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1.  NF-κB/STAT5/miR-155 network targets PU.1 in FLT3-ITD-driven acute myeloid leukemia 
Leukemia  2014;29(3):535-547.
Almost 30% of all acute myeloid leukemias (AML) are associated with an internal tandem duplication (ITD) in the juxtamembrane domain of FMS-like tyrosine kinase 3 receptor (FLT3). Patients with FLT3-ITD mutations tend to have a poor prognosis. MicroRNAs (miRNAs) have a pivotal role in myeloid differentiation and leukemia. MiRNA-155 (MiR-155) was found to be upregulated in FLT3-ITD-associated AMLs. In this study, we discovered that FLT3-ITD signaling induces the oncogenic miR-155. We show in vitro and in vivo that miR-155 expression is regulated by FLT3-ITD downstream targets nuclear factor-κB (p65) and signal transducer and activator of transcription 5 (STAT5). Further, we demonstrate that miR-155 targets the myeloid transcription factor PU.1. Knockdown of miR-155 or overexpression of PU.1 blocks proliferation and induces apoptosis of FLT3-ITD-associated leukemic cells. Our data demonstrate a novel network in which FLT3-ITD signaling induces oncogenic miR-155 by p65 and STAT5 in AML, thereby targeting transcription factor PU.1.
PMCID: PMC4490787  PMID: 25092144
2.  Iodine-131 dose-dependent gene expression: alterations in both normal and tumour thyroid tissues of post-Chernobyl thyroid cancers 
British Journal of Cancer  2013;109(8):2286-2294.
A strong, consistent association between childhood irradiation and subsequent thyroid cancer provides an excellent model for studying radiation carcinogenesis.
We evaluated gene expression in 63 paired RNA specimens from frozen normal and tumour thyroid tissues with individual iodine-131 (I-131) doses (0.008–8.6 Gy, no unirradiated controls) received from Chernobyl fallout during childhood (Ukrainian-American cohort). Approximately half of these randomly selected samples (32 tumour/normal tissue RNA specimens) were hybridised on 64 whole-genome microarrays (Agilent, 4 × 44 K). Associations between I-131 dose and gene expression were assessed separately in normal and tumour tissues using Kruskal−Wallis and linear trend tests. Of 155 genes significantly associated with I-131 after Bonferroni correction and with ⩾2-fold increase per dose category, we selected 95 genes. On the remaining 31 RNA samples these genes were used for validation purposes using qRT−PCR.
Expression of eight genes (ABCC3, C1orf9, C6orf62, FGFR1OP2, HEY2, NDOR1, STAT3, and UCP3) in normal tissue and six genes (ANKRD46, CD47, HNRNPH1, NDOR1, SCEL, and SERPINA1) in tumour tissue was significantly associated with I-131. PANTHER/DAVID pathway analyses demonstrated significant over-representation of genes coding for nucleic acid binding in normal and tumour tissues, and for p53, EGF, and FGF signalling pathways in tumour tissue.
The multistep process of radiation carcinogenesis begins in histologically normal thyroid tissue and may involve dose-dependent gene expression changes.
PMCID: PMC3798970  PMID: 24045656
Chernobyl; ionising radiation; iodine-131; gene expression; whole-genome microarray; thyroid cancer
3.  Reduction in growth threshold for pulmonary metastases: an opportunity for volumetry and its impact on treatment decisions 
The British Journal of Radiology  2012;85(1015):959-964.
This study compares tumour response assessment by automated CT volumetry and standard manual measurements regarding the impact on treatment decisions and patient outcome.
58 consecutive patients with 203 pulmonary metastases undergoing baseline and follow-up multirow detector CT (MDCT) under chemotherapy were assessed for response to chemotherapy. Tumour burden of pulmonary target lesions was quantified in three ways: (1) following response evaluation criteria in solid tumours (RECIST); (2) following the volume equivalents of RECIST (i.e. with a threshold of −65/+73%); and (3) using calculated limits for stable disease (SD). For volumetry, calculated limits had been set at ±38% prior to the study by repeated quantification of nodules scanned twice. Results were compared using non-weighted κ-values and were evaluated for their impact on treatment decisions and patient outcome.
In 15 (17%) of the 58 patients, the results of response assessment were inconsistent with 1 of the 3 methods, which would have had an impact on treatment decisions in 8 (13%). Patient outcome regarding therapy response could be verified in 5 (33%) of the 15 patients with inconsistent measurement results and was consistent with both RECIST and volumetry in 1, with calculated limits in 3 and with none in 1. Diagnosis as to the overall response was consistent with RECIST in six patients, with volumetry in six and with calculated limits in eight cases. There is an impact of different methods for therapy response assessment on treatment decisions.
A reduction of threshold for SD to ±30–40% of volume change seems reasonable when using volumetry.
PMCID: PMC3474043  PMID: 22745205
4.  Maintaining success, reducing treatment burden, focusing on survivorship: highlights from the third European consensus conference on diagnosis and treatment of germ-cell cancer 
Annals of Oncology  2012;24(4):878-888.
In November 2011, the Third European Consensus Conference on Diagnosis and Treatment of Germ-Cell Cancer (GCC) was held in Berlin, Germany. This third conference followed similar meetings in 2003 (Essen, Germany) and 2006 (Amsterdam, The Netherlands) [Schmoll H-J, Souchon R, Krege S et al. European consensus on diagnosis and treatment of germ-cell cancer: a report of the European Germ-Cell Cancer Consensus Group (EGCCCG). Ann Oncol 2004; 15: 1377–1399; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part I. Eur Urol 2008; 53: 478–496; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part II. Eur Urol 2008; 53: 497–513]. A panel of 56 of 60 invited GCC experts from all across Europe discussed all aspects on diagnosis and treatment of GCC, with a particular focus on acute and late toxic effects as well as on survivorship issues.
The panel consisted of oncologists, urologic surgeons, radiooncologists, pathologists and basic scientists, who are all actively involved in care of GCC patients. Panelists were chosen based on the publication activity in recent years. Before the meeting, panelists were asked to review the literature published since 2006 in 20 major areas concerning all aspects of diagnosis, treatment and follow-up of GCC patients, and to prepare an updated version of the previous recommendations to be discussed at the conference. In addition, ∼50 E-vote questions were drafted and presented at the conference to address the most controversial areas for a poll of expert opinions. Here, we present the main recommendations and controversies of this meeting. The votes of the panelists are added as online supplements.
PMCID: PMC3603440  PMID: 23152360
consensus conference; diagnosis; germ-cell cancer; late toxic effects; long-term follow-up; treatment
5.  Adrenaline: communication by electron emission. Effect of concentration and temperature. Product analysis 
Based on the recent findings about the ability of sexual hormones to emit electrons (eaq−) and to act as electron mediator, it was of interest to investigate adrenaline as an important neurotransmitter.
Materials and methods
Highest purity adrenaline (ADR) and chemicals were used for preparation of aqueous solutions (pH ~7.4). The excitation of ADR in singlet state was achieved by irradiation of airfree aqueous solution with monochromatic UV light at λ = 254 nm. The emitted “solvated electrons” (eaq−) were scavenged by chloroethanol, where the quantum yield of Cl− ions, Q(Cl−)=Q(eaq−). ADR degradation and formation of photolytic products were followed by HPLC analysis.
Results and conclusion
It was found that Q(eaq−) values decrease with increasing ADR concentration: for 2.5×10−5 mol/L ADR was determined as Q(eaq−)=6×10−3, whereas for 1×10−3 mol/L ADR was found to be 0.9×10−3. This is explained by formation of associates in ground state, which consume a part of emitted eaq−. As a main photolytic product aminochrome was determined.
PMCID: PMC3042237  PMID: 21347200
adrenaline; biological communication; electron consumer; electron emitter; electron mediator
6.  Tallness is associated with risk of testicular cancer: evidence for the nutrition hypothesis 
British Journal of Cancer  2008;99(9):1517-1521.
The pathogenesis of testicular germ cell tumours (GCTs) is potentially influenced by high-energy nutrition during infancy. As adult height is a proxy for childhood nutrition, we investigated the role of nutrition in GCT pathogenesis by comparing stature of patients with healthy men. In a matched case–control study, 6415 patients with GCT were compared with healthy army conscripts (1:6 matching modus) with regard to height (cm) and body mass index (BMI; kg/m2). Statistical analysis involved tabulation of descriptive height measures and BMI. Conditional logistic regression models were used to quantify the association of GCT with height, with odds ratios (OR) adjusted for BMI. The literature was searched for studies on stature in GCT patients. Body size is significantly associated with risk of GCT, very tall men (>195 cm) having a GCT risk of OR=3.35 (95% confidence intervals (CI): 2.88–3.90; adjusted). Short stature is protective (OR=0.798; 95% CI: 0.68–0.93). Both histologic subgroups are associated with tallness. Of 16 previous reports, 7 were confirmative, 5 had null and 4 equivocal results. The association of stature with GCT risk accords with the nutrition hypothesis of GCT. This study expands the current view of GCT tumorigenesis by suggesting that high-calorie intake in childhood promotes GCT precursors originating in utero.
PMCID: PMC2579680  PMID: 18827809
testicular cancer; body size; childhood nutrition; seminoma; non-seminoma; BMI
7.  Capecitabine plus oxaliplatin as first-line treatment in patients with advanced biliary system adenocarcinoma: a prospective multicentre phase II trial 
British Journal of Cancer  2008;98(2):309-315.
This prospective multicentre phase II study characterises the toxicity and activity of first-line capecitabine and oxaliplatin combination therapy (CAPOX) in advanced biliary system adenocarcinomas. Patients received oxaliplatin (130 mg m−2, day 1) plus capecitabine (1000 mg m−2 b.i.d., days 1–14) every 3 weeks. Patients were stratified prospectively into two groups based on location of the primary (gallbladder carcinoma (GBC) or extrahepatic cholangiocarcinoma (ECC) versus intrahepatic mass-forming type cholangiocarcinoma (ICC)). Sixty-five patients were evaluable. The response rate in 47 patients with GBC/ECC was 27% (4% complete responses), and in 23 patients (49%) stable disease (SD) was encountered. In 18 patients with ICC, we observed no objective responses, but 6 patients (33%) had SD. Median survival was 12.8 months (95% CI, 10.0–15.6) for patients with GBC or ECC (GBC: 8.2 months; 95% CI, 4.3–11.7; ECC: 16.8 months; 95% CI, 12.7–20.5), and 5.2 months (95% CI, 0.6–9.8) for ICC patients. In both cohorts, therapy was well tolerated. The most common grade 3–4 toxicity was peripheral sensory neuropathy (11 patients). Our data suggest that the CAPOX regimen is a well-tolerated and active treatment option for advanced ECC and GBC but might produce poorer results for ICC.
PMCID: PMC2361467  PMID: 18182984
capecitabine; chemotherapy; cholangiocarcinoma; gallbladder carcinoma; oxaliplatin
8.  Studies on p53, BAX and Bcl-2 protein expression and microsatellite instability in stage III (UICC) colon cancer treated by adjuvant chemotherapy: major prognostic impact of proapoptotic BAX 
British Journal of Cancer  2007;96(9):1409-1418.
We evaluated the expression patterns of proapoptotic BAX, antiapoptotic Bcl-2 and p53, the proposed upstream effector of these molecules, as potential prognostic markers in UICC stage III colon cancer by immunohistochemical staining. To identify high-frequency microsatellite instability (MSI+) individuals, we performed single-strand conformation polymorphism-based analysis for BAT26. A total of 188 patients who had received 5-fluorouracil (5-FU)-based adjuvant chemotherapy (5-FU/folinic acid or 5-FU/levamisole) were enrolled. Median follow-up was 84.5 months. We found that BAX, Bcl-2 and p53 protein expressions were high or positive in 59, 70 and 50% of 188 cases, respectively. MSI+ tumours were detected in 9% of 174 evaluable patients. BAX or Bcl-2 was correlated with a higher degree of differentiation or left-sided tumours (P=0.01 or P=0.03, respectively); MSI was correlated with right-sided tumours (P<0.0001). In contrast to p53, Bcl-2, or MSI, low BAX, advanced pN category, low grade of differentiation and treatment with 5-FU/levamisole were univariately associated with poorer disease-free survival (DFS) (P=0.0005, P=0.001, P=0.005 and P=0.01, respectively) and poorer overall survival (OS) (P=0.002, P=0.0001, P=0.003 and P=0.02, respectively). Besides pN category and treatment arm, BAX was an independent variable related to both OS and DFS (P=0.003 and P=0.001, respectively). In both univariate and multivariate analysis, the p53−/BAX high in comparison with the p53+/BAX high subset conferred a significantly improved DFS (P=0.03 and P=0.03, respectively) as well as a marginally improved OS (P=0.07 and P=0.08, respectively). BAX protein expression may be of central significance for clinical outcome to 5-FU-based adjuvant chemotherapy in stage III colon cancer, and bivariate analysis of p53/BAX possibly may provide further prognostic evidence.
PMCID: PMC2360187  PMID: 17426704
adjuvant chemotherapy; BAT26; BAX; Bcl-2; colon carcinoma; microsatellite instability; p53/BAX pathway; prognosis
9.  Capecitabine in combination with mitomycin C in patients with gastrointestinal cancer: results of an extended multicentre phase-I trial 
British Journal of Cancer  2004;91(5):834-838.
PMCID: PMC2409860  PMID: 15238990
capecitabine; mitomycin C; gastrointestinal cancer
11.  Pegylated liposomal doxorubicin in combination with mitomycin C, infusional 5-fluorouracil and sodium folinic acid. A phase-I-study in patients with upper gastrointestinal cancer 
British Journal of Cancer  2004;90(10):1893-1897.
PMCID: PMC2409460  PMID: 15138468
gastric cancer; infusional 5-fluorouracil; mitomycin C; pancreatic cancer; pegylated liposomal doxorubicin; sodium folinic acid
12.  Protracted infusional 5-fluorouracil plus high-dose folinic acid combined with bolus mitomycin C in patients with gastrointestinal cancer: a phase I/II dose escalation study 
British Journal of Cancer  2003;89(11):2051-2056.
PMCID: PMC2376864  PMID: 14647137
advanced gastrointestinal cancer; colorectal carcinoma; gastric cancer; mitomycin C; continuous infusional 5-flourouracil; phase I/II study
13.  First-line sequential high-dose VIP chemotherapy with autologous transplantation for patients with primary mediastinal nonseminomatous germ cell tumours: a prospective trial 
British Journal of Cancer  2003;89(1):29-35.
PMCID: PMC2394224  PMID: 12838296
extragonadal germ cell tumours; mediastinal primary; high-dose chemotherapy; autologous transplantation; nonseminomatous histology
14.  Treatment of neonatal thrombus formation with recombinant tissue plasminogen activator: six years experience and review of the literature 
BACKGROUND—Thrombosis is a relatively rare event in children. However, many conditions in the neonatal period result in an increased risk of thrombus formation. The major risk factor is the indwelling intravascular catheter. Numerous small studies have reported experience of thrombolytic treatment for neonatal thrombotic disease with a wide range of different thrombolytic agents in various forms of administration, dosage, and duration, but no conclusions on the most effective treatment for neonates has been reached.
OBJECTIVE—To assess the efficacy and safety of thrombolytic treatment of neonatal catheter related thrombus (CRT) formation with recombinant tissue plasminogen activator (rt-PA).
METHOD—Over a six year period, 14 neonates with CRT were treated with the same rt-PA protocol (an initial bolus of 0.7 mg/kg over 30-60 minutes followed by infusion of 0.2 mg/kg/h).
RESULTS—Complete clot dissolution was documented in 11 patients, and partial clot lysis in two patients, leading to a patency rate of 94%. In two cases, local bleeding occurred, resulting in treatment failure in one case. Finally, antithrombin III substitution was required in one case. No other complications such as severe bleeding were recognised.
CONCLUSION—With the use of close clinical and haematological monitoring on a neonatal intensive care unit combined with serial two dimensional colour echocardiography, the present rt-PA protocol was shown to be a safe and effective method of clot dissolution in neonates.

PMCID: PMC1721267  PMID: 11420316
15.  Treatment-induced anaemia and its potential clinical impact in patients receiving sequential high dose chemotherapy for metastatic testicular cancer 
British Journal of Cancer  2002;87(10):1066-1071.
First-line sequential high dose chemotherapy is under investigation in patients with ‘poor prognosis’ metastatic germ cell tumours in order to improve survival. Despite the use of autologous peripheral blood stem cell transplantation and granulocyte colony stimulating factor chemotherapy dose intensification is associated with severe haematotoxicity including anaemia, which may significantly affect quality of life and tolerability of chemotherapy. This study investigates the frequency and degree of anaemia in patients receiving first-line sequential high dose chemotherapy for metastatic testicular cancer and the impact of anaemia on treatment outcome. A total of 101 newly diagnosed patients with ‘poor prognosis’ metastatic nonseminomatous germ cell tumours were treated with one cycle of standard VIP followed by three cycles of HD-VIP-chemotherapy (etoposide, ifosfamide, cisplatin) within a large phase I/II study. Differential blood cell counts were taken prior, during and after every cycle of chemotherapy. Additionally, the numbers of red blood cell and platelet transfusions were recorded. Kaplan–Meier analyses were performed to correlate pre-treatment and post-treatment haemoglobin values to response and overall survival. Forty-eight per cent of the patients were classified anaemic (haemoglobin <12 g dl−1) prior to the start of chemotherapy. The application of sequential HD-VIP resulted in median haemoglobin nadirs between 7.8 g dl−1 (range 5.5–11.1 g dl−1) in the first cycle and 7.6 g dl−1 (range 6.0–11.4 g dl−1) in the third cycle despite the frequent use of red blood cell transfusions. Almost all patients (99%) had haemoglobin levels <10 g dl−1 at some timepoint during first-line sequential high dose chemotherapy. Overall, 97 patients received red blood cell transfusions with a median of 10 units (range 2–25) per patient during the four consecutive cycles of therapy. The time to first transfusion was shortest in patients with the lowest initial haemoglobin values. While there was no prediction of response or outcome by baseline haemoglobin-levels, a significant survival difference in favour of patients with a haemoglobin value >10.5 g dl−1 after completion of four cycles of therapy (at leukocyte recovery after the last cycle) compared to those with haemoglobin values <10.5 g dl−1 was found with 3-year overall survival rates of 87% vs 68%, respectively (P<0.05). Severe anaemia is a very frequent side effect of sequential dose intensive therapy in patients with germ cell cancer, with almost all patients becoming transfusion dependent. Despite the frequent use of red blood cell transfusions, median haemoglobin nadirs remained about 7.5–8 g dl−1 during therapy. A correlation of haemoglobin-values after completion of therapy to overall treatment outcome was found.
British Journal of Cancer (2002) 87, 1066–1071. doi:10.1038/sj.bjc.6600629
© 2002 Cancer Research UK
PMCID: PMC2376199  PMID: 12402143
germ cell tumour; anaemia; prognostic factors; autologous blood stem cell transplantation; chemotherapy; cisplatin
16.  A randomized trial of amifostine in patients with high-dose VIC chemotherapy plus autologous blood stem cell transplanation 
British Journal of Cancer  2001;84(3):313-320.
This pilot study evaluates the degree of side effects during high-dose chemotherapy (HD-VIC) plus autologous bone marrow transplant (HDCT) and its possible prevention by the cytoprotective thiol-derivate amifostine. Additionally, the in-patient medical costs of both treatment arms were compared. 40 patients with solid tumours were randomized to receive HD-VIC chemotherapy with or without amifostine (910 mg/m2 at day 1–3) given as a short infusion prior to carboplatin and ifosfamide. Patients were stratified according to pretreatment. HDCT consisted of an 18 h infusion of carboplatin (500 mg/m2/d over 18 h), ifosfamide (4 g/m2/d over 4 h) and etoposide (500 mg/m2/d) all given for 3 consecutive days. All patients received prophylactic application of G-CSF (5 μg kg−1 subcutaneously) to ameliorate neutropenia after treatment. Patients were monitored for nephrotoxicity, gastrointestinal side effects, haematopoietic recovery, as well as frequency of fever and infections. The median fall of the glomerular filtration rate (GFR) was 10% from baseline in the amifostine group (105 to 95 ml min−1) and 37% in the control patient group (107 to 67 ml min−1) (P< 0.01). Amifostine-treated patients revealed a less pronounced increase in albumine and low molecular weight protein urinary excretion. Stomatitis grade III/IV occurred in 25% without versus 0% of patients with amifostine (P = 0.01). Acute nausea/vomiting was frequently observed immediately during or after the application of amifostine despite intensive antiemetic prophylaxis consisting of 5-HT3-receptor antagonists/dexamethasone/trifluorpromazine. However, delayed emesis occurred more often in the control patients. Engraftment of neutrophil (> 500 μl−1) and thrombocytes (> 25 000 μl−1)were observed at days 9 versus 10 and 10 versus 12, respectively, both slightly in favour of the amifostine arm. In addition, a lower number of days with fever and a shortened duration of hospital stay were observed in the amifostine arm. The reduction of acute toxicity observed in the amifostine arm resulted in 30% savings in costs for supportive care (Euro 4396 versus Euro 3153 per patient). Taking into account the drug costs of amifostine, calculation of in-patient treatment costs from the start of chemotherapy to discharge revealed additional costs of Euro 540 per patient in the amifostine arm. This randomized pilot study indicates that both organ and haematotoxicity of HD-VIC chemotherapy can be ameliorated by the use of amifostine. Additionally, a nearly complete preservation of GFR was observed in amifostine-treated patients which may be advantageous if repetitive cycles of HDCT are planned. Larger randomized trials evaluating amifostine cytoprotection during high-dose chemotherapy are warranted. © 2001 Cancer Research Campaign
PMCID: PMC2363753  PMID: 11161394
toxicity; high-dose chemotherapy; PBSC transplantation; cytoprotection; amifostine; pharmacoeconomics
17.  A phase II study of paclitaxel, weekly, 24-hour continuous infusion 5-fluorouracil, folinic acid and cisplatin in patients with advanced gastric cancer 
British Journal of Cancer  2000;83(4):458-462.
To evaluate the toxicity and efficacy of combination chemotherapy with paclitaxel, cisplatin and 24 h continuous infusion of 5-FU/folinic acid in patients (pts) with unresectable, locally advanced or metastatic gastric adenocarcinoma. Forty-five chemotherapy-naive pts (28 male and 17 female) with a median age of 60 years (range 35–74) were enrolled. 5-FU 2 g/m2was given weekly over 24 h i.v. preceded by folinic acid 500 mg/m2as a 2 h infusion. Paclitaxel 175 mg/m2was administered as a 3 h-infusion on days 1 and 22 and cisplatin 50 mg/m2as 1 h infusion on days 8 and 29. Six weeks of therapy (days 1, 8, 15, 22, 29, 36) followed by 2 weeks rest were considered one cycle. A median of 3 cycles (range 1–4) were administered to 45 pts assessable for response, survival and toxicity. Five pts (11%) obtained a CR and 18 pts (40%) a PR (ORR 51%; 95% Cl: 35.8–66.3%). Responses were achieved in the liver, lymph nodes, lungs and at the site of the primary tumour. Nine pts (20%) had stable disease. Thirteen pts (29%) were considered to have failed treatment, 8 pts (18%) due to progressive disease and 5 pts (11%) who did not receive one complete cycle of therapy due to acute non-haematologic toxicity. The median progression-free and overall survival times were 9 months (range 1–36+) and 14 months (range 2–36+), respectively. Neutropenia WHO III°/IV° occurred in 7 pts (15%) with only 1 pt having grade IV. Additional non-haematologic WHO III°/IV° toxicities included nausea/vomiting in 5 (11%), alopecia in 22 (49%), and diarrhoea in 1 patient each (2%). Dose reductions or treatment delays were necessary in 8 pts (17%), mainly due to neutropenia. All pts were treated on an outpatient basis. The combination of paclitaxel, cisplatin and continuously infused 5-FU/folinic acid appears to be a highly active regimen for the treatment of pts with advanced gastric cancer. While the overall acceptable toxicity allows its use in the palliative setting, it may also be an attractive option to be tested for neoadjuvant or adjuvant treatment. © 2000 Cancer Research Campaign
PMCID: PMC2374647  PMID: 10945491
gastric cancer; metastatic; chemotherapy; paclitaxel; continuous infusion
18.  Predictive value of decreased p27Kip1 protein expression for the recurrence-free and long-term survival of prostate cancer patients 
British Journal of Cancer  1999;81(6):1052-1058.
The p27Kip1 gene has been identified as inductor of cell cycle arrest at the G1 checkpoint to prevent entry of somatic cells into the S phase of the cell cycle when substantial DNA damage has occurred. It has been suggested that decreased expression of the p27Kip1 protein may contribute to the development of human malignancies due to loss of critical antiproliferative mechanisms. In the present study, 95 specimens (T1–T4) from 95 randomly selected patients undergoing radical prostatectomy at the Urological Department of Hannover University (82 patients) as well as in the Josef Hospital Regensburg (13 patients) between 1981 and 1992 for whom tissue blocks for immunohistochemical investigation were available, were investigated for different biological and clinical characteristics as possible predictors for recurrence-free and long-term survival: age, depth of tumour infiltration, histological grade, lymph node status, as well as decreased expression of the p27Kip1 protein. After a median follow-up up of 56 months (24–151 months), seven of 21 (33%) patients (Group 1) with loss of p27Kip1 protein expression or a relative amount of <10% of positively stained tumour cells developed recurrent disease in contrast to 17 of 74 (23%) patients (Group 2) with retained p27Kip1 protein expression (≥10% of positively stained tumour cells). The median recurrence-free survival was 14 months (5–40 months) for patients from Group 1 and 31 months (7–133 months) for Group 2 patients (P = 0.02). In multivariate analysis, loss of p27Kip1 protein expression was identified as the only independent prognostic parameter for recurrence-free survival. In contrast, neither the univariate nor the multivariate analysis showed a correlation between loss of p27Kip1 protein expression and the long-term survival of the patients. Prospective studies are urgently needed to confirm the independent prognostic value of decreased p27Kip1 protein expression together with overexpression of the p53 tumour suppressor protein in patients with localized prostate cancer. The availability of more refined prognostically important biological variables in addition to established prognostic factors like tumour stage or Gleason score might help decision making in patients at high risk for the development of local recurrence or systemic tumour progression. © 1999 Cancer Research Campaign
PMCID: PMC2362945  PMID: 10576664
prostate cancer; prognosis; p27Kip1 gene
19.  Analysis of risk factors for cisplatin-induced ototoxicity in patients with testicular cancer. 
British Journal of Cancer  1998;77(8):1355-1362.
This study evaluates the degree and relevance of persisting ototoxicity after cisplatin-based standard-dose chemotherapy for testicular cancer, with emphasis on identification of potential factors for an increased risk of this late sequel. Hearing thresholds of 86 patients with a median age of 31 years (range 21-53 years) and a median follow-up time of 58 months (range 15-159 months) were assessed by conventional pure-tone audiometry. Interviews were conducted evaluating the patients' history with special regard to audiological risk factors, as well as circumstances of ototoxic symptoms. Details concerning treatment and patient variables were extracted retrospectively from the patients' charts. An additional screening programme assessed current body functions, blood parameters and other late toxicities. Symptomatic ototoxicity persisted in 20% of patients (59% tinnitus, 18% hearing loss, 23% both), while 10% had experienced completely reversible ototoxic symptoms for a duration of 1-18 months after treatment. Symptoms were bilateral in 81% of patients. Hearing thresholds were compatible with cisplatin-induced hearing loss in 42% of audiograms performed. Subjective (history) and objective (audiogram) findings were not always consistent. The following statistically significant risk factors for ototoxicity were established: high cumulative dose of cisplatin (P < 0.0001); history of noise exposure (P = 0.006). Additionally, high doses of vincristine (P = 0.001) seemed to result in reversible ototoxic symptoms. No other independent risk factors were identified. In conclusion, persisting ototoxicity represents a clinical sequel for approximately 20% of testicular cancer patients treated at standard dose but may affect more than 50% of patients receiving cumulative doses of cisplatin > 400 mg m(-2). Previous noise exposure may also result in a threefold increased risk for cisplatin ototoxicity. Future studies should use these risk factors as important stratification criteria for trials aiming at the evaluation and prevention of cisplatin-induced ototoxicity.
PMCID: PMC2150148  PMID: 9579846
20.  Nuclease-sensitive sites in the two major intracellular simian virus 40 nucleoproteins. 
Journal of Virology  1983;46(3):1034-1038.
Simian virus 40 nucleoprotein isolated from the nuclei of infected cells contains a nuclease-sensitive site adjacent to the viral origin of replication (between 0.66 and 0.73 map unit). Nuclear extracts were subfractionated by sucrose gradient centrifugation to yield provirions (200S) and simian virus 40 chromatin (80S). The 80S fraction was cleaved either by DNase I or by an endonuclease endogenous to BSC-1 cells with high preference for the 0.66 to 0.73 region. The 200S fraction was treated to release core particles that were sensitive to nuclease cleavage; however, DNase I showed little or no preference for the 0.66 to 0.73 region of the provirion core nucleoprotein.
PMCID: PMC256580  PMID: 6304335
21.  Distribution of DNase I-sensitive sites in simian virus 40 nucleoprotein complexes from disrupted virus particles. 
Journal of Virology  1981;37(3):908-915.
Nucleoprotein complexes (core particles) released from simian virus 40 (SV40) virions were compared with similar complexes (SV40 chromatin) extracted from nuclei of infected cells. Core particles were sensitive to cleavage by DNase I at about the same enzyme concentration required to cleave SV40 chromatin. DNase I preferentially cleaved SV40 chromatin adjacent to the viral origin of replication; however, cleavage of core particles occurred with much less selectivity. The difference between these nucleoproteins was not due to a structural alteration induced by the virion disruption procedure, since SV40 chromatin retained its pattern of DNase I-sensitive sites when subjected top this treatment. On the other hand, core particles did not acquire the nuclease-sensitive feature typical of SV40 chromatin when they were exposed to infected cell nuclei and the Triton X-100-EDTA extraction procedure. Hence, the nuclease-sensitive feature was lost or altered during the normal process of virion assembly and maturation.
PMCID: PMC171087  PMID: 6262535
22.  Metabolism of 3-chloro-, 4-chloro-, and 3,5-dichlorobenzoate by a pseudomonad. 
Pseudomonas sp. WR912 was isolated by continuous enrichment in three steps with 3-chloro-, 4-chloro-, and finally 3,5-dichlorobenzoate as sole source of carbon and energy. The doubling times of the pure culture with these growth substrates were 2.6, 3.3, and 5.2 h, respectively. Stoichiometric amounts of chloride were eliminated during growth. Oxygen uptake rates with chlorinated benzoates revealed low stereospecificity of the initial benzoate 1,2-dioxygenation. Dihydrodi-hydroxybenzoate dehydrogenase, catechol 1,2-dixoygenase, and muconate cycloisomerase activities were found in cell-free extracts. The ortho cleavage activity for catechols appeared to involve induction of isoenzymes with different stereospecificity towards chlorocatechols. A catabolic pathway for chlorocatechols was proposed on the basis of similarity to chlorophenoxyacetate catabolism, and cometabolism of 3,5-dimethylbenzoate by chlorobenzoate-induced cells yielded 2,5-dihydro-2,4-dimethyl-5-oxo-furan-2-acetic acid.
PMCID: PMC243232  PMID: 453823
23.  Marrow transplantation in treatment of children with aplastic anaemia or acute leukaemia. 
Archives of Disease in Childhood  1976;51(6):403-410.
Seventy-six patients, aged 2 to 17 years, were treated with bone marrow transplantation for severe aplastic anaemia or acute leukaemia refractory to conventional therapy. 16 of the 22 patients (73%) who received marrow transplantations for aplastic anaemia are surviving, 12 of these for over one year. In acute leukaemia, using preparation with cyclophosphamide and total body irradiation, 8 of 33 patients (24%) receiving allogeneic and 5 of 8 (63%) receiving syngeneic transplantations are continuing in remission from 3 months to beyond 2 years. The longest continuing remission off therapy is now over 4 1/2 years after preparation with total body irradiation. The major causes of failure remain graft-versus-host disease, infection, graft rejection (aplastic anaemia), and leukaemic relapse.
PMCID: PMC1546004  PMID: 8016
24.  Experimental Acute Lead Encephalopathy in the Juvenile Rhesus Monkey* 
Lead subacetate (0.5g) and 1000 units of vitamin D were given three times a week to four newly-weaned rhesus monkeys. In addition, two animals received only the vitamin D. The poisoned animals had an increase in the urinary excretion of δ-aminolevulinic acid, an elevated content of lead in the blood, and a fall in hemoglobin concentration. Between 6 and 18 weeks the animals suddenly developed ataxia, nystagmus, generalized weakness, and convulsions. At this time the animals were killed by perfusion of fixative and the brain prepared for light and electron microscopic studies. Definite morphological evidence of disease was confined to the central nervous system, except for one animal which showed the characteristic renal inclusions of lead poisoning. All animals showed PAS-positive globules associated with blood vessels and an exudative edema involving the white matter of the cerebral hemispheres and cerebellum. Ultra-structurally, this appeared as a granular precipitate within an expanded extracellular space. Alterations of nerve fibers were not seen in the white matter but axonal swelling was observed in the cerebral cortex. The perikaryon and neuropil appeared normal. The control animals showed no significant cerebral changes.
PMCID: PMC1475124  PMID: 4208657

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