 and December 1999, 614 patients with SCLC stages I-IV were randomly assigned to the standard arm (309 patients) or the experimental arm (305 patients). Treatment courses were repeated every 21 days for a maximum of six courses. All patients were evaluated for response rate, survival, and toxicities every two courses. The primary endpoint was survival. Survival curves were estimated with the Kaplan-Meier method and compared using the log-rank test. All statistical tests were two-sided.RESULTS:A total of 608 patients were evaluable for all endpoints (standard arm 307 patients, experimental arm 301 patients). The hazard ratio [HR] of death for patients receiving the standard treatment was statistically significantly higher than that for patients receiving the experimental treatment (HR = 1.22, 95% confidence interval [CI] = 1.03 to 1.45; P =.024). Progression-free survival was also statistically significantly shorter for patients in the standard arm relative to that of patients in the experimental arm (HR = 1.21, 95% CI = 1.03 to 1.42). There were no differences in the response rates (complete and partial combined) to the treatments (standard arm: 69.4%, 95% CI = 63.9% to 74.5%; experimental arm: 72.1%, 95% CI = 66.7% to 77.1%; difference = 2.7%, 95% CI = 4.5% to 9.9%). Rates of severe grade of anemia, leukocytopenia, neutropenia, and thrombocytopenia were lower in the experimental arm than in the standard arm.CONCLUSION:Patients with previously untreated SCLC who received paclitaxel, etoposide, and carboplatin showed improved overall and progression-free survival and less frequent hematologic toxicities than those who received the standard therapy.

Patienten mit lokal fortgeschrittenen nicht-kleinzelligen Lungenkarzinomen (NSCLC) werden zunehmend häufig einer neoadjuvanten Therapie zugeführt. Dabei erlangt das Ausmaß der erzielten therapieinduzierten Tumorregression prognostische Bedeutung. Zur Bestimmung des Regressionsgrades werden die Befunde nach folgendem Schema klassifiziert: – Grad I: keine oder nur geringgradige, vorwiegend spontane Tumorregression in Primärtumor (PT) und mediastinalen Lymphknoten (LK), – Grad II: morphologische Zeichen der therapieinduzierten Tumorregression mit – Grad II a: mindestens 10% vitalem Tumorgewebe im PT und/oder mehr als kleinherdigem Befall mediastinaler LK, – Grad II b: weniger als 10% vitalem Tumorgewebe im PT und/oder allenfalls kleinherdiger Befall mediastinaler LK, – Grad III: komplette Tumorregression ohne Nachweis vitalen Tumorgewebes in PT und mediastinalen LK. Dabei zeigen Patienten mit einer ausgeprägten therapieinduzierten Tumorregression (Grad IIb/III) signifikant längere Überlebenszeiten. Bei gesonderter Betrachtung der Tumorregression in PT und LK ergibt sich ein heterogenes Bild. Während morphologische Zeichen einer therapieinduzierten Tumorregression häufiger im PT als in den LK–Metastasen nachzuweisen sind, wird eine Tumorfreiheit häufiger in den LK–Metastasen erzielt. Bei einer ausgeprägten therapieinduzierten Tumorregression findet sich der Resttumor häufiger in der Lunge als in den LK. Ein Grund für diese Unterschiede dürfte in der i.a. deutlich größeren Tumormasse des PT liegen.