The effect of chemotherapy on health-related quality of life in mesothelioma: results from the SWAMP trial.

BACKGROUND: The effect of chemotherapy on health-related quality of life (HRQoL) in malignant pleural mesothelioma (MPM) is poorly understood. Patient-individualised prognostication and prediction of treatment response from chemotherapy is useful but little evidence exists to guide practice. METHOD: Consecutive patients with MPM who were fit for first-line chemotherapy with pemetrexed and cisplatin\carboplatin were recruited and followed up for a minimum of 12 months. This study focussed on the HRQoL outcomes of these patients using the EQ-5D, EORTC QLQ-C30 and LC13. RESULTS: Seventy-three patients were recruited of which 58 received chemotherapy and 15 opted for best supportive care (BSC). Compliance with HRQoL questionnaires was 98% at baseline. The chemotherapy group maintained HRQoL compared with the BSC group whose overall HRQoL fell (P=0.006) with worsening dyspnoea and pain. The impact of chemotherapy was irrespective of histological subtype although those with non-epithelioid disease had worse HRQoL at later time points (P=0.012). Additionally, those with a falling mesothelin or improvement on modified-RECIST CT at early follow-up had a better HRQoL at 16 weeks. CONCLUSIONS: HRQoL was maintained following chemotherapy compared with a self-selected BSC group. Once chemotherapy is initiated, a falling mesothelin or improved RECIST CT findings infer a quality-of-life advantage.

The South West Area Mesothelioma and Pemetrexed trial: a multicentre prospective observational study evaluating novel markers of chemotherapy response and prognostication.

BACKGROUND: Robust markers that predict prognosis and detect early treatment response in malignant pleural mesothelioma (MPM) would enhance patient care. METHODS: Consecutive patients with MPM who were considered fit for first-line chemotherapy were prospectively recruited. Patients of similar performance status opting for best supportive care were included as a comparator group. Baseline and interval CT, PET-CT and serum markers (mesothelin, fibulin-3 and neutrophil-lymphocyte ratio (NLR)) were obtained, and patients followed up for a minimum 12 months. FINDINGS: Seventy-three patients were recruited (58 chemotherapy/15 comparator arm). Baseline TGV (total glycolytic volume on PET-CT) was an independent predictor of worse overall survival (OS) (P=0.001). Change in interval TGV(baseline/after two cycles of chemotherapy) did not predict OS or chemotherapy response on CT. Baseline NLR<4 was an independent predictor of better OS (median survival 453 (IQR 272-576) days vs NLR⩾4, 257 (IQR 147-490), P=0.002). Although baseline serum mesothelin did not predict OS, a falling level at 8 weeks significantly predicted longer time to progression (TTP) (P<0.001). INTERPRETATION: Neutrophil-lymphocyte ratio and baseline TGV predict prognosis in malignant pleural mesothelioma (MPM), but PET-CT is unhelpful in monitoring chemotherapy response. Serum mesothelin is a useful early treatment response marker when measured serially during chemotherapy and may have a role in evaluating patients' treatment response.

Patients' experiences following breast cancer treatment: an exploratory survey of personal and work experiences of breast cancer patients from three European countries.

Improved treatments for early breast cancer have led to a significant increase in overall survival. While evidence regarding potential long-term sequelae of adjuvant treatments exists, relatively little research reports patients' own perceptions of change before and after adjuvant chemotherapy (AC). This study aimed to identify key ongoing issues associated with AC in daily life. An online survey developed for this study was completed by 198 women (mean age 49.7 years) in the UK, France and Germany who had AC 1-5 years previously for oestrogen receptor positive, HER2 negative early breast cancer. Women without AC and endocrine therapy, those treated with Trastuzumab or who had recurrent disease were excluded. A third of women who responded were currently unable to perform their former family role. The majority had needed support, particularly with child care, during treatment. While 54% were in full-time employment before diagnosis this had reduced to 32% following AC. Of those women still working, over half reported difficulties with tiredness or concentration. Most (85.8%) were satisfied with healthcare professionals' treatment information, but only 29.7% received information about returning to work. This exploratory survey highlights areas of women's lives affected 1-5 years following AC for early breast cancer. The impact on returning to work and issues surrounding childcare particularly, require further study.

Expert UK consensus on the definition of high risk of recurrence in HER2-negative early breast cancer: A modified Delphi panel.

BACKGROUND: There is currently no standardised definition for patients at high risk of recurrence of human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (eBC; stages 1-3) after surgery. This modified Delphi panel aimed to establish expert UK consensus on this definition, separately considering hormone receptor (HR)-positive and triple-negative (TN) patients. METHODS: Over three consecutive rounds, results were collected from 29, 24 and 22 UK senior breast cancer oncologists and surgeons, respectively. The first round aimed to determine key risk factors in each patient subgroup; subsequent rounds aimed to establish appropriate risk thresholds. Consensus was pre-defined as ≥70% of respondents. RESULTS: Expert consensus was achieved on need to assess age, tumour size, tumour grade, number of positive lymph nodes, inflammatory breast cancer and risk prediction tools in all HER2-negative patients. There was additional agreement on use of tumour profiling tests and biomarkers in HR-positive patients, and pathologic complete response (pCR) status in TN patients. Thresholds for high recurrence risk were subsequently agreed. In HR-positive patients, these included age <35 years, tumour size >5 cm (as independent risk factors); tumour grade 3 (independently and combined with other high-risk factors); number of positive nodes ≥4 (independently) and ≥1 (combined). For TN patients, the following thresholds reached consensus, both independently and in combination with other factors: tumour size >2 cm, tumour grade 3, number of positive nodes ≥1. CONCLUSIONS: The results may be a valuable reference point to guide recurrence risk assessment and decision-making after surgery in the HER2-negative eBC population.

The epidemiology of cervical spondylotic myelopathy.

OBJECTIVES: This is an observational study looking at the epidemiology of cervical spondylotic myelopathy of patients presenting to our hospital. MATERIALS AND METHODS: The notes and MRI scans of 41 patients presenting to the Leicester General Hospital with a clinical diagnosis of cervical myelopathy between January 2004 and December 2008 were reviewed retrospectively. RESULTS: Cervical myelopathy was found to be more common in male patients to the ratio of approximately 2.7:1, with an average age at diagnosis of 63.8 years. Multi-level disease was seen in the majority of patients, with C5/6 being the most commonly affected level. CONCLUSIONS: Cervical myelopathy predominantly affects men in their 7th decade of life. It is often a multi-level disease with C5/6 being the most commonly affected. It has little in common with cervical radiculopathy and is more analogous to lumber spinal stenosis.

The preferences and experiences of different bisphosphonate treatments in women with breast cancer.

OBJECTIVE: The objective of this study was to examine women's experiences with oral and intravenous (i.v.) bisphosphonate therapy, the impact that treatment had on bone pain and Quality of Life (QoL), and their preferences if choice were available between oral and i.v. administration. METHODS: This was a prospective study of women with metastatic breast cancer receiving either oral or i.v. bisphosphonate therapy. Semi-structured interview techniques and QoL questionnaires were employed. Participants in the study were interviewed three times, once in person and twice by telephone. RESULTS: A total of 79 patients from eight UK hospitals participated in the study; 35 were receiving oral bisphosphonate medication and 44 i.v. treatments. Self-reported adherence to oral therapy was good although 21% had chosen not to take their drugs at some time. Most had adapted their lifestyle to accommodate oral therapy with 29/37(74%) completely satisfied. However 9/37(24%) expressed dissatisfaction with constraints especially the time required to stand upright after taking their tablets. By 6 months 23/25 (91%) of patients receiving (i.v.) therapies were generally satisfied with the frequency and 22/25 (88%) with the convenience especially if given concurrently with chemotherapy. Overall 25/54 (46%) patients reported improved bone pain scores on the validated FACT-BP scale from baseline to 6 months. CONCLUSIONS: Both oral and i.v. therapies have disadvantages but were acceptable to most patients some of whom had reduced bone pain over time. More data regarding acceptability, adherence, and patients' preference for bisphosphonate therapies are required. Until randomised trials demonstrate superior efficacy for one mode of bisphosphonate therapy over another, we suggest offering patients a choice of bisphosphonate therapy.

Lumbar vertebral haemangioma causing pathological fracture, epidural haemorrhage, and cord compression: a case report and review of literature.

CONTEXT: Vertebral haemangiomas are recognized to be one of the commonest benign tumours of the vertebral column, occurring mostly in the thoracic spine. The vast majority of these are asymptomatic. Infrequently, these can turn symptomatic and cause neurological deficit (cord compression) through any of four reported mechanisms: (1) epidural extension; (2) expansion of the involved vertebra(e) causing spinal canal stenosis; (3) spontaneous epidural haemorrhage; (4) pathological burst fracture. Thoracic haemangiomas have been reported to be more likely to produce cord compression than lumbar haemangiomas. FINDINGS: A forty-nine year old male with acute onset spinal cord compression from a pathological fracture in a first lumbar vertebral haemangioma. An MRI delineated the haemangioma and extent of bleeding that caused the cord compression. These were confirmed during surgery and the haematoma was evacuated. The spine was instrumented from T12 to L2, and a cement vertebroplasty was performed intra-operatively. Written consent for publication was obtained from the patient. CLINICAL RELEVANCE: The junctional location of the first lumbar vertebra, and the structural weakness from normal bone being replaced by the haemangioma, probably caused it to fracture under axial loading. This pathological fracture caused bleeding from the vascularized bone, resulting in cord compression.

A prospective randomised phase II trial of thalidomide with carboplatin compared with carboplatin alone as a first-line therapy in women with ovarian cancer, with evaluation of potential surrogate markers of angiogenesis.

OBJECTIVES: To compare the safety and efficacy of thalidomide in combination with carboplatin to carboplatin alone as a first-line therapy in women with ovarian cancer and to evaluate the anti-angiogenic effects of thalidomide by measurement of surrogate markers of angiogenesis. METHODS: Forty patients with Stage IC-IV ovarian cancer were randomly assigned to receive either carboplatin (AUC 7) intravenously every four weeks for up to six doses (n = 20) or carboplatin at the same dose and schedule, plus thalidomide 100 mg orally daily for six months (n = 20). RESULTS: After median follow-up of 1.95 years, there was no difference in the overall response rate (90% in carboplatin arm, 75% in combination arm; p = 0.41). Increased incidence of symptoms of constipation, dizziness, tiredness and peripheral neuropathy was observed in the combination arm. There was a significant fall in CA-125 and E-selectin in both arms after treatment and VCAM-1 in the carboplatin arm. No significant difference between the two arms was observed in any of the markers analysed. CONCLUSIONS: In our trial the addition of thalidomide to carboplatin was well tolerated with no increased efficacy. The fall in some of the angiogenic markers in both groups may reflect tumour response rather than any specific anti-angiogenic effect of thalidomide.

Treating Brain Metastases from Breast Cancer: Outcomes after Stereotactic Radiosurgery.

AIMS: Stereotactic radiosurgery (SRS) is an alternative to surgery or whole brain radiotherapy for the control of single or multiple brain metastases in patients with breast cancer. To date, there is no clear consensus on factors that might predict overall survival following SRS. The aim of this study was to assess the overall survival of breast cancer patients with brain metastases treated with SRS at a single centre and to examine the factors that might influence survival. MATERIALS AND METHODS: A retrospective analysis of consecutive patients with breast cancer and brain metastases, considered suitable for SRS by the regional neuro-oncology multidisciplinary team. All patients were treated at a single National Health Service centre. RESULTS: In total, 91 patients received SRS between 2013 and 2017, of whom 15 (16.5%) were alive at the time of analysis. The median overall survival post-SRS was 15.7 months (interquartile range 7.7-23.8 months) with no significant effect of age on survival (67 patients ≤ 65 years, 16.3 months; 26 patients > 65 years, 11.4 months, P = 0.129). The primary tumour receptor status was an important determinant of outcome: 31 oestrogen receptor positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) patients had a median overall survival of 13.8 months, 14 ER+/HER2+ patients had a median overall survival of 21.4 months, 30 ER-/HER2+ patients had a median overall survival of 20.4 months and 16 patients with triple negative breast cancer (TNBC) had a median overall survival of 8.5 months. A larger total volume of tumour treated (>10 cm3), but not the number of individual metastases treated, was associated with worse survival (P = 0.0002) in this series. Patients with stable extracranial disease at the time of SRS had improved overall survival compared with those with progressive extracranial disease (30 patients stable extracranial disease overall survival = 20.1 months versus 33 patients progressive extracranial disease overall survival = 11.4 months; P = 0.0011). Seventeen patients had no extracranial disease at the time of SRS, with a median overall survival of 13.1 months. CONCLUSIONS: This single-centre series of consecutive patients with brain metastases from breast cancer, treated with SRS, had a similar overall survival compared with previous studies of SRS. TNBC and ER+/HER2- histology, metastatic volumes >10 cm3 and progressive extracranial disease at the time of SRS were associated with worse survival.

Dupuytren's contracture: an audit of the outcomes of surgery.

This multi-centre postal questionnaire study was conducted by the Audit Committee of the BSSH to assess the outcomes of surgery for Dupuytren's Contracture using subjective data provided by 1177 patients at a mean follow-up of 27 (SD 8) months after surgery. Surgery for Dupuytren's contracture achieved a high rate of full, or almost full, correction in 826 patients (75%) but had a high incidence of post-operative patient-reported complications of 46%. A higher complication rate was seen in those patients with worse initial deformities. The rate of contracture recurrence or persistence was 158 of 1037 (15%). The severity of contracture correlated with the final hand function measured using the PEM score. Recurrence was more common in patients with greater initial deformity. Recurrence was less common if good correction was achieved at surgery. The relevance and limitations of this data are discussed.

Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C.

PURPOSE: N-Benzoyl staurosporine (PKC412) is a protein kinase C inhibitor with antitumor activity in laboratory models. We determined the toxicity of oral PKC412 administered daily for repeat cycles of 28 days. PATIENTS AND METHODS: Thirty-two patients with advanced solid cancers were treated at seven dose levels (12.5 to 300 mg daily) for a total of 68 cycles. RESULTS: The most frequent treatment-related toxicities were nausea, vomiting, fatigue, and diarrhea. At the two top dose levels (225 and 300 mg/d), 15 of 16 patients experienced nausea/vomiting (common toxicity criteria [CTC], version 1), grade 2 in nine of 16 and grade 3 in three of 16 patients; and six of 16 patients developed CTC grade 2 diarrhea. After 1 month of treatment, there were significant reductions in circulating lymphocyte (P <.02) and monocyte (P <.01) counts in patients receiving doses > or = 100 mg/d. Nevertheless, only two patients developed myelosuppression (both grade 2). Of two patients with progressive cholangiocarcinoma, one attained stable disease lasting 4.5 months and one a partial response lasting 4 months. There was a linear relationship between PKC412 dose and area under the curve (0-24 hours) and maximum plasma concentration with marked interpatient variability. The estimated median elimination half-life was 1.6 days (range, 0.9 to 4.0 days), and a metabolite with a median half-life of 36 days was detected. Steady-state PKC412 plasma levels at the top three dose cohorts (150 to 300 mg) were five to 10 times the cellular 50% inhibitory concentration for PKC412 of 0.2 to 0.7 micromol/L. CONCLUSION: PKC412 can be safely administered by chronic oral therapy, and 150 mg/d is suitable for phase II studies. The pharmacokinetics and lack of conventional toxicity indicate that pharmacodynamic measures may be additionally needed to optimize the drug dose and schedule.

Phase I study of the novel cyclic AMP (cAMP) analogue 8-chloro-cAMP in patients with cancer: toxicity, hormonal, and immunological effects.

The cyclic AMP (cAMP)-dependent protein kinase regulatory subunit RI is overexpressed in cancer cells. 8-Chloro-cAMP (8-Cl-cAMP) is an RII site-specific analogue that down-regulates RI and inhibits the growth of a wide range of cancer cells in vitro and in vivo. We performed a Phase I trial of 8-Cl-cAMP in 32 patients with malignancies that were refractory to standard treatments. 8-Cl-cAMP was initially given in a 1-month cycle by constant infusion at 0.005 mg/kg/h for 21 days, followed by 1 week of rest. The dose was escalated to 0.045 mg/kg/h, but hypercalcemia became the dose-limiting toxicity. The length of drug administration was, therefore, reduced to 5 days per week for the first 3 weeks of the cycle, but it was not possible to increase the drug dose without producing hypercalcemia. Hence, the length of drug administration was reduced to 3 days per week for the first 3 weeks of the cycle. The maximum tolerated dose for this regimen was 0.15 mg/kg/h, and the dose-limiting toxicities were reversible hypercalcemia and hepatotoxicity. Stable disease for > or =4 months was observed in two patients treated at > or =0.045 mg/kg. cAMP-dependent protein kinase is involved in hormone- and cytokine-mediated signaling, and so representative hormone, cytokine, and peripheral lymphocyte subsets were measured. The drug had a parathyroid hormone-like effect on calcium homeostasis and significantly increased circulating luteinizing hormone and 17-hydoxyprogesterone levels (P < 0.02 and P < 0.0006, respectively). We conclude that 8-Cl-cAMP is well tolerated without attendant myelotoxicity, and in this study, it was associated with biological effects. In Phase II studies, a dose of 0.11 mg/kg/h for 3 days per week would be appropriate.

Phase I study of intrapleural batimastat (BB-94), a matrix metalloproteinase inhibitor, in the treatment of malignant pleural effusions.

Tumor cells and associated stromal cells secrete matrix metalloproteinases (MMPs), contributing to invasion, angiogenesis, and metastasis. Batimastat (BB-94) is a broad-spectrum MMP inhibitor that causes resolution of ascites and/or tumor growth delay in animal models of breast, ovarian, and colorectal cancer. We recruited 18 patients with cytologically positive malignant pleural effusions into a Phase I study of intrapleural BB-94. Three patients received single doses of BB-94 at each dose level: 15, 30, 60, 105, 135, and 300 mg/m2. Two patients were retreated with a second course at 60 and 105 mg/m2. BB-94 was detectable in plasma 1 h after intrapleural administration, and peak levels of 20-200 ng/ml occurred after 4 h to 1 week. BB-94 persisted in the plasma for up to 12 weeks, at levels exceeding the IC50s for target MMPs. Peak values were higher, and persistence in the plasma was longer after higher doses of BB-94. The treatment was well tolerated. Toxic effects included low-grade fever for 24-48 h (6 of 18 patients, 33%) and reversible asymptomatic elevation of liver enzymes (8 patients, 44%). Toxicity seemed unrelated to BB-94 dose or plasma levels. Sixteen patients evaluable for response required significantly fewer pleural aspirations in the 3 months after BB-94 compared with the 3 months before. Seven patients (44%) required no further pleural aspiration until death/last follow-up. After 1 month, patients treated with 60-300 mg/m2 BB-94 had significantly better dyspnea scores, indicating improved exercise tolerance, compared with baseline scores the day after BB-94. The maximum tolerated intrapleural dose remains to be defined, but it is clear that intrapleural BB-94 is well tolerated, with evidence of local activity.

A phase II study of razoxane, an antiangiogenic topoisomerase II inhibitor, in renal cell cancer with assessment of potential surrogate markers of angiogenesis.

Renal cell carcinoma (RCC) is an angiogenic tumor resistant to standard cytotoxic chemotherapeutic agents. Although often responsive to immunomodulatory agents including interleukin 2 and IFN-alpha, the overall results in randomized Phase III studies are disappointing with only modest improvements in overall survival. This Phase II study evaluated the efficacy and tolerability of razoxane, an antiangiogenic topoisomerase II inhibitor, in 40 patients (32 men, 8 women; age: range, 31-76 years; median, 58 years) with inoperable RCC. Twenty patients received razoxane 125 mg p.o., twice a day for 5 days each week for 8 weeks (one cycle). This was repeated in patients with stable disease (StD), but was discontinued after 16 weeks if there was no evidence of an objective response. Because minimal toxicity was seen, subsequent patients (n = 20) were treated until progressive disease (PD) was documented. Of 38 evaluable patients, 11 (29%) had StD for a minimum of 4 months, and the remainder had PD. Median overall survival was 7.3 months. Duration of survival was significantly better in patients with StD compared with those with PD (P = 0.003). The effect of treatment on six potential surrogate serum/plasma (vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), urokinase plasminogen activator soluble receptor (uPAsr), E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and von Willebrand's factor (vWF) and two urinary (VEGF and bFGF) markers of angiogenesis was evaluated before and after 1 cycle of treatment. Pretreatment serum VEGF and E-selectin levels above the median value were associated with a poor prognosis. Serum VCAM-1 levels and urinary VEGF levels rose significantly after one cycle in patients with PD but not in those with StD. Serum VEGF, bFGF, VCAM-1 and vWF, plasma uPAsr and urinary bFGF levels were significantly higher in PD patients compared with StD patients before and/or after 1 cycle of treatment. In conclusion, razoxane is an antiangiogenic agent that has minimal toxicity and that requires further evaluation in combination with other active agents in the treatment of RCC. Surrogate serum and urinary markers of angiogenesis may have a role to play in predicting disease response and overall survival in RCC.

Phase II study of exatecan mesylate (DX-8951f) as first line therapy for advanced non-small cell lung cancer.

BACKGROUND: Exatecan mesylate (DX-8951f) is a water soluble analogue of camptothecin that inhibits topoisomerase I. This multi-centre phase II study evaluated the activity of single agent exatecan in previously untreated patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with histologically or cytologically proven stage IIIb or IV NSCLC were treated with exatecan 0.5 mg/m(2) per day by 30 min intra-venous (i.v.) infusion for 5 days every 3 weeks to a maximum of six cycles. Measurable disease was documented prior to study entry and patients were re-staged every two cycles. Pharmacokinetic (PK) sampling was performed during cycle one. RESULTS: 39 patients (32 patients ECOG performance status 0 or 1; 29 male and ten female; mean age 63 years) were entered into the study. Thirty-three completed at least two cycles of exatecan and 11 completed six cycles. Two patients (5.1%, 95% C.I. 0.3-21.3%) had a partial response, 7 (18.0%) minor response and 8 (20.5%) stable disease. Median time to tumour progression (TTP) was 88 days and median overall survival 262 days. The main toxicity was reversible neutropenia. PK analysis of exatecan demonstrated a mean clearance of 2.28 l/h per m(2), volume of distribution 18.2 l/m(2) and mean elimination half-life of 7.9 h. CONCLUSIONS: Exatecan mesylate has limited activity in advanced NSCLC and is not recommended for further evaluation as a single agent in this tumour type. PK data from this trial supports results established in phase I studies.

Evaluation of toremifene for reversal of multidrug resistance in renal cell cancer patients treated with vinblastine.

PURPOSE: Expression of P-glycoprotein (Pgp), which confers the multidrug resistance (MDR) phenotype, is thought to contribute to the insensitivity of renal cell cancer (RCC) to chemotherapy. The development of Pgp inhibitors for clinical application has been hampered by unacceptable toxicity at doses required to achieve adequate cellular concentration. Toremifene is able to reverse MDR and sensitise RCC to vinblastine in vitro. However, in vivo toremifene is tightly bound to serum proteins, in particular the acute phase protein alpha1-acid glycoprotein (AAG), which may limit tissue availability. In this phase I-II study we assessed the tolerability of short courses of high dose toremifene in combination with vinblastine and evaluated the key determinants of MDR reversal in vivo. METHODS: Twenty-seven patients with metastatic RCC received escalating doses of oral toremifene for 3 days every 2 weeks in combination with vinblastine 6 mg/m2 i.v. on day 3 of each cycle. The serum concentration of toremifene, its metabolites and AAG were measured and the effect of patients' serum on inhibition of Pgp in vitro was determined. RESULTS: Twenty-six patients were evaluable for response. Eight patients (31%) had stable disease and 18 patients (69%) progressive disease. The mean serum concentration of toremifene at 780 mg daily for 3 days was 7.82 microM [standard deviation (SD) 2.48, range 2.50 to 14.70], which exceeds that known to reverse MDR in vitro. The serum concentration of the major metabolite of toremifene, N-demethyltoremifene, which also reverses MDR, was 5.13 microM (SD 1.78, range 1.80 to 9.00). In 60% of patients the pre-treatment AAG concentration was above that known to block the effects of toremifene in vitro. However, addition of serum from patients on toremifene to MCF-7 adr cells in vitro inhibited Pgp-mediated efflux of rhodamine 123. CONCLUSIONS: We have shown that short course, high-dose toremifene in combination with vinblastine is generally well tolerated and that the concentration of toremifene required to reverse MDR in vitro is achievable in vivo.

Evaluation of the alkaline comet assay and urinary 3-methyladenine excretion for monitoring DNA damage in melanoma patients treated with dacarbazine and tamoxifen.

PURPOSE: To develop, using dacarbazine as a model, reliable techniques for measuring DNA damage and repair as pharmacodynamic endpoints for patients receiving chemotherapy. METHODS: A group of 39 patients with malignant melanoma were treated with dacarbazine 1 g/m(2) i.v. every 21 days. Tamoxifen 20 mg daily was commenced 24 h after the first infusion and continued until 3 weeks after the last cycle of chemotherapy. DNA strand breaks formed during dacarbazine-induced DNA damage and repair were measured in individual cells by the alkaline comet assay. DNA methyl adducts were quantified by measuring urinary 3-methyladenine (3-MeA) excretion using immunoaffinity ELISA. Venous blood was taken on cycles 1 and 2 for separation of peripheral blood lymphocytes (PBLs) for measurement of DNA strand breaks. RESULTS: Wide interpatient variation in PBL DNA strand breaks occurred following chemotherapy, with a peak at 4 h (median 26.6 h, interquartile range 14.75-40.5 h) and incomplete repair by 24 h. Similarly, there was a range of 3-MeA excretion with peak levels 4-10 h after chemotherapy (median 33 nmol/h, interquartile range 20.4-48.65 nmol/h). Peak 3-MeA excretion was positively correlated with DNA strand breaks at 4 h (Spearman's correlation coefficient, r=0.39, P=0.036) and 24 h (r=0.46, P=0.01). Drug-induced emesis correlated with PBL DNA strand breaks (Mann Whitney U-test, P=0.03) but not with peak 3-MeA excretion. CONCLUSIONS: DNA damage and repair following cytotoxic chemotherapy can be measured in vivo by the alkaline comet assay and by urinary 3-MeA excretion in patients receiving chemotherapy.

Blood sampling techniques for lactate and pyruvate estimation: a reappraisal.

The effects of venestasis and hand exercise on antecubital vein blood lactate and pyruvate concentrations have been re-examined. The results show that venestasis for up to 5 min has no effect, while hand exercise for as little as 20 s causes a marked increase in blood lactate and pyruvate concentrations. The implications of these findings are discussed.

The weekend effect: short-term mortality following admission with a hip fracture.

We retrospectively reviewed 2989 consecutive patients with a mean age of 81 (21 to 105) and a female to male ratio of 5:2 who were admitted to our hip fracture unit between July 2009 and February 2013. We compared weekday and weekend admission and weekday and weekend surgery 30-day mortality rates for hip fractures treated both surgically and conservatively. After adjusting for confounders, weekend admission was independently and significantly associated with a rise in 30-day mortality (odds ratio (OR) 1.4, 95% confidence interval (CI) 1.02 to 1.9; p = 0.039) for patients undergoing hip fracture surgery. There was no increase in mortality associated with weekend surgery (OR 1.2, 95% CI 0.8 to 1.7; p = 0.39). All hip fracture patients, whether managed surgically or conservatively, were more likely to die as an inpatient when admitted at the weekend (OR 1.4, 95% CI 1.02 to 1.80; p = 0.032), despite our unit having a comparatively low overall inpatient mortality (8.7%). Hip fracture patients admitted over the weekend appear to have a greater risk of death despite having a consultant-led service.