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Non-metastatic prostate cancer (PCa) patients are at increased risk for osteoporosis and fractures mainly due to androgen deprivation therapy (ADT)-associated hypogonadism, but this remains largely underdiagnosed and untreated. In this study, we examine the value of pre-screening calcaneal QUS in identifying patients who should be referred for screening for osteoporosis using dual-energy X-Ray absorptiometry (DXA). In a single-center retrospective cross-sectional cohort study, we analysed data on DXA and calcaneal QUS measurements systematically collected between 2011 and 2013 in all non-metastatic PCa patients attending our Uro-Oncological Clinic at the Leiden University Medical Center. Receiver operating characteristic curves were used to assess the positive (PPV) and negative (NPV) predictive values of QUS T-scores of 0, −1.0, and − 1.8 in identifying DXA-diagnosed osteoporosis (T-scores ≤ − 2.5 and ≤ −2) at lumbar spine and/or femoral neck. Complete sets of data were available in 256 patients, median age 70.9 (53.6–89.5) years; 93.0 % had received local treatment, 84.4 % with additional ADT. Prevalence of osteoporosis and osteopenia was respectively 10.5 % and 53 %. Mean QUS T-score was −0.54 ± 1.58. Whereas PPV at any QUS T-score was <25 %, precluding the use of QUS as surrogate for DXA in screening for osteoporosis, QUS T-scores of −1.0 to 0.0 had a NPV of ≥94.5 % for DXA T-scores ≤ 2.5 and ≤ −2 at any site, confidently identifying patients least likely to have osteoporosis, thereby significantly reducing the number of patients requiring DXA screening for diagnosing osteoporosis by up to two-third. Osteoporosis screening is a significant unmet need in non-metastatic prostate cancer patients treated with ADT, and QUS may represent a valuable alternative pre-screening strategy to overcome logistics, time demands, and economic barriers encountered with current strategies for osteoporosis screening in these patients.

See alsoFreyssinet J‐M, Toti F. Membrane microparticle determination: at least seeing what’s being sized! This issue, pp 311–4.

Background: Cancer, in particular mucinous adenocarcinoma, is associated with venous thromboembolism (VTE). Tissue factor (TF), initiator of coagulation, plays a central role in the paradigm that clotting and tumor growth form a vicious circle, in which hypercoagulability facilitates the aggressive biology of cancer and vice versa. Expression of TF in tumors is associated with poor differentiation and poor prognosis. Patient/methods: We investigated the association between clinically manifest VTE and procoagulant properties of circulating microparticles (MP) isolated from blood of unselected pancreatic and breast adenocarcinoma patients' consecutive subjects, who presented with ultrasound or CT‐scan confirmed VTE, and healthy subjects. Results: Patients with disseminated breast and pancreatic cancer had significantly increased levels of MP‐associated TF activity compared with healthy controls, subjects with idiopathic acute VTE and non‐metastatic cancer patients. Patients with both high MP‐associated TF‐activity and MP‐associated epithelial mucin (MUC1) had a lower survival rate at 3–9 months follow‐up than those with low TF‐activity and no MUC1 expression: the likelihood of survival was 0.42 (95% CI: 0.19– 0.94) for an individual with these two predictor variables present, after adjustment for other factors (age cohort, type of cancer, VTE) in the Cox proportional hazards model. Conclusions: Our results suggest an important role for MP‐associated TF and MUC1 in the pathogenesis of thrombosis in disseminated mucinous adenocarcinoma patients. Future studies should reveal the mechanism underlying the observed associations.

Background: The incidence of venous thrombosis (VT) for cancer patients is increased compared with patients without cancer, but estimations of the incidence for different types of cancer have rarely been made because of the low incidence of various types of cancer. Large registries offer an opportunity to study the risk of VT in large cohorts of cancer patients, which is essential in decisions on prophylactic anti‐coagulant treatment. Methods: This cohort study estimates the incidence of VT in cancer patients by using record linkage of a Cancer Registry and an Anticoagulation Clinic database in the Netherlands. Cumulative incidences in patients with different types of malignancies were estimated. We calculated relative risks (RRs) in relation to the presence of distant metastases and treatment. Results: Tumors of the bone, ovary, brain, and pancreas are associated with the highest incidence of VT (37.7, 32.6, 32.1, and 22.7/1000/0.5 year). Patients with distant metastases had a 1.9‐fold increased risk [RRadj: 1.9; 95% confidence interval (CI): 1.6–2.3]. Chemotherapy leads to a 2.2‐fold increased risk (RRadj: 2.2; 95% CI: 1.8–2.7) and hormonal therapy leads to a 1.6‐fold increased risk (RRadj: 1.6; 95% CI: 1.3–2.1) compared with patients not using these treatment modalities. Patients with radiotherapy or surgery did not have an increased risk. Conclusions: We compared the overall incidences of VT in the first half year in our study to the risk of major bleeding as described in the literature. For patients with distant metastases, for several types of cancer, prophylactic anti‐thrombotic treatment could be beneficial.

Background:Well known risk factors for upper extremity deep venous thrombosis are the presence of a central venous catheter (CVC) and malignancy, but other potential risk factors, such as surgery, injury and hormone replacement therapy (HRT), have not yet been explored. Methods:We performed a population-based case-control study including 179 consecutive patients, aged 18–70 years with upper extremity deep venous thrombosis and 2399 control subjects. Participants reported on acquired risk factors in a questionnaire and factor V Leiden and prothrombin 20210A mutation were ascertained. Information on CVC was obtained from discharge letters. Results:Forty-two patients (23%) and one control subject (0.04%) had a CVC (ORadj: 1136, 95% CI: 153–8448, adjusted for age and sex). Cancer patients without a CVC had an eightfold increased risk of venous thrombosis of the arm (ORcrude: 7.7, 95% CI: 4.6–13.0). Other evident risk factors were prothrombotic mutations, surgery, immobilization of the arm (plaster cast), oral contraceptive use and family history, with odds ratios varying from 2.0 up to 13.1. The risk in the presence of injury and during puerperium was twofold or more increased, although not significantly. In contrast HRT, unusual exercise, travel and obesity did not increase the risk. Hormone users had an increased risk in the presence of prothrombotic mutations or surgery. Obese persons (BMI > 30 kg m−2) undergoing surgery had a 23-fold increased risk of arm thrombosis compared with non-obese persons not undergoing surgery. Conclusion:A CVC is a very strong risk factor for arm thrombosis. Most risk factors for thrombosis in the leg are also risk factors for arm thrombosis.

Background: Only limited data on the incidence of venous thrombosis in different types of malignancy are available. Patients with adenocarcinoma are believed to have the highest risk of developing venous thrombosis. Objectives: To study the incidence of thrombosis in patients with lung cancer, with an emphasis on the comparison between adenocarcinoma and squamous cell carcinoma, we have performed a cohort study of patients with non‐small‐cell lung cancer. In addition the risk associated with treatment and extent of disease was assessed. Patients/methods: A total of 537 patients with a first diagnosis of lung carcinoma were included. Patient and tumor characteristics as well as venous thrombotic events were recorded from the medical records and from the Anticoagulation Clinic. Results: Thrombotic risk in lung cancer patients was 20‐fold higher than in the general population (standardized morbidity ratio (SMR): 20.0 (14.6–27.4). In the group of patients with squamous cell cancer we found 10 (10/258) cases (incidence: 21.2 per 1000 years) of venous thrombosis whereas in the group of patients with adenocarcinoma 14 (14/133) cases (incidence: 66.7 per 1000 years) occured. The crude adjusted hazard ratio was 3.1 (95% CI: 1.4–6.9). The risk increased during chemotherapy and radiotherapy and in the presence of metastases. Conclusions: The risk of venous thrombosis in lung cancer patients is increased 20‐fold compared to the general population. Patients with adenocarcinoma have a higher risk than patients squamous cell carcinoma. During chemotherapy or radiotherapy and in the presence of metastases the risk is even higher.

Non-protein bound iron (NPBI) is able to catalyse oxidative reactions, causing damage to vital structures. Adverse effects induced by cisplatin seem, in part, to be mediated by free radicals. In the present study, we have measured plasma NPBI, various other iron parameters and antioxidants in 28 cancer patients undergoing cisplatin-based chemotherapy at various time points before and during chemotherapy. No NPBI was present prior to therapy, but within 1–4 days following the first administration of chemotherapy, mean NPBI rose significantly to 10.6±6.6 µmol/l (range, 0.6–21.3 µmol/l) in 18 (64.3%) of the 28 patients measured. The rise in NPBI was accompanied by a significant rise in total plasma iron and ferritin and a marked decrease in the latent iron-binding capacity. Concomitantly, plasma vitamins C and E decreased significantly, indicating consumption of antioxidants. Similar observations were also made during the fourth chemotherapy cycle. The increase in NPBI preceded and correlated significantly with chemotherapy toxicity, such as a decrease in leucocyte count and haemoglobin, with a transient rise in various liver enzymes and with known cisplatin-related toxicity, i.e. the loss of renal and hearing function. In conclusion, cisplatin chemotherapy induces oxidative damage which rapidly leads to release of iron from intracellular proteins and the appearance of NPBI. Bone marrow, red blood cells, liver and kidney seem to be a likely source of NPBI. The observed high levels of NPBI may be a major causative determinant in chemotherapy-induced toxicity.

The incidence and the severity of chemotherapy-associated oral mucositis were determined in a retrospective analysis of 150 patients with various solid tumors. In addition, possible risk factors for the development of mucositis were identified. Patients were treated with chemotherapeutic regimens appropriate to tumor type and disease stage on an in- or outpatient basis. Mucositis was scored using the World Health Organization (WHO) criteria. Eighty-seven episodes of mucositis occurred in 47 (31%) patients. Twenty-six patients each experienced only one episode, whereas 21 patients had up to eight episodes of mucositis. The 1,281 chemotherapy cycles that have been analyzed included 87 cycles in which mucositis was observed. In 16 patients (11%) only slight oral mucosal changes were recorded (maximum WHO score 1), while 25 patients (17%) experienced mild to moderate mucositis (maximum WHO score 2), and in 6 patients (4%) mucositis was moderate to severe (maximum WHO score 3). No grade 4 mucositis developed. In 24 of the 47 patients with mucositis (51%) clinical features of acute pseudomembranous candidiasis were present. Leukopenia, leukopenic fever, and use of corticosteroids and central venous catheters were associated with the chemotherapy cycles with mucositis. Multivariate analysis identified the administration of paclitaxel, doxorubicin, or etoposide as independent risk factor (adjusted rate ratios 8.06, 7.35, and 6.70, respectively), whereas low body mass was associated with a slightly increased risk (adjusted rate ratio 0.92) for the development of mucositis. In conclusion, almost one-third of patients receiving chemotherapy for solid tumors experienced one or more episodes of mild to more severe oral mucositis, indicating that this is a frequent complication in such patients.

Thirty-three metastatic melanoma patients were vaccinated according to a phase I-II study with an allogeneic melanoma cell line that was genetically modified by transfection with a plasmid containing the gene encoding human interleukin 2 (IL-2). The cell line expresses the major melanoma-associated antigens and the HLA class I alleles HLA-A1, -A2, -B8, and Cw7. All patients shared one or more HLA class I alleles with this cell line vaccine. Patients were immunized by three vaccinations, each consisting of 60 X 106 irradiated (100 Gy) melanoma cells (secreting 120 ng of IL-2/106 cells/24 hr) administered subcutaneously at weekly intervals for 3 consecutive weeks. Side effects of treatment consisted of swelling of locoregional lymph nodes and induration at the site of injection, i.e., a delayed-type hypersensitivity (DTH) reaction. In three patients, vaccination induced inflammatory responses in distant metastases containing necrosis or apoptosis along with T cell infiltration. Apoptosis occurred only in Bcl-2-negative areas, not in Bcl-2-expressing parts of the metastases. Two other patients experienced complete or partial regression of subcutaneous metastases. Seven patients had protracted stabilization (4 to >46 months) of soft tissue metastases, including one patient who developed vitiligo after vaccination. Immune responses to the vaccine could be detected in 67% of the 27 patients measured. Vaccination was shown to induce a variable change in the number of anti-vaccine cytotoxic T lymphocytes (CTLs) in peripheral blood, which did not correlate with response to treatment. However, in two of five patients the frequency of anti-autologous tumor CTLs measured was significantly higher than before vaccination. This study demonstrates the feasibility, safety, and therapeutic potential of vaccination of humans with allogeneic, gene-modified tumor cells, and that frequencies of vaccine-specific CTLs among patient lymphocytes can be determined by using a modified limited dilution analysis (LDA).

Monoclonal antibodies toward rabbit liver cytochrome P-450 isozyme 6 (P-450 6) were used to identify several recombinant clones from a pBR322 cDNA library that express beta-lactamase-P-450 6 hybrid proteins. The nucleic acid sequence and predicted amino acid sequence of a rabbit P-450 6 cDNA shows a high degree of homology with rat P-450c and mouse P1-450. When used as a probe to rescreen the library, the P-450 6 cDNA hybridized to several heterologous classes of cDNAs. One such class was shown to encode P-450 4 by comparison of its predicted amino acid sequence to amino acid sequences of cysteine-containing tryptic peptides derived from P-450 4. DNA sequence analysis of a cDNA clone belonging to a third class demonstrated that it contained a 131-base-pair intervening sequencing when compared to the cDNA coding for P-450 6. This sequence corresponds in location to intron E of the rat P-450c gene. Blot-hybridization analysis demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) dramatically induced P-450 4 and 6 mRNAs, which differ in size. The sizes of these mRNAs differ from their analogs in the mouse as a result of divergence in the 3' untranslated portions of the mRNAs.

Recombinant human interleukin-2 (IL-2), administered to cancer patients by continuous intravenous (IV) infusion (3 x 10(6) U/m2/d), was found to induce the in vivo production of colony-stimulating factors (CSF). Plasma obtained from patients during IL-2 treatment stimulated in vitro colony formation of normal human bone marrow cells, depleted of mononuclear phagocytes and T lymphocytes. This colony-stimulating activity (CSA) was identified as IL-5, granulocyte-macrophage CSF (GM- CSF), and macrophage CSF (M-CSF), by the ability of specific antibodies against these factors to neutralize their effects. The presence of IL-2- induced GM-CSF and M-CSF was also demonstrated by specific radioimmunoassays. During IL-2 treatment, plasma also contained detectable levels of IL-6, which was measured in a bioassay. Using a cDNA-polymerase chain reaction (PCR) with specific primer sets for the various CSF, we showed that IL-2 treatment induced the expression of mRNA for M-CSF, GM-CSF, IL-3, and IL-5, but not for granulocyte CSF (G- CSF) in peripheral blood mononuclear cells, suggesting differential expression of CSF in vivo in response to IL-2. Furthermore, no negative regulators of hematopoiesis, such as interferon gamma (IFN-gamma) or tumor necrosis factor-alpha (TNF-alpha), were found in plasma. These data illustrate that in vivo administration of high-dose IL-2 may result in a stimulatory effect on hematopoiesis. The induction of detectable levels of IL-5 and GM-CSF in the circulation may explain the eosinophilia and neutrophilia observed in these patients.

In 7 of 37 patients with cutaneous melanoma, mutations in the N-ras gene were found. The primary tumors of these seven patients were exclusively localized on body sites continuously exposed to sunlight. Moreover, the ras mutations were all at or near dipyrimidine sites known to be targets of UV damage. Two primary tumors were biclonal with respect to ras mutation. An active role for UV irradiation in induction of the mutations is suggested.

Anthracyclines (ACs) cause cardiac side-effects which may result in cardiomyopathy. Identification of early biomarkers for this condition is thus useful. The N-terminal split product of proBrain Natriuretic Peptide (Nt-pBNP) may be such a biomarker and was included in an exploratory study to identify biomarkers for the cardiac side-effects of ACs.Three groups were studied: patients who completed a full course of AC-based chemotherapy (group I), patients starting AC-based therapy (group II) and a group of gender, age and BMI-matched controls (group III). Blood samples were taken and ECG recordings made. For group I, measurements were done from ≈1 month after the completion of therapy and 3 times thereafter and compared with the controls from whom samples were collected once. In group II samples were drawn pre-dose, at cessation, and after 24 hrs for each course. Nt-pBNP was measured in duplicate using a competitive EIA. Statistical analysis included paired and non-paired t-test to detect differences between the time points and groups.Mean (SD) Nt-pBNP in the patients who completed AC-therapy was 754 (177) pmol/L which was higher (p<0.01) than in the controls 588 (80) pmol/L. There was a tendency for Nt-pro-BNP to slightly decline over time in group I but this was not significant (p=0.21). In group II Ntpro-BNP increased during the 1stAC course from 530 (54) pmol/L pre-dose to 612 (52) pmol/L (p<0.05) immediately post-dose and further to 789 (124) pmol/L at 24 hours (p=0.001). The pre-dose value before the 3rdAC course was 721 (115) pmol/L and thereby higher than the pre-dose value before the 1stAC course (p=0.01), and increased to a maximum 1019 (227) pmol/L (p<0.05). Nt-pBNP seems a promising biomarker for the cardiac effects of ACs and will be explored further.Clinical Pharmacology & Therapeutics (2004) 75, P59–P59; doi: 10.1016/j.clpt.2003.11.224