Weekly AUC2 carboplatin in acquired platinum-resistant ovarian cancer with or without oral phenoxodiol, a sensitizer of platinum cytotoxicity: the phase III OVATURE multicenter randomized study.

BACKGROUND: Platinum-resistant ovarian cancer (PROC) constitutes a therapeutic dilemma with limited efficacy from traditional cytotoxic agents. Based on prior data suggesting that scheduling alterations of platinum would increase activity, the aim of the present study was to assess the potential therapeutic benefit of phenoxodiol (PXD), a novel biomodulator shown to have chemoresistance reversing potential, when combined with weekly AUC2-carboplatin in PROC patients. PATIENTS AND METHODS: A multicenter randomized double-blind placebo controlled phase-III-study was conducted to compare oral PXD plus AUC2-carboplatin (group 1) versus placebo plus AUC2-carboplatin (group 2) weekly in PROC patients. The primary end point was progression-free-survival (PFS). Secondary objectives included overall survival (OS), response rates, duration of response and quality of life. RESULTS: The study was terminated early 14 April 2009, after recruitment of 142 patients due to feasibility and recruitment challenges. A total of 142 patients were randomized. The groups were well balanced in terms of important baseline characteristics. The median PFS for group 1 was 15.4 weeks [95% confidence interval (CI) 11.1-21.0] versus 20.1 weeks for group 2 (95% CI = 13.1-33.4); P = 0.3. The objective response rate and median survival in group 1 versus group 2 was 0% versus 1% and 38.3 weeks (95% CI 32.0-45.3) versus 45.7 weeks (95% CI 35.6-58.0), respectively. PXD appeared to be well tolerated. The main reason for dose modification in both groups was hematologic toxicity. CONCLUSIONS: Orally delivered PXD showed no evidence of clinical activity, when combined with weekly AUC2-carboplatin in PROC. In addition, single-agent weekly AUC2-carboplatin appeared to be inactive by response criteria in a homogenously defined population of PROC. This has implications for the design of future studies.

Retrospective imaging audit and cost analysis of medical oncology inpatients admitted to Westmead Hospital.

BACKGROUND: Cancer patients often require complex and expensive admissions necessitating multiple investigations. We conducted an audit of cost of imaging performed on medical oncology inpatients in a teaching hospital in New South Wales. AIMS: Our overall aim was to assess cost and appropriateness of imaging studies in inpatients. METHODS: Data were collected on 219 consecutive evaluable inpatients admitted to Westmead Hospital (August-October 2012). A panel of oncology doctors assessed cost and appropriateness of imaging. RESULTS: The total expenditure for the cohort was $106,488.15 over 624 investigations (range: 0-26, median: two per admission). Of this sum, $8881.91 (8%) was deemed inappropriate. The most frequently ordered test was chest X-ray (251). Imaging cost per admission was $0-2478 (range), $324.95 (median), $486.99 (mean). Cost trended to increase with age of patient ($186.40 (18-40), $477.22 (41-65), $489.50 (66-75), $575.33 (>75) ). Mean cost was higher for patients treated with palliative ($493.98) vs curative ($307.59) intent. Mean cost was higher for patients consulted by palliative care and other subspecialties. There was variation of average cost by discharge destination - other hospital ($262.23), palliative care unit ($334.08), home ($480.84) and death ($769.93). Although imaging ordered was deemed overwhelmingly clinically appropriate, approximately $35,000/year is spent on inappropriate tests, mostly due to duplication or scans that could have been performed as an outpatient. CONCLUSION: Our audit supports that the current spending patterns on imaging within our department is predominantly appropriate and necessary. Duplication and expenditure may be reduced by improving electronic access from the ward to outpatient scan results.

A realist process evaluation of an intervention to promote competencies in interprofessional collaboration among interdisciplinary integrated care teams for older people: Study protocol.

Background: International policy is increasingly committed to placing interdisciplinary team-working at the centre of health and social care integration across the lifespan. The National Clinical Programme for Older People in Ireland has a critical role in the design and implementation of the National Older Person's Service Model, which aims to shift the delivery of care away from acute hospitals towards community-based care. Interdisciplinary Community Specialist Teams for older persons (CST-OPs) play an important role in this service model. To support the development of competencies for interprofessional collaboration and an interdisciplinary team-based approach to care integration, a culture shift will be required within care delivery. Design:This study builds upon a collaborative partnership project which co-designed a framework describing core competencies for interprofessional collaboration in CST-OPs. A realist-informed process evaluation of the framework will be undertaken as the competencies described in the framework are being fostered in newly developed CST-OPs under the national scale-up of the service model. Realist evaluation approaches reveal what worked, why it worked (or did not), for whom and under what circumstances. Three iterative and integrated work packages are proposed which combine multiple methods of data collection, analysis and synthesis. Prospective data collection will be undertaken within four CST-OPs, including qualitative exploration of the care experiences of older people and family carers. Discussion: The realist explanatory theory will provide an understanding of how interprofessional collaboration can be fostered and sustained in various contexts of care integration for older people. It will underpin curriculum development for team-based education and training of health and social care professionals, a key priority area in the national Irish health strategy. It will provide healthcare leaders with knowledge of the resources and supports required to harness the benefits of interprofessional collaboration and to realise the goals of integrated care for older people.

Implementing Integrated Care in Practice - Learning from MDTs Driving the Integrated Care Programme for Older Persons in Ireland.

The importance of multidisciplinary teams (MDTs) as critical implementation drivers emerged from this case study conducted with three pioneer sites implementing integrated care for older persons in Ireland as part of the Integrated Care Programme for Older Persons (ICPOP). We describe the practices of MDTs learning to deliver integrated care in service delivery settings, including the framework, resourcing, strategies, challenges and barriers they encounter. The study was conducted by a team of researchers in collaboration with ICPOP at both national programme and pioneer site levels. Qualitative methods of participant observation, workshopping, and documentary analysis were used to build a rich description, and using organisational and systems lenses identification of critical factors as both themes and resources for learning. The case study suggests the MDT is an essential driver of integrated care delivery. For example, ICPOP MDTs working across pioneer sites develop new service models and care opportunities, troubleshoot and challenge the systemic status quo, and disrupt professional silos. However, they also deliver on programme goals. Nonetheless, progress is constrained by organisational factors including fragmented funding structures, high turnover of senior level decision-makers, a lack of multiannual funding and complex professional arrangements. This study finds ICPOP offers practical and timely insight to inform health system reform. It embraces the complexity of delivery at national, local and community levels. The MDT emerges as an essential mechanism to manage such complexity and deliver on wider reform goals such as patient-centredness and timely access.

Operationalizing autonomy: solutions for mental health nursing practice.

The new Mental Health Act (2001) became a law on 1 November 2006. The new Act, reflective of international legislative norms, outlines an agenda for the mental health services in Ireland which, in part, aims to maximize patient autonomy. This paper seeks to contextualize autonomy within nurse-patient interactions in the mental health care setting. The acceptance of autonomy as an unconditional principle, as outlined within traditional bioethics, is challenged. The paper draws on the social critique of normative ethics and suggests an alternative framework within which to operationalize patient autonomy. The authors conclude that a broader, more contextualized perspective on autonomy would more suitably inform mental health nursing. Narrative ethics and a framework of 'protective responsibility' are offered as an alternative to more traditional approaches. Practice-based initiatives to maximize patient autonomy and facilitate-reasoned ethical decision making are outlined.

Combined reconstruction of chronic posterior cruciate ligament and posterolateral corner deficiency. A two- to nine-year follow-up study.

We report a retrospective analysis of the results of combined arthroscopically-assisted posterior cruciate ligament reconstruction and open reconstruction of the posterolateral corner in 19 patients with chronic (three or more months) symptomatic instability and pain in the knee. All the operations were performed between 1996 and 2003 and all the patients were assessed pre- and post-operatively by physical examination and by applying three different ligament rating scores. All also had weight-bearing radiographs, MR scans and an examination under anaesthesia and arthroscopy pre-operatively. The posterior cruciate ligament reconstruction was performed using an arthroscopically-assisted single anterolateral bundle technique and the posterolateral corner structures were reconstructed using an open Larson type of tenodesis. The mean follow up was 66.8 months (24 to 110). Pre-operatively, all the patients had a grade III posterior sag according to Clancy and demonstrated more than 20 degrees of external rotation compared with the opposite normal knee on the Dial test. Post-operatively, seven patients (37%) had no residual posterior sag, 11 (58%) had a grade I posterior sag and one (5%) had a grade II posterior sag. In five patients (26%) there was persistent minimal posterolateral laxity. The Lysholm score improved from a mean of 41.2 (28 to 53) to 76.5 (57 to 100) (p = 0.0001) and the Tegner score from a mean of 2.6 (1 to 4) to 6.4 (4 to 9) (p = 0.0001). We conclude that while a combined reconstruction of chronic posterior cruciate ligament and posterolateral corner instability improves the function of the knee, it does not restore complete stability.

Isolated erythroglycans have a high-affinity interaction with wheat germ agglutinin but are poorly accessible in situ.

The sugar and cell specificities of wheat germ agglutinin have been studied extensively. In particular, it is well established that wheat germ agglutinin will interact with highly sialylated glycoconjugates of the type carried by the erythrocyte glycoprotein, glycophorin (Adair, W.L. and Kornfeld, S. (1974) J. Biol. Chem. 249, 4696-4704). We have found that polylactosamines isolated from adult and fetal erythrocytes can have a high-affinity interaction with immobilized wheat germ agglutinin. In fact, this interaction is much stronger than the sialic acid-dependent interaction. Using flow microfluorimetry in conjunction with various serological and enzymatic pretreatments, we have measured the extent to which polylactosamines contribute to wheat germ agglutinin binding. We have found that most of the neuraminidase-resistant receptors on erythrocytes are polylactosamine in nature. However, this residual binding of wheat germ agglutinin to neuraminidase-treated erythrocytes is of much lower apparent affinity than the sialic acid-dependent interaction. The lower reactivity of polylactosamines at the erythrocyte surface suggests that these large glycans are actually poorly accessible.

Drug resistance in clinical practice: patterns of treatment failure in advanced breast and ovarian cancer.

We have analyzed the patterns of disease progression in patients with advanced breast and ovarian cancer receiving systemic therapy. Approximately 50% of patients developed progressive disease in a new, rather than a previously documented, disease site. Even when disease progressed in a previously involved disease site, in only half the cases was this identified as the bulk disease site before commencing treatment. The CNS was rarely a new site of disease progression in our patients, a finding that contrasts with a report that identified the CNS as the predominant new disease site in advanced breast cancer patients relapsing following a complete response. Progression of disease on second line treatment commonly occurred at sites of known disease. A number of factors influencing the pattern of disease progression have been examined. Disease progression on endocrine therapy tended to be more common in a previously involved disease site than in patients receiving cytotoxic therapy. There was a trend for patients who progressed within 6 months of chemotherapy to do so in an old site, whereas new disease sites predominated among those progressing later. Strategies for overcoming the causes of treatment failure should take account of the patterns of disease progression. Our results question the wisdom of always ceasing existing therapy when progressive disease is first documented.

Inhibition of ANKRD1 sensitizes human ovarian cancer cells to endoplasmic reticulum stress-induced apoptosis.

High expression of Ankyrin Repeat Domain 1 (ANKRD1) in ovarian carcinoma is associated with poor survival, and in ovarian cancer cell lines is associated with platinum resistance. Importantly, decreasing ANKRD1 expression using siRNA increases cisplatin sensitivity. In this study, we investigated possible mechanisms underlying the association of ANKRD1 with cisplatin response. We first demonstrated that cisplatin-induced apoptosis in ovarian cancer cell lines was associated with endoplasmic reticulum (ER) stress, evidenced by induction of Glucose-Regulated Protein 78 (GRP78), growth arrest- and DNA damage-inducible gene 153 (GADD153) and increased intracellular Ca(2+) release. The level of sensitivity to cisplatin-induced apoptosis was associated with ANKRD1 protein levels and poly (ADP-ribose) polymerase (PARP) cleavage. COLO 316 ovarian cancer cells, which express high ANKRD1 levels, were relatively resistant to cisplatin, and ER stress-induced apoptosis, whereas OAW42 and PEO14 cells, which express lower ANKRD1 levels, are more sensitive to ER stress-induced apoptosis. Furthermore, we show that overexpression of ANKRD1 attenuated cisplatin-induced cytotoxicity, and conversely siRNA knockdown of ANKRD1 sensitized ovarian cancer cells to cisplatin and ER stress-induced apoptosis associated with induction of GADD153, and downregulation of BCL2 and BCL-XL. Taken together, these results suggest that ANKRD1 has a significant role in the regulation of apoptosis in human ovarian cancer cells, and is a potential molecular target to enhance sensitivity of ovarian cancer to chemotherapy.

Continuous infusion of vincristine, ifosfamide and epirubicin over 6 weeks in treatment-resistant advanced breast cancer.

28 patients with recurrent advanced breast cancer were treated with a salvage regimen consisting of vincristine, epirubicin and ifosfamide/mesna (VIE). All patients had poor prognostic characteristics defined as relapse within 12 months of chemotherapy or as relapse within a radiotherapy field. Chemotherapy was infused continuously through a central venous catheter using a portable pump. Ifosfamide (3 g/m2) mixed with mesna (3 g/m2) was infused for 7 days followed by epirubicin (50 mg/m2) mixed with vincristine (1.5 mg/m2) over a further seven days and alternated for a total of 6 weeks. 9 of the 28 patients (32%) responded to VIE (six partial and three complete responses). This included 6 of the 18 patients (33%) who had previously received doxorubicin or mitoxantrone, 6 of the 17 patients (35%) who had an inoperable in-field relapse after radiotherapy for locally advanced cancer, and 5 of the 21 patients (24%) relapsing within 6 months of previous chemotherapy. Median duration of response and overall survival were 3.7 and 6.9 months, respectively. Myelotoxicity was mild. One patient had neutropenic sepsis, 3 patients ahd grade 3 nausea and vomiting and one patient developed paralytic ileus attributed to vincristine. Central venous catheter complications occurred in 12 of 33 catheters requiring removal in 6. Continuous infusional chemotherapy using vincristine, epirubicin and ifosfamide achieves a 32% overall response rate in treatment-resistant advanced breast cancer, and is associated with minimal toxicity and a short treatment period. VIE may be a suitable alternative to conventional chemotherapy.

Elevated germ cell markers in carcinoma of uncertain primary site do not predict response to platinum based chemotherapy.

We carried out a retrospective review of the medical records of patients with metastatic carcinoma of unknown primary and either raised alpha fetoprotein (AFP) or beta human chorionic gonadotrophin (beta HCG) over a period of 6 years at three teaching hospital oncology units to assess response to platinum based chemotherapy. 15 patients were identified who fitted these criteria. Of these, 3 received no treatment because of poor functional status, 2 patients received only radiotherapy for symptomatic disease and died within 3 months of diagnosis and 1 patient died 2 weeks after diagnosis having received his first cycle of cisplatin-based chemotherapy. 9 patients received at least 2 cycles of chemotherapy. A complete tumour response was seen in only one patient who presented with midline lymphadenopathy and remains disease-free 46 months after treatment. This presentation was consistent with disease already known to herald platinum sensitivity. In the other 8 patients, there was only one partial response that lasted 2 months. The median survival for this group of 9 patients was 4.5 months (range 3 to > 46 months). Our data do not support the postulate that elevated germ cell markers in patients with carcinoma of unknown primary predict a response to cisplatin based chemotherapy.

Heterogeneous repair of platinum-DNA adducts by protein extracts from mammalian tissues.

Cis-diamminedichloroplatinum (II) (cisplatin) is a mainstay of human cancer chemotherapy. In addition to its antitumour effects however, cisplatin is toxic to normal tissues, causing dose-limiting nephrotoxicity and neurotoxicity. On the other hand, myelosuppression is uncommon. In the light of data suggesting a role for DNA repair mechanisms as determinants of cellular cisplatin sensitivity, we postulated that varying DNA repair capacities between tissues could explain the patterns of organ toxicity seen in clinical practice. Using a novel cell-free assay of repair of cisplatin-DNA adducts, we find that the DNA repair capacity of protein extracts from different tissues varies significantly in our assay, but does not directly correlate with the organ toxicity profile of cisplatin.

A comparison of two quality-of-life questionnaires for cancer clinical trials: the functional living index--cancer (FLIC) and the quality of life questionnaire core module (QLQ-C30).

Choosing a measure instrument for a study raises the question of whether instruments designed for the same purpose produce the same results. We investigated this question for two instruments designed to measure subjective quality of life (QOL) in cancer clinical trials: the Functional Living Index-Cancer (FLIC) and the Quality of Life Questionnaire Core module (QLQ-C30). These were administered concurrently to 98 cancer patients. Four patient groups were defined: (1) well, no chemotherapy (n = 23); (2) adjuvant chemotherapy (n = 24); (3) stable disease, active chemotherapy (n = 24); (4) progressive disease (n = 27). Both instruments have global, role, social, emotional, pain, and nausea scales; QLQ-C30 also assesses physical function, cognitive function, and fatigue, while FLIC assesses hardship. Correlation analysis indicated convergent validity for the global, role, emotional, pain and nausea dimensions, but not the social dimension. Both instruments indicated that groups 1 and 2 had better QOL than group 4 in at least one dimension. However, different dimension-specific results meant that qualitatively different conclusions would have been drawn if either instrument had been used singly: FLIC indicated that group 1 had better role function that group 4 and suffered less hardship and that group 1 suffered less nausea than group 3, while the QLQ-C30 data indicated that group 2 had better physical function than group 4. The only consistent result was for pain: both instruments indicated group 4 had more pain than either groups 1 or 2. Thus the choice of QOL instrument for use in a particular trial will affect both the results and conclusions. It is important, therefore, to consider carefully which instrument is most likely to detect important differences relevant to the patients' lives in that setting.

Loss of allelic heterozygosity on distal chromosome 1p in Merkel cell carcinoma. A marker of neural crest origins?

The location of genes involved in tumor evolution has been inferred from experiments in which loss of constitutional heterozygosity has been detected in tumor DNA at high frequency in specific chromosome regions. For example, cytogenetic and molecular abnormalities on chromosome 1p have been reported in tumors such as malignant melanoma and neuroblastoma which arise in cells derived from embryonic neural crest tissue. To extend these observations, we have examined tumor DNA from three cases of Merkel cell carcinoma for evidence of loss of constitutional heterozygosity on the short arm of chromosome 1. In all three cases, heterozygous allelic deletions of varying extent on distal chromosome 1p were detected in tumor DNA. Comparisons with neural crest tumors suggest that loss of heterozygosity on distal chromosome 1p in Merkel cell tumors may be a marker of neural crest origin.

Carboplatin and paclitaxel interact antagonistically in a megakaryoblast cell line--a potential mechanism for paclitaxel-mediated sparing of carboplatin-induced thrombocytopenia.

PURPOSE: Clinical observation has shown that paclitaxel ameliorates the antiplatelet toxicity of carboplatin when the two drugs are combined, although antitumour activity and white cell toxicity are at least additive. We hypothesized that this is due to an interaction between the two drugs at the level of the platelet precursor. METHODS: We measured inhibition of growth of the megakaryoblast cell line MEG-01 following exposure to paclitaxel and carboplatin singly or combined. Drug interaction was assessed by median effect analysis. RESULTS: An antagonistic interaction was observed, and this was most marked at drug concentrations giving a low level of growth inhibition (P < 0.002, sign test). The interaction was not sequence-dependent. There was no significant difference in whole-cell accumulation of platinum or the amount of platinum adducts on DNA following combined treatment in comparison with carboplatin alone. CONCLUSIONS: These results provide the first evidence of an antagonistic interaction between paclitaxel and carboplatin in a platelet precursor and provide an explanation for the platelet-sparing effect of the combination of these chemotherapeutic agents. While the mechanisms underlying the interaction described in this report are yet to be fully elucidated, this study provides evidence that the antagonism between paclitaxel and carboplatin in MEG-01 cells is not due to reduced platination of DNA.

Parent training skills and methadone maintenance: clinical opportunities and challenges.

Children raised in substance abusing families show high rates of behavioural and emotional problems, in particular oppositional, defiant and non-compliant behaviours. While a range of social and individual factors correlate with poor parenting, it is often the quality of the parent-child relationship that mediates the effects of most other risk factors on child development. By addressing this relationship using behavioural family interventions, child behaviour problems have been reduced in multiple problem families. However, there has been little attempt to systematically evaluate such programs in substance abusing families. It is argued that methadone replacement programs provide a window of opportunity to deliver well-validated parent training programs that enhance the quality of parent-child relations. However, it is likely that such programs would need to be medium to long term and address issues beyond parent child relationships. How such interventions may be delivered and evaluated is discussed.

Scleroderma in association with the use of docetaxel (taxotere) for breast cancer.

The taxanes, paclitaxel (Taxol) and docetaxal (Taxotere), are a new class of anti-microtubule agents which have shown cytotoxic activity in a number of solid tumours. Phase I and II trials confirm that docetaxal is highly active in the treatment of metastatic breast cancer. Reported toxicities of docetaxel include, dose limiting neutropenia, alopecia, skin reactions and fluid retention. Here we report the first case of rapid onset, diffuse scleroderma-like illness, which occurred in a 59-year-old female receiving treatment with docetaxel for locally invasive and advanced metastatic breast cancer.

Establishment of an in vitro model for cisplatin resistance in human neuroblastoma cell lines.

Two unique cisplatin-resistant neuroblastoma (NB) cell lines have been derived from the established lines IMR-32 and SK-N-SH by treatment with escalating doses of cisplatin. IMR/CP.20 was 6.6-fold and SK/CP.15 was 3.8-fold more resistant to the cytotoxic effects of cisplatin than the parent lines. The parent SK-N-SH cells were 16.6-fold more resistant to the effects of cisplatin than IMR-32 cells. The cisplatin-resistant cell lines demonstrated alterations to their morphology, but there was no change in the cell growth characteristics of the resistant compared to the sensitive lines. Cytogenetic analysis revealed that clonal selection of parental subclones had occurred with additional chromosomal changes in both resistant lines. Both IMR/CP.20 and SK/CP.15 lines were cross-resistant to aphidicolin and to L-phenylalanine mustard. The IMR/CP.20 line was 7.3-fold more resistant to mitomycin C than the parent line. Neither cisplatin-resistant NB line was cross-resistant to 5-fluorouracil, etoposide or doxorubicin. All NB lines had low levels of DNA repair compared to HeLa or CHO-K1 cells. However, the IMR/CP.20 cell line showed a significantly higher ability to effect DNA repair than the parent IMR-32 line, indicating that the increased resistance to cisplatin observed in this line may, in part, be due to an enhanced DNA repair capacity.

Mechanisms determining sensitivity to cisplatin in three mutant Chinese hamster ovary cell lines.

To gain insight into factors determining the response of tumours to cisplatin, we studied pathways involved in resistance to cisplatin: drug uptake, cytoplasmic detoxification and DNA repair, in three cisplatin-sensitive Chinese hamster ovary (CHO)2 mutant cell lines. The mutant lines, CHO-MMC6, CHO-MMC1, CHO-MMS2, displayed inherent sensitivity to cisplatin (2.2, 4.1 and 10.6-fold, respectively) compared to the CHO-K1 line from which they were derived. CHO-MMS2 was the only mutant to show sensitivity to UV and this was slight (< 2-fold). None of the mutants displayed increased sensitivity to X-irradiation. The CHO-MMS2 cell line appeared to have multiple mechanisms involved in its sensitivity to cisplatin, including increased drug accumulation, decreased levels of glutathione and a decreased capacity for DNA repair. The CHO-MMC1 mutant demonstrated reduced ability for DNA repair in a host cell reactivation assay, but no difference in drug accumulation or glutathione levels compared to the parent. The CHO-MMC6 cell line was not defective in any of the mechanisms studied. These three mutant cell lines demonstrate that similar mechanisms may account for inherent sensitivity or resistance to cisplatin, and suggest that multiple mechanisms may determine the sensitivity of human tumours to cisplatin.

Adenocarcinoma of the duodenum with liver metastases. Complete remission and long-term survival with 5-fluorouracil chemotherapy--a case report.

Primary duodenal carcinoma is an uncommon malignancy, and experience with chemotherapeutic regimes in this condition is limited. We report a case of duodenal carcinoma with liver metastases in which complete remission was achieved with 5-fluorouracil chemotherapy. The patient remains well 30 months after completing treatment.