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PURPOSE To evaluate the efficacy and tolerability of two doses of gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS This was a randomized, double-blind, parallel-group, multicenter phase II trial. Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens (at least one containing platinum) were randomized to receive either 250-mg or 500-mg oral doses of gefitinib once daily. RESULTS Efficacy was similar for the 250- and 500-mg/d groups. Objective tumor response rates were 18.4% (95% confidence interval [CI], 11.5 to 27.3) and 19.0% (95% CI, 12.1 to 27.9); among evaluable patients, symptom improvement rates were 40.3% (95% CI, 28.5 to 53.0) and 37.0% (95% CI, 26.0 to 49.1); median progression-free survival times were 2.7 and 2.8 months; and median overall survival times were 7.6 and 8.0 months, respectively. Symptom improvements were recorded for 69.2% (250 mg/d) and 85.7% (500 mg/d) of patients with a tumor response. Adverse events (AEs) at both dose levels were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent in the higher-dose group. Withdrawal due to drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib 250 and 500 mg/d, respectively. CONCLUSION Gefitinib showed clinically meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients. At 250 mg/d, gefitinib had a favorable AE profile. Gefitinib 250 mg/d is an important, novel treatment option for patients with pretreated advanced NSCLC.

Background Delayed surgery after stabilization of infants with congenital diaphragmatic hernia (CDH) is an accepted strategy. However, the evidence favoring delayed versus immediate surgical repair is limited. We present an extremely rare case of a very low-birth-weight infant with prenatally diagnosed left-sided CDH and unexpected transmural bowel perforations developing within the postnatal stabilization period. Case Report A neonate born at 31st week of gestation with a birth weight of 1,470 g with antenatally diagnosed left-sided CDH presented with bowel dilation leading to transmural bowel perforations on the 2nd day of life. Meconium pleuroperitonitis resulted in severe systemic inflammatory response syndrome, pulmonary hypertension, multiple organ failure, and death. Conclusion In neonates with CDH deteriorating under standard postnatal management, intestinal perforation, and early surgical intervention should be considered.

Aims: To analyze the relationship between maternal, cord blood and neonatal procalcitonin (PCT) levels in preterm deliveries with and without histologically proven chorioamnionitis (HCA). Methods: 91 mother-infant pairs from 24+0 to 33+0 gestational weeks were analyzed. Procalcitonin was measured in all mothers within 24 hours before and subsequently in cord blood and in neonates within the first two hours after delivery. PCT levels were analysed in relationship to HCA and clinical outcome. Results: HCA was confirmed in 28 cases (31%). We found no differences in PCT values between HCA positive and negative groups in maternal blood (0.1±0.1 vs 0.09±0.09 ng/L, P = 0.76). PCT values in cord blood and neonates were significantly higher in the HCA positive compared to HCA negative group (0.23±0.1 vs 1.2±2.7 ng/L, P < 0.001 and 0.89±3.4 vs 4.2±9.3 ng/L, P < 0.0001 respectively). PCT values in neonates were significantly higher than those of cord blood. Levels were not influenced by the mode of delivery, gestational age or premature rupture of membranes. Chorioamnionitis was more frequently associated with early onset neonatal sepsis (36% in HCA group vs 5% in non HCA group, P < 0.0001). Comparison of other clinical data revealed no differences between HCA positive and negative groups. Conclusion: This study showed higher PCT in cord and neonatal blood in the presence of proven histological chorioamnionitis. The measurement of PCT in mothers' blood is not helpful for diagnosis of HCA. The changes in PCT values shown suggest its production and release by fetal tissue.

Randomized phase III trials have established the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as first-line treatment for EGFR mutation-positive advanced non-small-cell lung cancer (EGFR Mut+ NSCLC). This retrospective cohort study examined the management patterns and outcomes of patients with EGFR Mut+ NSCLC in a real-world setting.Data were extracted from the US Flatiron Electronic Health Record-derived database. Adult patients with stage IIIB/IV EGFR Mut+ NSCLC (exon 19 deletion or exon 21 L858R mutation) who had received first-line systemic therapy between 2011 and 2016 were included. Demographic and clinical characteristics were analyzed. Outcomes evaluated were time to next treatment (a surrogate for progression-free survival) and overall survival.Of the 22,258 patients with advanced NSCLC in the database, 961 met the inclusion criteria. Median age was 69.0 years (range: 61-78) and the majority were female (68.0%), with stage IV (93.9%), non-squamous cell carcinoma (97.4%). EGFR tyrosine kinase inhibitors were the most widely prescribed first-line therapy (72.8%). The likelihood of receiving an EGFR tyrosine kinase inhibitor or chemotherapy was unaffected by the type of medical insurance patients had. Patients treated with an EGFR tyrosine kinase inhibitor had significantly longer time to next treatment than those given other first-line systemic therapies (p0.0001). There were no significant differences in overall survival according to treatment type.Results from this large US cohort study reflect those obtained in randomized trials of patients with advanced EGFR Mut+ NSCLC and demonstrate their transferability into a real-world setting.

BackgroundRandomized phase III trials have established the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as first-line treatment for EGFR mutation-positive advanced non-small-cell lung cancer (EGFR Mut+ NSCLC). This retrospective cohort study examined the management patterns and outcomes of patients with EGFR Mut+ NSCLC in a real-world setting.Materials and methodsData were extracted from the US Flatiron Electronic Health Record-derived database. Adult patients with stage IIIB/IV EGFR Mut+ NSCLC (exon 19 deletion or exon 21 L858R mutation) who had received first-line systemic therapy between 2011 and 2016 were included. Demographic and clinical characteristics were analyzed. Outcomes evaluated were time to next treatment (a surrogate for progression-free survival) and overall survival.ResultsOf the 22,258 patients with advanced NSCLC in the database, 961 met the inclusion criteria. Median age was 69.0 years (range: 61-78) and the majority were female (68.0%), with stage IV (93.9%), non-squamous cell carcinoma (97.4%). EGFR tyrosine kinase inhibitors were the most widely prescribed first-line therapy (72.8%). The likelihood of receiving an EGFR tyrosine kinase inhibitor or chemotherapy was unaffected by the type of medical insurance patients had. Patients treated with an EGFR tyrosine kinase inhibitor had significantly longer time to next treatment than those given other first-line systemic therapies (p < 0.0001). There were no significant differences in overall survival according to treatment type.ConclusionResults from this large US cohort study reflect those obtained in randomized trials of patients with advanced EGFR Mut+ NSCLC and demonstrate their transferability into a real-world setting.

OBJECTIVES:Breastfeeding is known to reduce infant morbidity and improve well-being. Nevertheless, breastfeeding rates remain low despite public health efforts. Our study aims to investigate the effect of controlled limited formula usage during birth hospitalisation on breastfeeding, using the primary hypothesis that early limited formula feeds in infants with early weight loss will not adversely affect the rate of exclusive or any breastfeeding as measured at discharge, 3 and 6 months of age. MATERIAL AND METHODS:We randomly assigned 104 healthy term infants, 24 to 48 hours old, with ≥ 5% loss of birth weight to controlled limited formula (CLF) intervention (10 ml formula by syringe after each breastfeeding, discontinued at onset of lactation) or control group (standard approach, SA). Groups were compared for demographic data and breastfeeding rates at discharge, 3 months and 6 months of age (p-values adjusted for multiple testing). RESULTS:Fifty newborns were analysed in CLF and 50 in SA group. There were no differences in demographic data or clinical characteristics between groups. We found no evidence of difference between treatment groups in the rates of exclusive as well as any breastfeeding at discharge (p-value 0.2 and >0.99 respectively), 3 months (p-value 0.12 and 0.10) and 6 months of infants' age (p-value 0.45 and 0.34 respectively). The percentage weight loss during hospitalisation was significantly higher in the SA group (7.3% in CLF group, 8.4% in SA group, p = 0.002). CONCLUSION:The study shows that controlled limited formula use does not have an adverse effect on rates of breastfeeding in the short and long term. Larger studies are needed to confirm a possible potential in controlled limited formula use to support establishing breastfeeding and to help to improve the rates of breastfeeding overall. TRIAL REGISTRATION:ISRCTN registry ISRCTN61915183.

Summary Background Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2; also known as ERBB2), was investigated in combination with chemotherapy for first-line treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer. Methods ToGA (Trastuzumab for Gastric Cancer) was an open-label, international, phase 3, randomised controlled trial undertaken in 122 centres in 24 countries. Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation. Participants were randomly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine plus cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab. Allocation was by block randomisation stratified by Eastern Cooperative Oncology Group performance status, chemotherapy regimen, extent of disease, primary cancer site, and measurability of disease, implemented with a central interactive voice recognition system. The primary endpoint was overall survival in all randomised patients who received study medication at least once. This trial is registered with ClinicalTrials.gov, number NCT01041404. Findings 594 patients were randomly assigned to study treatment (trastuzumab plus chemotherapy, n=298; chemotherapy alone, n=296), of whom 584 were included in the primary analysis (n=294; n=290). Median follow-up was 18·6 months (IQR 11–25) in the trastuzumab plus chemotherapy group and 17·1 months (9–25) in the chemotherapy alone group. Median overall survival was 13·8 months (95% CI 12–16) in those assigned to trastuzumab plus chemotherapy compared with 11·1 months (10–13) in those assigned to chemotherapy alone (hazard ratio 0·74; 95% CI 0·60–0·91; p=0·0046). The most common adverse events in both groups were nausea (trastuzumab plus chemotherapy, 197 [67%] vs chemotherapy alone, 184 [63%]), vomiting (147 [50%] vs 134 [46%]), and neutropenia (157 [53%] vs 165 [57%]). Rates of overall grade 3 or 4 adverse events (201 [68%] vs 198 [68%]) and cardiac adverse events (17 [6%] vs 18 [6%]) did not differ between groups. Interpretation Trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer. Funding F Hoffmann-La Roche.

Purpose Pharmacokinetics (PKs) and safety results from phase II/III trials suggest that, if high trastuzumab serum concentrations are reached early during treatment for human epidermal growth factor receptor 2 (HER2)–positive breast cancer, patients will gain clinical benefit, and the synergistic effects of trastuzumab and chemotherapy will be maximized. This phase I/II study evaluated the PKs, efficacy, and safety of a novel, intensive loading regimen of trastuzumab in women with HER2-positive metastatic breast cancer (MBC). Patients and Methods An intensive loading regimen of trastuzumab was given (6 mg/kg intravenously on days 1, 8, and 15 followed by 6 mg/kg every 3 weeks from day 22) to women age 18 years or older with HER2-positive MBC who may have received previous surgery, radiotherapy, and/or chemotherapy. Study medication was continued until disease progression or withdrawal occurred. Results All eligible women (N = 72) received at least one dose of trastuzumab. Median estimated trough concentration of trastuzumab at the end of 3 weeks of the intensive loading regimen (total of 18 mg/kg of trastuzumab administered) of cycle 1 was 119 mg/L, which is higher than steady-state trough concentrations with a conventional weekly or every-3-week regimen (64.9 or 47.3 mg/L, respectively). No new or unexpected adverse events or increased cardiotoxicity were reported during the study. In patients with measurable disease (n = 47), response rate was 23.4%. Median time to progression was 7.7 months (in all patients). Conclusion An intensive loading regimen of trastuzumab achieved higher-than-steady–state serum concentrations during cycle 1, was well tolerated, and had a good efficacy profile.

Summary Background The monoclonal antibody trastuzumab has survival benefit when given with chemotherapy to patients with early, operable, and metastatic breast cancer that has HER2 (also known as ERBB2) overexpression or amplification. We aimed to assess event-free survival in patients with HER2-positive locally advanced or inflammatory breast cancer receiving neoadjuvant chemotherapy with or without 1 year of trastuzumab. Methods We compared 1 year of treatment with trastuzumab (given as neoadjuvant and adjuvant treatment; n=117) with no trastuzumab (118), in women with HER2-positive locally advanced or inflammatory breast cancer treated with a neoadjuvant chemotherapy regimen consisting of doxorubicin, paclitaxel, cyclophosphamide, methotrexate, and fluorouracil. Randomisation was done with a computer program and minimisation technique, taking account of geographical area, disease stage, and hormone receptor status. Investigators were informed of treatment allocation. A parallel cohort of 99 patients with HER2-negative disease was included and treated with the same chemotherapy regimen. Primary endpoint was event-free survival. Analysis was by intention to treat. This study is registered, number ISRCTN86043495. Findings Trastuzumab significantly improved event-free survival in patients with HER2-positive breast cancer (3-year event-free survival, 71% [95% CI 61–78; n=36 events] with trastuzumab, vs 56% [46–65; n=51 events] without; hazard ratio 0·59 [95% CI 0·38–0·90]; p=0·013). Trastuzumab was well tolerated and, despite concurrent administration with doxorubicin, only two patients (2%) developed symptomatic cardiac failure. Both responded to cardiac drugs. Interpretation The addition of neoadjuvant and adjuvant trastuzumab to neoadjuvant chemotherapy should be considered for women with HER2-positive locally advanced or inflammatory breast cancer to improve event-free survival, survival, and clinical and pathological tumour responses. Funding F Hoffmann-La Roche.

PurposeTAnDEM is the first randomized phase III study to combine a hormonal agent and trastuzumab without chemotherapy as treatment for human epidermal growth factor receptor 2 (HER2)/hormone receptor–copositive metastatic breast cancer (MBC).Patients and MethodsPostmenopausal women with HER2/hormone receptor–copositive MBC were randomly assigned to anastrozole (1 mg/d orally) with or without trastuzumab (4 mg/kg intravenous infusion on day 1, then 2 mg/kg every week) until progression. The primary end point was progression-free survival (PFS) in the intent-to-treat population.ResultsOverall, 103 patients received trastuzumab plus anastrozole; 104 received anastrozole alone. Patients in the trastuzumab plus anastrozole arm experienced significant improvements in PFS compared with patients receiving anastrozole alone (hazard ratio = 0.63; 95% CI, 0.47 to 0.84; median PFS, 4.8 v 2.4 months; log-rank P = .0016). In patients with centrally confirmed hormone receptor positivity (n = 150), median PFS was 5.6 and 3.8 months in the trastuzumab plus anastrozole and anastrozole alone arms, respectively (log-rank P = .006). Overall survival in the overall and centrally confirmed hormone receptor–positive populations showed no statistically significant treatment difference; however, 70% of patients in the anastrozole alone arm crossed over to receive trastuzumab after progression on anastrozole alone. Incidence of grade 3 and 4 adverse events was 23% and 5%, respectively, in the trastuzumab plus anastrozole arm, and 15% and 1%, respectively, in the anastrozole alone arm; one patient in the combination arm experienced New York Heart Association class II congestive heart failure.ConclusionTrastuzumab plus anastrozole improves outcomes for patients with HER2/hormone receptor–copositive MBC compared with anastrozole alone, although adverse events and serious adverse events were more frequent with the combination.

PURPOSE: To investigate the tolerability, pharmacokinetics, and antitumor activity of the oral, selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 in patients with solid malignant tumors. PATIENTS AND METHODS: This was an open, phase I, escalating multiple-dose tolerability and pharmacokinetic trial. ZD1839 was administered once daily for 14 consecutive days followed by 14 days off treatment. Dose escalation started at 50 mg/d and continued to 925 mg or until consistent dose-limiting toxicity (DLT) was observed. RESULTS: Sixty-four patients were entered at eight dose levels. The most frequent dose-related grade 1 and 2 adverse events were an acne-like (or folliculitis) rash, nausea, and diarrhea. Three of nine patients treated at 700 mg/d developed DLT (reversible grade 3 diarrhea); grade 3 and 4 events were uncommon. Exposure to ZD1839 was dose proportional, and the mean terminal half-life was 48 hours (range, 37 to 65). Four of 16 patients with non–small-cell lung cancer (NSCLC) had objective partial responses observed from ZD1839 300 to 700 mg/d. Overall, 16 patients remained on study for ≥ 3 months, with seven of these patients (five with NSCLC, including three of the patients with partial response) remaining on study for ≥ 6 months. CONCLUSION: ZD1839 was well tolerated, with DLT observed at a dose well above that at which antitumor activity was seen. Pharmacokinetic analysis confirmed that ZD1839 was suitable for administration as a once-daily oral tablet formulation. Phase II monotherapy and phase III combination trials in NSCLC are being conducted to investigate further the efficacy, tolerability, and optimal daily dose of ZD1839.

Objective Developmental assessment is a core paediatric competency, but research demonstrates teaching gaps. This single-blinded, randomised controlled study compares three teaching approaches to developmental assessment in a large group setting based on a student9s self-perception and objective competency assessment. Design Students were randomised into one of the following: ▸ a didactic lecture followed by self-study with online resources (control group), ▸ a didactic lecture and small group tutorial (small group) ▸ a combined didactic lecture and interactive component using audio-visual equipment (Interactive Developmental Teaching-IDT group). Competency scores (based on the Royal College of Paediatrics and Child Health (RCPCH) scoring system, adapted for undergraduates), mean scores of self-reported confidence and degree of motivation were compared between groups. Results 114 students participated. Statistically significant difference between mean assessment scores was demonstrated for the small group (38.0; 95% CI 36.5 to 39.6) and the IDT group (37.9; 95% CI 36.5 to 39.4) compared to the control group (34.8; 95% CI 33.2 to 36.4). Students’ self-reported confidence, acquisition of knowledge and degree of motivation to practice was higher in IDT and small groups compared to the didactically taught control group. Teaching costs, if measured by trainer9s time, were one-fifth in the IDT group compared to the small group teaching. Conclusions The IDT is an effective teaching method in large groups, improves competencies compared to didactic lecturing, and is as effective as small group teaching. Adoption of the IDT appears to facilitate learning and can be easily delivered with falling ratios of teachers to students.

Mehrfachmalignome, allgemein definiert als multiple, autonom und voneinander unabhängig auftretende Tumoren im Körper eines individuellen Patienten, werden als eine relative Seltenheit angesehen. Durch sich ständig verbessernde diagnostische Methoden und neue Therapieansätze, welche dazu verhelfen, dass zunehmende Zahlen an Patienten die bedrohliche Erkrankung eines Malignoms durch eine kurative Therapie überleben, ist zu erwarten, dass die Inzidenzzahlen und die klinische Relevanz der Mehrfachmalignome an Wichtigkeit zunimmt. Aus der Datenbank des Tumorzentrums (Comprehensive Cancer Center) Tübingen wurden 348 Patienten identifiziert, bei denen innerhalb des Zeitraumes 1995-2005 Mehrfachmalignome diagnostiziert wurden und mindestens ein Malignom im Gastrointestinaltrakt lokalisiert war. Für die Definition der Mehrfachmalignome wurden die Kriterien von Waren und Gates60 angewandt. Aus der Datenbank und den Akten des Archivs der Universitätsklinik Tübingen wurden Daten zu Patientengeschlecht, -Alter, Malignomanzahl, Malignomlokalisation, Zeitintervalle zwischen den Diagnosestellungen der Mehrfachmalignome, Erkrankungsstadien, Familien-, Berufs- und Raucheranamnesen, sowie Überlebenszeiten der Patienten erhoben. Mit Hilfe des statistischen Programmes JMP wurde die statistische Analyse des Datenmaterials vorgenommen. Das Patientenprofil der gegebenen Gruppe und die klinischen Eigenschaften der Mehrfachmalignome in diesem Patientengut wurden beschrieben. In der gesamten Patientengruppe von 348 Mehrfachmalignomträgern wurden in 312 (89,7%) Fällen Doppelmalignome, in 28 (8,0%) Fällen Dreifachmalignome, in 7 (2,0%) Fällen Vierfachmalignome und in einem Fall (0,3%) ein Fünffachmalignom gefunden. 232 (66,7%) Patienten waren männlichen Geschlechts, 116 (33,3%) weiblichen Geschlechts. Es fanden sich 190 (54,6%) metachrone, 93 (26,7%) simultane und 65 (18,7%) synchrone Malignome in der gesamten Patientengruppe. Die Altersverteilung der Patientengruppe ergab annähernd eine Normalverteilung mit Höhepunkt bei der Altersgruppe der 60-69-Jährigen. Im arithmetischen Mittel betrug das Patientenalter bei Erstdiagnose 63,4 Jahre. Die häufigsten Malignomlokalisationen der gesamten Patientengruppe waren Rektum (11,5%), Kolon (10,3%) und Pharynx (7,2%). Bei Frauen traten Malignome des Kolons (F=21,2% vs. M=14,2%), Rektums (F=18,3% vs. M=16,2%) und des Magens (F=7,1% vs. M=4,6%) etwas häufiger als bei den Männern auf. Bei Männern traten dagegen Malignome des Pharynx (M=14,6% vs. F=2,5%), Ösophagus (M=13,0% vs. F=3,7%) und der Leber (M=3,6% vs. F=0,8%) häufiger auf. Im Vergleich zu Erstmalignomen nahm bei Zweitmalignomen die Häufigkeit der Ösophagus- (4,0% vs. 11,3%), Magen- (3,5% vs. 8,9%) und Pankreasmalignome (0 vs. 4,5%) tendenziell zu. Die häufigste Lokalisationskombination bei Doppelmalignomen der gesamten Patientengruppe waren Ösophagus-Pharynx (11,5%) und Kolon-Rektum (8,7%). Bei Patienten der Raucher-Untergruppe waren am häufigsten Malignome des Pharynx (20,9%), Ösophagus (16,4%) und Rektums (11,2%) vertreten. Im Vergleich dazu waren bei der Nichtraucher-Untergruppe am häufigsten Kolon (20,8%), Rektum (18,8%) und Mamma (9,4%) betroffen. Bei 93 (37,7%) der Patienten mit synchronen und metachronen Malignomen wurde das Zweitmalignom innerhalb des ersten Jahres nach dem Indextumor diagnostiziert. Bei 31,2% dieser Fälle wurde das Zweitmalignom schon innerhalb der ersten 1,5 Monate nach dem Indextumor diagnostiziert. Das Zeitintervall zwischen Erst- und Zweitmalignomdiagnose betrug im Median 1,7 Jahre (Q1 0,5 Jahre; Q3 3,5 Jahre) bei den Männern und 2,0 Jahre (Q1 0,4 Jahre; Q3 3,6 Jahre) bei den Frauen. Die Mediane Überlebenszeit der Männer betrug 25,7 Monate (Spannweite 115,4 Monate; Q1 11,6 Monate; Q3 50,8 Monate) im Vergleich zu 39,4 Monaten (Spannweite 109,2 Monate; Q1 22,3 Monate; Q3 60,1 Monate) bei den Frauen. In unserer Patientengruppe wurden die meisten Erst- und Zweitmalignome in den Stadien T1 oder T2, N0 oder N1, M0 und G2 diagnostiziert. Es zeigte sich eine Tendenz zugunsten höherer Stadien der Zweit- im Vergleich zu Erstmalignomen. Das Auftreten von Mehrfachmalignomen stellt ein relevantes klinisches Problem dar. Kenntnisse über das Vorkommen und die klinischen Eigenschaften der Mehrfachmalignome werden zunehmend wichtiger für die richtige Diagnosestellung, sowie die Gewährleistung einer adäquaten Nachsorge krebskranker Patienten und die Prävention. Bei Betreuung von Mehrfachmalignom-Patienten sollten unter anderem deren anamnestisch bekannte Risikofaktoren sowie Geschlecht und möglicherweise die geographische Region in Betracht gezogen werden. Auch bei einer kurz zurückliegenden Diagnose eines Malignoms sollte bei neuen Symptomen nicht automatisch von Problemen des diagnostizierten Malignoms oder dessen möglichen Metastasen ausgegangen werden, sondern auch an die Möglichkeit der Entwicklung eines Zweit- bzw. Drittmalignoms gedacht werden. Multiple primary malignancies (MPMs) have been considered a relatively rare phenomenon. However, with improved diagnostic methods and therapeutic options that lead to a growing number of long-term cancer survivors, the incidence and importance of MPMs in clinical practice is expected to increase. In our study 348 patients with multiple primary malignancies were selected from the database of the Comprehensive Cancer Center Tübingen and their data retrospectively analyzed. All patients must have had at least one tumour originating from the gastrointestinal system and all diagnoses established between 1995 and 2005. The objective of the study was to describe patient profiles in our study group and to analyze the clinical characteristics of multiple primary malignancies in this patient population. Among the 348 patients, 312 (89.7%) had two primary tumours, 28 (8.0%) had three, 7 (2.0%) had four and one patient had five primary malignancies. One hundred and ninety (54.6%) cases were metachronous, 93 (26.7%) simultaneous and 65 (18.7%) synchronous cancers. Metachronous malignant tumours were more common in female patients, whereas simultaneous cancers occurred more often in males. The most common age group was that of 60-69 year-olds. Tumour localisations most frequently involved in MPMs of the digestive system were rectum (11.5%), colon (10.3%) and pharynx (7.2%). In female patients higher occurrences were observed compared to males in colon (21.2% vs.14.2%), rectum (18.3% vs 16.2%) and stomach (7.1% vs. 4.6% respectively). Conversely, male patients presented with a higher number of tumours of the pharynx (14.6% vs. 2.5%), esophagus (13.0% vs. 3.7%) and liver (3.6% vs. 0.8%) compared to females. Oesophageal, stomach and pancreatic cancers showed a slight increase in numbers as a second primary compared to the Indextumours (4.0% vs. 11.3%; 3.5% vs. 8.9% and 0 vs. 4.5% respectively). The most commonly associated non-gastrointestinal tumour types included skin (5.5%), breast (5.3%), prostate (5.1%) and hematopoietic system (3.2%). In 37.7% of patients with synchronous or metachronous cancers the second malignancy developed within one year of the first diagnosis. Interestingly, in nearly one third of those patients (31.2%) the second malignancy was diagnosed already within 6 weeks of the diagnosis of the first tumour. The median time interval between the first and the second MPM was 1.7 years in male and 2.0 years in female patients. The median time of survival for men was 25.7 months compared to women with 39.4 months. Most of the MPMs were diagnosed at the stage of T1 or T2, N0 or N1, M0 and G2. However, there was a tendency towards a higher stage in second primaries compared to Indextumours. Multiple primary malignancies pose a relevant problem to clinical medicine. Their early diagnosis is based on the awareness of the existing risk of a second or more primary tumour in cancer patients. Complemented with multidisciplinary treatment strategies as well as improved follow-up methods and preventive techniques using the known clinical characteristics and possible risk factors, the survival of these patients may substantially increase.

Background Dysregulation of the epidermal growth factor receptor (HER1/EGFR) has been reported in colorectal cancer (CRC). Erlotinib is a potent inhibitor of HER1/EGFR-mediated signaling. This trial of patients with metastatic CRC (MCRC) examined the safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of erlotinib in combination with capecitabine and oxaliplatin (XELOX), a regimen with established efficacy. Patients and methods Patients previously untreated or treated with one line of 5-fluorouracil and/or irinotecan received escalating oral doses of erlotinib (daily), capecitabine (days 1–14) and i.v. oxaliplatin (day 1 of a 21-day cycle). Results The first six patients in cohort 1 (erlotinib 100 mg/day, capecitabine 825 mg/m2 twice daily, oxaliplatin 130 mg/m2) had no dose-limiting toxicities (DLTs). In cohort 2 (capecitabine increased to 1000 mg/m2 twice daily), two of six patients had DLTs. When cohort 2 was expanded to 11 patients two further DLTs occurred, exceeding the definition of MTD. Cohort 1 was expanded to 12 patients, and no DLTs occurred. The most common adverse events (AEs) were diarrhea and rash. There was a trend for reduced capecitabine concentrations in the presence of erlotinib. While this was not statistically significant, the possibility of an interaction affecting capecitabine PK cannot be excluded. Antitumor activity was observed in both cohorts (one complete and four partial responses, and stable disease in 11 patients). Conclusion The MTD for this combination in MCRC is capecitabine 825 mg/m2 twice daily days 1–14, oxaliplatin 130 mg/m2 day 1 and erlotinib 100 mg/day of a 21-day cycle. The combination was well tolerated at the MTD, with no unexpected AEs. The use of this combination in MCRC warrants further investigation.

Purpose: Erlotinib (Tarceva) is a potent epidermal growth factor receptor (HER1) inhibitor. Infusional 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX) is a standard therapy for colorectal cancer. This trial assessed the maximum tolerated dose (MTD), safety, preliminary efficacy, and pharmacokinetics of erlotinib combined with FOLFOX. Experimental Design: Patients with advanced solid tumors were sequentially enrolled into three cohorts (cohort 1: 100 mg/d erlotinib, 65 mg/m2 oxaliplatin, 200 mg/m2 leucovorin, 400 mg/m2 bolus 5-FU, and 400 mg/m2 continuous infusion 5-FU; cohort 2: oxaliplatin increased to 85 mg/m2 and 5-FU infusion increased to 600 mg/m2; and cohort 3: erlotinib increased to 150 mg/d). Results: Thirty-two patients were enrolled (23 with colorectal cancer): no dose-limiting toxicities (DLT) were observed in cohort 1. In cohort 2, two of nine patients experienced a DLT (both diarrhea). In cohort 3, two of nine patients had a DLT (diarrhea and staphylococcal septicemia). Cohort 3 determined the MTD cohort and expanded to 17 patients in total. The most common adverse events were diarrhea, nausea, stomatitis, and rash (primarily mild/moderate). No pharmacokinetics interactions were observed. One patient (colorectal cancer) had a complete response, seven patients had a partial response, and nine had stable disease. Conclusions: The MTD was defined as follows: 150 mg/d erlotinib, 85 mg/m2 oxaliplatin; 200 mg/m2 leucovorin, 400 mg/m2 bolus 5-FU, and 600 mg/m2 infusion 5-FU. At the MTD, the combination was well tolerated and showed antitumor activity, warranting further investigation in patients with advanced colorectal cancer and other solid tumors.

Aims Reducing inter examiner variability is crucial for exams. Training of examiners is seen as essential in ensuring validity and reliability of clinical examinations. We aimed to develop an interactive online package to aid training of examiners assessing undergraduate paediatric students and to evaluate inter examiner variability. Methods Using publicly available Google Sites, we created an online tool to train examiners for their role in paediatric undergraduate clinical skills assessments. It comprised a sequence of five videos of students, each presenting a clinical case(history and examination of a child). These case presentations were scored (scale 0–15 for the total score) by examiners online using an interactive mark sheet that automatically recorded the scores. Subsequently, examiners could compare their scores against an average given by a panel of senior expert examiners. In addition, recorded data were analysed for overall mean scores and standard deviation (SD). The students were ranked according to performance (1 excellent, 1 clear fail and three in between) using predetermined criteria Results Total of 31 participants, 18 of them fully completed the online package. Conclusions Trainee examiners considered the tool helpful, especially if they were to perform the clinical skills assessments for the first time. Results demonstrate variation of scores is higher among trainee examiners, apart from student number 2. Overall scores given by trainee examiners tend to be lower compared to experienced expert examiners.

The feasibility and utility of assessing quality of life (QoL) and disease-related symptoms in patients with advanced cancer have been evaluated in two Phase I clinical trials of p.o. administered ZD1839 ('Iressa'), an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced cancer.Functional Assessment of Cancer Therapy (FACT) questionnaires, including disease-specific subscales for lung, head and neck, colorectal, prostate, and ovarian cancer, were completed by patients in two open-label, Phase I, escalating multiple-dose safety and tolerability trials.In 157 patients, 92% of whom had received prior therapy, compliance in returning FACT questionnaires was 87% (European/Australian trial) and 57% (United States trial). This did not appear to be influenced by dose level or tumor type. For patients with colorectal, prostate, or ovarian cancer, median QoL [FACT and Trial Outcome Index (TOI)] scores deteriorated over time. In contrast, for patients with non-small cell lung cancer (NSCLC) or head and neck cancer, median FACT and TOI scores did not deteriorate significantly, and in the United States trial, head and neck cancer scores improved significantly over time. In patients with NSCLC, symptom-related scores measured by the Lung Cancer Subscale of FACT-L appeared sensitive to clinical change.QoL (FACT-L) questionnaires were used successfully in the Phase I clinical trials of ZD1839. They appeared to be a sensitive tool to monitor clinical changes for the five tumor types in these trials and showed that ZD1839 has the potential to improve patients' QoL.

To evaluate the efficacy and tolerability of two doses of gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non-small-cell lung cancer (NSCLC).This was a randomized, double-blind, parallel-group, multicenter phase II trial. Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens (at least one containing platinum) were randomly assigned to receive either 250-mg or 500-mg oral doses of gefitinib once daily.Efficacy was similar for the 250- and 500-mg/d groups. Objective tumor response rates were 18.4% (95% confidence interval [CI], 11.5 to 27.3) and 19.0% (95% CI, 12.1 to 27.9); among evaluable patients, symptom improvement rates were 40.3% (95% CI, 28.5 to 53.0) and 37.0% (95% CI, 26.0 to 49.1); median progression-free survival times were 2.7 and 2.8 months; and median overall survival times were 7.6 and 8.0 months, respectively. Symptom improvements were recorded for 69.2% (250 mg/d) and 85.7% (500 mg/d) of patients with a tumor response. Adverse events (AEs) at both dose levels were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent in the higher-dose group. Withdrawal due to drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib 250 and 500 mg/d, respectively.Gefitinib showed clinically meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients. At 250 mg/d, gefitinib had a favorable AE profile. Gefitinib 250 mg/d is an important, novel treatment option for patients with pretreated advanced NSCLC [corrected]

PURPOSE: To establish the safety and tolerability of ZD1839 (Iressa), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and to explore its pharmacokinetic and pharmacodynamic effects in patients with selected solid tumor types. PATIENTS AND METHODS: This was a phase I dose-escalating trial of oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28 days. Patients with either advanced non–small-cell lung, ovarian, head and neck, prostate, or colorectal cancer were recruited. RESULTS: Eighty-eight patients received ZD1839 (150 to 1,000 mg/d). At 1,000 mg/d, five of 12 patients experienced dose-limiting toxicity (grade 3 diarrhea [four patients] and grade 3 somnolence [one patient]). The most frequent drug-related adverse events (AEs) were acne-like rash (64%) and diarrhea (47%), which were generally mild (grade 1/2) and reversible on cessation of treatment. No change in ZD1839 safety profile was observed with prolonged administration. Pharmacokinetic analysis showed steady-state exposure to ZD1839 in 98% of patients by day 7. Nineteen patients had stable disease and received ZD1839 for ≥ 3 months; seven of these patients remained on study drug for ≥ 6 months. Serial skin biopsies taken before treatment and at approximately day 28 revealed changes indicative of inhibition of the EGFR signaling pathway. CONCLUSION: ZD1839 was generally well tolerated, with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting toxicity observed at 1,000 mg/d. ZD1839 treatment resulted in clinically meaningful disease stabilization across a range of tumor types and doses. Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was predicted from the mode of action of ZD1839.

PURPOSE: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (Iressa; AstraZeneca Pharmaceuticals, Alderley Park, United Kingdom) is under development as an anticancer agent. We studied the pharmacodynamic effects of ZD1839 on EGFR in the skin, an EGFR-dependent tissue, in cancer patients participating in ZD1839 phase I clinical trials. PATIENTS AND METHODS: We studied 104 pre– and/or on–ZD1839 therapy (≈ at day 28 of therapy) skin biopsies from 65 patients receiving escalating doses of daily oral ZD1839. We measured ZD1839 effects on EGFR activation by immunohistochemistry using an antibody specific for the activated (phosphorylated) EGFR. Effects on receptor signaling (activated mitogen-activated protein kinase [MAPK]), proliferation, p27KIP1, and maturation were also assessed. RESULTS: Histopathologically, the stratum corneum of the epidermis was thinner during therapy (P < .001). In hair follicles, prominent keratin plugs and microorganisms were found in dilated infundibula. ZD1839 suppressed EGFR phosphorylation in all EGFR-expressing cells (P < .001). In addition, ZD1839 inhibited MAPK activation (P < .001) and reduced keratinocyte proliferation index (P < .001). Concomitantly, ZD1839 increased the expression of p27KIP1 (P < .001) and maturation markers (P < .001) and increased apoptosis (P < .001). These effects were observed at all dose levels, before reaching dose-limiting toxicities. CONCLUSION: ZD1839 inhibits EGFR activation and affects downstream receptor-dependent processes in vivo. These effects were profound at doses well below the one producing unacceptable toxicity, a finding that strongly supports pharmacodynamic assessments to select optimal doses instead of a maximum-tolerated dose for definitive efficacy and safety trials.