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

Origin of pyroxenites in the oceanic mantle and their implications on the reactive percolation of depleted melts

Pyroxenites are diffuse in fertile mantle peridotites and considered an important component in the mantle source of oceanic basalts. They are rarely documented in abyssal and ophiolitic peridotites representing residual mantle after melt generation, and few studies defining their origin are to date available. We present a field-based microstructural and geochemical investigation of the pyroxenite layers associated with depleted peridotites from the Mt. Maggiore ophiolitic body (Corsica, France). Field and petrographic evidence indicate that pyroxenite formation preceded the melt\u2013rock interaction history that affected this mantle sector during Jurassic exhumation, namely (1) spinel-facies reactive porous flow leading to partial dissolution of the pyroxenites, and (2) plagioclase-facies melt impregnation leading to [plagioclase + orthopyroxene] interstitial crystallization. Pyroxenes show major element compositions similar to abyssal pyroxenites from slow-spreading ridges, indicative of magmatic segregation at pressures higher than 7 kbar. Both the parental melts of pyroxenites and the melts involved in the subsequent percolation were characterized by Na2O-poor, LREE-depleted compositions, consistent with unaggregated melt increments. This implies that they represent the continuous evolution of similarly depleted melts leading to different processes (pyroxenite segregation and later melt\u2013rock interaction) during their upward migration. To support the genetic relation and the continuity between the formation of pyroxenites and the subsequent melt\u2013rock interaction history, we modeled all the documented processes in sequence, i.e.: (1) formation of single-melt increments after 6% mantle decompressional fractional melting; (2) high-pressure segregation of pyroxenites; (3) spinel-facies reactive porous flow, (4) plagioclase-facies melt impregnation. The early fractionation of pyroxenites leads to a decrease in pyroxene saturation that is necessary for the subsequent reactive porous flow process, without any significant change in the melt REE composition

Evaluation of mode equivalence of the MSKCC Bowel Function Instrument, LASA Quality of Life, and Subjective Significance Questionnaire items administered by Web, interactive voice response system (IVRS), and paper

To assess the equivalence of patient-reported outcome (PRO) survey responses across Web, interactive voice response system (IVRS), and paper modes of administration

Patient-Reported Outcomes in Clinical Trials of Rare Diseases

The science of measuring patient-reported outcomes (PROs) has advanced substantially in recent decades, allowing evaluation of how patients feel and function in clinical research. Assessment of the patient experience in populations with rare diseases can be successfully achieved using PRO measures when careful planning and rigorous methods are employed. A number of challenges exist when designing and implementing PRO analyses in rare disease contexts, including heterogeneity of outcomes, availability of suitable measures, recruitment, and selection of appropriate data collection methods. Strategies to address these exist and have been employed in past clinical research, particularly in pediatric populations. PRO assessments in rare disease clinical trials have been particularly successful through partnerships between investigators, PRO methodologists, and patient organizations. The overall goal of PRO measurement is to understand the patient experience and it provides an essential part of evaluating the impact of disease and treatment

Melt migration and melt-rock reaction in the Alpine-Apennine peridotites: Insights on mantle dynamics in extending lithosphere

The compositional variability of the lithospheric mantle at extensional settings is largely caused by the reactive percolation of uprising melts in the thermal boundary layer and in lithospheric environments. The Alpine-Apennine (A-A) ophiolites are predominantly constituted by mantle peridotites and are widely thought to represent analogs of the oceanic lithosphere formed at ocean/continent transition and slow- to ultraslow-spreading settings. Structural and geochemical studies on the A-A mantle peridotites have revealed that they preserve significant compositional and isotopic heterogeneity at variable scale, reflecting a long-lived multi-stage melt migration, intrusion and melt-rock interaction history, occurred at different lithospheric depths during progressive uplift. The A-A mantle peridotites thus constitute a unique window on mantle dynamics and lithosphere-asthenosphere interactions in very slow spreading environments. In this work, we review field, microstructural and chemical-isotopic evidence on the major stages of melt percolation and melt-rock interaction recorded by the A-A peridotites and discuss their consequences in creating chemical-isotopic heterogeneities at variable scales and enhancing weakening and deformation of the extending mantle. Focus will be on three most important stages: (i) old (pre-Jurassic) pyroxenite emplacement, and the significant isotopic modification induced in the host mantle by pyroxenite-derived melts, (ii) melt-peridotite interactions during Jurassic mantle exhumation, i.e. the open-system reactive porous flow at spinel facies depths causing bulk depletion (origin of reactive harzburgites and dunites), and the shallower melt impregnation which originated plagioclase-rich peridotites and an overall mantle refertilization. We infer that migrating melts largely originated as shallow, variably depleted, melt fractions, and acquired Si-rich composition by reactive dissolution of mantle pyroxenes during upward migration. Such melt-rock reaction processes share significant similarities with those documented in modern oceanic peridotites from slow- to ultraslow-spreading environments and track the progressive exhumation of large mantle sectors at shallow depths in oceanic settings where a thicker thermal boundary layer exists, as a consequence of slow-spreading rate

The prevalence and pattern of chemotherapy-induced peripheral neuropathy among women with breast cancer receiving care in a large community oncology practice

Purpose To describe the prevalence, severity, and risk factors of chemotherapy-induced peripheral neuropathy (CIPN) and its impact on function and quality of life (QOL) among women treated for breast cancer in a large U.S. Community Oncology practice. Methods Women previously treated with taxane-based chemotherapy for early-stage breast cancer completed the EORTC QLQ–C30, QLQ–BR23, and QLQ–CIPN20. Subscales are scored 0–100; higher scores indicate greater symptom severity. Pre-specified hypotheses were tested. Results 126 women with mean age 56.7 years (SD 11.8) were stage I–II (79.4%) or stage III (20.6%) at the time of the survey; 65.1% were White and 27.8% were Black or African American. The mean time since last taxane chemotherapy cycle was 144.9 weeks (SD 112.9). 73.0% reported having CIPN. QLQ–CIPN20 mean scores for the sensory, motor, and autonomic subscales were 18.9 (SD 23.1), 18.6 (SD 18.7), and 17.1 (SD 21.8), respectively. CIPN symptom severity was negatively correlated with global health status/QOL and physical and role functioning (range of r = -0.46 to -0.72). It was not associated with age, body mass index, diabetes, or cumulative taxane dosage, but was greater for Black or African American women (e.g., sensory, p<0.002). CIPN sensory impairment was marginally greater for patients treated with paclitaxel compared to docetaxel (p<0.064). Conclusions CIPN was prevalent in this community oncology practice and significantly impacts function and QOL. These data highlight the importance of developing methods to mitigate CIPN, and for screening for CIPN particularly among Black or African American women

Emerging uses of patient generated health data in clinical research

Recent advancements in consumer directed personal computing technology have led to the generation of biomedically-relevant data streams with potential health applications. This has catalyzed international interest in Patient Generated Health Data (PGHD), defined as "health-related data - including health history, symptoms, biometric data, treatment history, lifestyle choices, and other information-created, recorded, gathered, or inferred by or from patients or their designees (i.e. care partners or those who assist them) to help address a health concern."(Shapiro et al., 2012) PGHD offers several opportunities to improve the efficiency and output of clinical trials, particularly within oncology. These range from using PGHD to understand mechanisms of action of therapeutic strategies, to understanding and predicting treatment-related toxicity, to designing interventions to improve adherence and clinical outcomes. To facilitate the optimal use of PGHD, methodological research around considerations related to feasibility, validation, measure selection, and modeling of PGHD streams is needed. With successful integration, PGHD can catalyze the application of "big data" to cancer clinical research, creating both "n of 1" and population-level observations, and generating new insights into the nature of health and disease

Sleep quality in individuals diagnosed with colorectal cancer: Factors associated with sleep disturbance as patients transition off treatment

To identify patient characteristics associated with sleep disturbance and worsening of sleep in individuals diagnosed with localized colorectal cancer and assess heterogeneity in these relationships. Methods: Data were from the MY-Health study, a community-based observational study of adults diagnosed with cancer. Patient-Reported Outcomes Measurement Information System® Sleep Disturbance, Anxiety, Depression, Fatigue, and Pain Interference measures were administered. Participants self-reported demographics, comorbidities, and treatment information. Regression mixture and multiple regression models were used to evaluate the relationship between sleep disturbance and patient characteristics cross-sectionally at an average of 10 months after diagnosis (n = 613) as well as change in sleep disturbance over a 6-month period (n = 361). Results: Pain, anxiety, fatigue, and the existence of multiple comorbid conditions had statistically significant relationships with sleep disturbance (B = 0.09, 0.22, 0.29, and 1.53, respectively; P < 0.05). Retirement (B = -2.49) was associated with sleep quality in the cross-sectional model. Worsening anxiety (B = 0.14) and fatigue (B = 0.20) were associated with worsening sleep disturbance, and more severe sleep disturbance 10 months after diagnosis (B = -0.21) was associated with improvement in sleep quality after diagnosis (P < 0.05). No evidence of latent subgroups of patients (heterogeneity) was present. Conclusions: Pain, anxiety, fatigue, employment, and comorbid conditions were associated with sleep disturbance, but regression coefficients were small (< |2.5|). Results suggest that screening for anxiety, depression, fatigue, or pain is not sufficient for identifying sleep disturbance. Given the negative consequences of sleep disturbance, sleep disturbance screening may be warranted

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