Implications of subcutaneous or intravenous delivery of trastuzumab: further insight from patient interviews in the PrefHer study

BACKGROUND: The 2 Cohort randomised PrefHer trial examined the preferences of HER2+ve primary breast cancer patients for intravenous (IV) or subcutaneous (SC) delivery of trastuzumab via a Single Injectable Device (SID) or hand-held syringe (HHS). The novel approach and design of the study permitted an in-depth exploration of patients' experiences, the impact that different modes of delivery had on patients' well-being and implications for future management. METHODS: The preferences, experiences and general comments of patients in the PrefHer study were collected via specific semi-structured interview schedules. Exploratory analyses of data were conducted using standard methodology. The final question invited patients to make further comments, which were divided into 9 thematic categories - future delivery, compliments, time/convenience, practical considerations, pain/discomfort, study design, side-effects, psychological impact, and perceived efficacy. RESULTS: 267/467 (57%) patients made 396 additional comments, 7 were neutral, 305 positive and 86 negative. The three top categories generating the largest number of comments were compliments and gratitude about staff and being part of PrefHer (75/396; 19%), the potential future delivery of SC trastuzumab (73/396; 18%), and practical considerations about SC administration (60/396; 15%). CONCLUSIONS: Eliciting patient preferences about routes of administration of drugs via comprehensive interviews within a randomised cross-over trial yielded rich and important information. The few negative comments made demonstrated a need for proper staff training in SC administration Patients were grateful to have been part of the trial, and would have liked to continue with SC delivery. The possibility of home administration in the future also seemed acceptable. EUDRACT NUMBER: 2010-024099-25

Genesis of oceanic oxide gabbros and gabbronorites during reactive melt migration at transform walls (Doldrums Megatransform System; 7-8°N Mid-Atlantic Ridge)

The Doldrums Megatransform System (~7-8°N, Mid-Atlantic Ridge) shows a complex architecture including four intra-transform ridge segments bounded by five active transform faults. Lower crustal rocks are exposed along the Doldrums and Vernadsky transform walls that bound the northernmost intra-transform ridge segment. The recovered gabbros are characterized by variably evolved chemical compositions, ranging from olivine gabbros to gabbronorites and oxide gabbros, and lack the most primitive gabbroic endmembers (troctolites, dunites). Notably, the numerous recovered gabbronorites show up to 20 vol% of coarse-grained orthopyroxene. Although covariations in mineral and bulk-rock chemical compositions of the olivine and oxide gabbros define trends of crystallization from a common parental melt, the gabbronorites show elevated light over heavy rare earth elements (LREE/HREE) ratios in both bulk-rock and mineral compositions. These features are not consistent with a petrological evolution driven solely by fractional crystallization, which cannot produce the preferential enrichments in highly incompatible elements documented in the orthopyroxene-bearing lithologies. We suggest that gabbronorites crystallized from evolved melts percolating and partly assimilating a pre-existing olivine gabbro matrix. Saturation in orthopyroxene and selective enrichments in LREE relative to M-HREE are both triggered by an increase in assimilated crystal mass, which ranges from negligible in the oxide-gabbros to abundant in the gabbronorites. This melt-rock reaction process has been related to lateral melt migration beneath ridge-transform intersections, where variably evolved melts injected from the peripheral parts of the melting region towards the transform zone may interact with a gabbroic crystal mush to form abundant oxide-bearing gabbronoritic associations

Crustal Contamination and Hybridization of an Embryonic Oceanic Crust during the Red Sea Rifting (Tihama Asir Igneous Complex, Saudi Arabia)

The Red Sea rift system represents a key case study of the transition from a continental to an oceanic rift. The Red Sea rifting initiated in Late Oligocene to Early Miocene (24-23 Ma) and was accompanied by extensive magmatism throughout the rifted basin, from Afar and Yemen to northern Egypt. Here, we present a petrological and geochemical study of two gabbro bodies and associated basalts from the Tihama Asir igneous complex, which formed at 24-20 Ma within the rifted Arabian-Nubian Shield (ANS). The Tihama Asir is therefore an ideal location to study the initial phase of syn-rift magmatism and its influence on the geodynamic evolution of the Red Sea rift system. The most primitive olivine gabbros present modal, bulk and mineral compositions consistent with formation from Mid-Ocean Ridge Basalt (MORB)-type parental melts, whereas the evolved olivine-free gabbros and oxide-bearing gabbros show saturation of phlogopite and a crystal line of descent diverging from fractional crystallization trends. In detail, whole-rock and mineral compositions in the most evolved lithologies show high Light over Middle Rare Earth Elements (LREE/MREE) ratios (La-N/Sm-N = 0.89-1.31) and selective enrichments in Sr, K and highly incompatible elements (Rb, Ba, U, Th). We relate these geochemical characteristics to a process of progressive assimilation of host continental crust during the emplacement of the gabbroic plutons. Interestingly, high LREE/MREE ratios (La-N/Sm-N = 1.45-4.58) and high Rb, Ba, Th and U contents also characterize the basaltic dike swarms associated to the gabbros. Incompatible trace element compositions of these basalts approach those of the melts that formed the most hybridized gabbros. Therefore, we propose that the dike swarms represent melts partially contaminated by assimilation of continental crust material, extracted from the underlying gabbroic crystal mush. Our results suggest that early syn-rift magmatism led to the partial replacement of the thinned continental crust by MORB-type gabbroic bodies, in turn suggesting that oceanic magmatism started prior to continental break-up. Extensive syn-rift magmatism is consistent with the interpretation of the southern Red Sea rift system as a volcanic rifted margin. One possible implication of this study is that extensive but diffuse syn-rift magmatism possibly hampered continental break-up, leading to a protracted rifting stage

Orbital Interaction Mechanisms of Conductance Enhancement and Rectification by Dithiocarboxylate Anchoring Group

We study computationally the electron transport properties of dithiocarboxylate terminated molecular junctions. Transport properties are computed self-consistently within density functional theory and nonequilibrium Green's functions formalism. A microscopic origin of the experimentally observed current amplification by dithiocarboxylate anchoring groups is established. For the 4,4'-biphenyl bis(dithiocarboxylate) junction, we find that the interaction of the lowest unoccupied molecular orbital (LUMO) of the dithiocarboxylate anchoring group with LUMO and highest occupied molecular orbital (HOMO) of the biphenyl part results in bonding and antibonding resonances in the transmission spectrum in the vicinity of the electrode Fermi energy. A new microscopic mechanism of rectification is predicted based on the electronic structure of asymmetrical anchoring groups. We show that the peaks in the transmission spectra of 4'-thiolato-biphenyl-4-dithiocarboxylate junction respond differently to the applied voltage. Depending upon the origin of a transmission resonance in the orbital interaction picture, its energy can be shifted along with the chemical potential of the electrode to which the molecule is more strongly or more weakly coupled

Electronic patient self-assessment and management (SAM): a novel framework for cancer survivorship

<p>Abstract</p> <p>Background</p> <p>We propose a novel framework for management of cancer survivorship: electronic patient Self-Assessment and Management (SAM). SAM is a framework for transfer of information to and from patients in such a way as to increase both the patient's and the health care provider's understanding of the patient's progress, and to help ensure that patient care follows best practice.</p> <p>Methods</p> <p>Patients who participate in the SAM system are contacted by email at regular intervals and asked to complete validated questionnaires online. Patient responses on these questionnaires are then analyzed in order to provide patients with real-time, online information about their progress and to provide them with tailored and standardized medical advice. Patient-level data from the questionnaires are ported in real time to the patient's health care provider to be uploaded to clinic notes. An initial version of SAM has been developed at Memorial Sloan-Kettering Cancer Center (MSKCC) and the University of California, San Francisco (UCSF) for aiding the clinical management of patients after surgery for prostate cancer.</p> <p>Results</p> <p>Pilot testing at MSKCC and UCSF suggests that implementation of SAM systems are feasible, with no major problems with compliance (> 70% response rate) or security.</p> <p>Conclusion</p> <p>SAM is a conceptually simple framework for passing information to and from patients in such a way as to increase both the patient's and the health care provider's understanding of the patient's progress, and to help ensure that patient care follows best practice.</p

Evaluation of Phage Display Discovered Peptides as Ligands for Prostate-Specific Membrane Antigen (PSMA)

The aim of this study was to identify potential ligands of PSMA suitable for further development as novel PSMA-targeted peptides using phage display technology. The human PSMA protein was immobilized as a target followed by incubation with a 15-mer phage display random peptide library. After one round of prescreening and two rounds of screening, high-stringency screening at the third round of panning was performed to identify the highest affinity binders. Phages which had a specific binding activity to PSMA in human prostate cancer cells were isolated and the DNA corresponding to the 15-mers were sequenced to provide three consensus sequences: GDHSPFT, SHFSVGS and EVPRLSLLAVFL as well as other sequences that did not display consensus. Two of the peptide sequences deduced from DNA sequencing of binding phages, SHSFSVGSGDHSPFT and GRFLTGGTGRLLRIS were labeled with 5-carboxyfluorescein and shown to bind and co-internalize with PSMA on human prostate cancer cells by fluorescence microscopy. The high stringency requirements yielded peptides with affinities KD∼1 μM or greater which are suitable starting points for affinity maturation. While these values were less than anticipated, the high stringency did yield peptide sequences that apparently bound to different surfaces on PSMA. These peptide sequences could be the basis for further development of peptides for prostate cancer tumor imaging and therapy. © 2013 Shen et al

No man’s land: information needs and resources of men with metastatic castrate resistant prostate cancer

The majority of men treated for prostate cancer will eventually develop castrate resistant disease (CRPC) with metastases (mCRPC). There are several options for further treatment: chemotherapy, third-line hormone therapy, radium, immunotherapy and palliation. Current ASCO guidelines for survivors of prostate cancer recommend that an individual’s information needs at all stages of disease are assessed, and that patients are provided with or referred to the appropriate sources for information and support. Earlier reviews have highlighted the dearth of such services and we wished to see if the situation had improved more recently. Unfortunately we conclude that there is still a lack of good quality congruent information easily accessible specifically for men with mCRPC and insufficient data regarding the risks, harms and benefits of different management plans. More research providing a clear evidence base about treatment consequences using patient reported outcome measures is required

Claimed Co-ethnics and Kin-State Citizenship in Southeastern Europe

The paper introduces the often neglected concept of 'claimed co-ethnics' in the analysis of citizenship policies. It argues that this is an interstitial category that further complicates the triadic nexus between national minorities, nationalising states and kin-states. The 'claimed co-ethnics' are defined as people who are recognised by the citizenship (or ethnizenship) conferring state as belonging to its main ethnic group, although they themselves do not embrace that definition. In addition to bringing the issue of claimed co-ethnics into focus, the paper elucidates how citizenship policies can affect groups that challenge the exact fit between ethnicity and nation, showing how national governments through particular citizenship policies and categorisation practices engage in the construction of these groups. The paper shows that the triadic nexus framework, which has had a strong influence on citizenship and minorities scholarship, needs to be revised to include unidirectional relations between the elements of the triadic nexus. The paper is based on the comparison between the cases of ethnic Vlachs (in the context of Albania and Greece) and Bunjevci (in the context of Serbia and Croatia).European Commission - Seventh Framework Programme (FP7

Pain outcomes in patients with bone metastases from advanced cancer: assessment and management with bone-targeting agents

Bone metastases in advanced cancer frequently cause painful complications that impair patient physical activity and negatively affect quality of life. Pain is often underreported and poorly managed in these patients. The most commonly used pain assessment instruments are visual analogue scales, a single-item measure, and the Brief Pain Inventory Questionnaire-Short Form. The World Health Organization analgesic ladder and the Analgesic Quantification Algorithm are used to evaluate analgesic use. Bone-targeting agents, such as denosumab or bisphosphonates, prevent skeletal complications (i.e., radiation to bone, pathologic fractures, surgery to bone, and spinal cord compression) and can also improve pain outcomes in patients with metastatic bone disease. We have reviewed pain outcomes and analgesic use and reported pain data from an integrated analysis of randomized controlled studies of denosumab versus the bisphosphonate zoledronic acid (ZA) in patients with bone metastases from advanced solid tumors. Intravenous bisphosphonates improved pain outcomes in patients with bone metastases from solid tumors. Compared with ZA, denosumab further prevented pain worsening and delayed the need for treatment with strong opioids. In patients with no or mild pain at baseline, denosumab reduced the risk of increasing pain severity and delayed pain worsening along with the time to increased pain interference compared with ZA, suggesting that use of denosumab (with appropriate calcium and vitamin D supplementation) before patients develop bone pain may improve outcomes. These data also support the use of validated pain assessments to optimize treatment and reduce the burden of pain associated with metastatic bone disease

Evaluation of different recall periods for the US National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)

Aims—The U.S. National Cancer Institute recently developed the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). PRO-CTCAE is a library of questions for clinical trial participants to self-report symptomatic adverse events (e.g., nausea). The objective of this study is to inform evidence-based selection of a recall period when PRO-CTCAE is included in a trial. We evaluated differences between 1-week, 2-week, 3-week, and 4-week recall periods, using daily reporting as the reference. Methods—English-speaking patients with cancer receiving chemotherapy and/or radiotherapy were enrolled at four U.S. cancer centers and affiliated community clinics. Participants completed 27 PRO-CTCAE items electronically daily for 28 days, and then weekly over 4 weeks, using 1-week, 2-week, 3-week, and 4-week recall periods. For each recall period, mean differences, effect sizes, and intraclass correlation coefficients were calculated to evaluate agreement between the maximum of daily ratings and the corresponding ratings obtained using longer recall periods (e.g., maximum of daily scores over 7 days vs. 1-week recall). Analyses were repeated using the average of daily scores within each recall period rather than the maximum of daily scores. Results—127 subjects completed questionnaires (57% male; median age 57). The median of the 27 mean differences in scores on the PRO-CTCAE 5-point response scale comparing the maximum daily versus the longer recall period (and corresponding effect size), was −0.20 (−0.20) for 1-week recall; −0.36 (−0.31) for 2-week recall; −0.45 (−0.39) for 3-week recall; and −0.47 (−0.40) for 4-week recall. The median intraclass correlation across 27 items between the maximum of daily ratings and the corresponding longer recall ratings for 1-week recall was 0.70 (range: 0.54–0.82); 2-week recall: 0.74 (range: 0.58–0.83); 3-week recall: 0.72 (range: 0.61–0.84); and 4-week recall: 0.72 (range: 0.64–0.86). Similar results were observed for all analyses using the average of daily scores rather than the maximum of daily scores. Conclusions—1-week recall corresponds best to daily reporting. Although intraclass correlations remain stable over time, there are small but progressively larger differences between daily and longer recall periods at 2, 3, and 4 weeks, respectively. The preferred recall period for the PRO-CTCAE is the past 7 days, although investigators may opt for recall periods of 2, 3, or 4 weeks with an understanding that there may be some information loss