Surrogate endpoints for HTA decisions of breast cancer drugs: utility and pitfalls.

PURPOSE OF REVIEW: Health technology assessment (HTA) of cancer drugs is important to identify whether drugs should be publicly funded. With increasing use of surrogate end points in clinical trials including breast cancer, a review of literature was done to synthesize evidence for validation of these surrogate end points and their potential role in HTA decisions pertaining to breast cancer. FINDINGS: Disease free survival (DFS) in human epidermal receptor 2 (HER2) positive early breast cancer remains the only validated surrogate end point. Other surrogate end points like pathological complete response (pCR) and event free survival (EFS) in early breast cancer (EBC) and objective response rate (ORR) and progression free survival (PFS) in advanced disease have not been validated for overall survival (OS). Moreover, surrogate end points for quality of life (QOL) have not been established and drugs that improve PFS can have detrimental effect on QOL. End points like pCR have excellent prognostic utility in individual patients but have weak correlation with survival at trial level. SUMMARY: Most surrogate end points used in breast cancer do not predict OS or QOL which makes it challenging to use them for decisions regarding public funding of cancer drugs. These findings are relevant to HTA agencies prior to making drug reimbursement decisions.

Malignant Superior Vena Cava Syndrome: A Scoping Review.

Malignant superior vena cava syndrome (SVCS) is a clinical problem that results from the obstruction of blood flow in the superior vena cava by an underlying malignancy. This may occur due to external compression, neoplastic invasion of the vessel wall, or internal obstruction with bland or tumor thrombus. Although symptoms are typically mild, SVCS can cause neurologic, hemodynamic, and respiratory compromise. Classic management options include supportive measures, chemotherapy, radiation therapy, surgery, and endovascular stenting. New targeted therapeutics and techniques have also recently been developed, which may have a role in management. Nevertheless, few evidence-based guidelines exist to guide treatment of malignant SVCS, and these recommendations are typically restricted to individual disease sites. Furthermore, there are no recent systematic literature reviews that address this question. Here, we present a theoretical case to frame this clinical problem and synthesize updated evidence published in the past decade relating to the management of malignant SVCS through a comprehensive literature review.

Industry Relationships With Medical Oncologists: Who Are the High-Payment Physicians?

PURPOSE: Many oncologists have relationships with industry. Previous work has shown that these payments are usually modest; however, there exist a subset of medical oncologists who receive more than $100,000 US dollars (USD) annually. Here, we describe the characteristics of these physicians. METHODS: This retrospective cohort study used the Open Payments data set to identify all US-based medical oncologists/hematologists who received $100,000+ USD in general payments linked to cancer medications in 2018. Open Payments and a web-based search were used to identify physician characteristics, demographics, research profile, and leadership positions. RESULTS: One hundred thirty-nine medical oncologists received > $100,000 USD in general payments. The median payment was $154,613 USD, and the total payment was $24.2 million USD. These high-payment physicians represent 1% of all US medical oncologists (N = 10,620) yet account for 37% of all industry payments in 2018. Sixty percent (84 of 139) and 21% (29 of 139) of these high-payment physicians hold hospital and specialty association leadership roles, respectively. One quarter (24%, 33 of 139) serve on journal editorial boards, and 10% (14 of 139) have authored clinical practice guidelines; 72% (100 of 139) hold faculty appointments. CONCLUSION: A small number of medical oncologists receive very high payments from the pharmaceutical industry. These physicians hold major leadership roles within oncology. Further work is needed to understand the extent to which these conflicts of interest may shape clinical practice and policy.

Trends in drug revenue among major pharmaceutical companies: A 2010-2019 cohort study.

BACKGROUND: Over the past 2 decades there has been a substantial increase in the number of new cancer medicines; this has been accompanied by a dramatic rise in drug costs. It is unknown how these trends impact the revenue of the pharmaceutical sector. METHODS: Retrospective cohort study to characterize temporal trends of revenue generated from cancer medicines as a proportion of total drug revenue among 10 large pharmaceutical companies from 2010 to 2019. Itemized product-sales data publicly available through company websites or annual filings were used to identify annual drug revenue. Revenue data were adjusted for inflation and converted to 2019 US dollars. RESULTS: During the study period, cumulative annual revenue generated from cancer drugs increased by 70%: from $55.8 billion to $95.1 billion, while cumulative revenue from nononcology drugs decreased 18%: from $342.2 billion to $281.5 billion. The proportion of total drug revenue generated from oncology drugs increased substantially over the study period: from 14% in 2010 to 25% in 2019 (τ = 1.0, P < .001). CONCLUSIONS: Among 10 of the world's largest pharmaceutical companies, revenues generated from the sale of cancer drugs have increased by 70% over the past decade, while revenues from other medicines have decreased by 18%. Revenues from cancer drugs now account for one-quarter of the net revenues from these companies. Further work is needed to understand if this increase in sales revenue reflects industry profit, and to what extent increased spending has translated into improvements in patient and population outcomes.

Factors associated with an increased risk of recurrence in patients diagnosed with high-grade endometrial cancer undergoing minimally invasive surgery: A study of the society of gynecologic oncology of Canada (GOC) community of practice (CoP).

BACKGROUND: Minimally invasive surgery (MIS) is a standard surgical approach for comprehensive surgical staging in women with endometrial cancer. As rates and complexity of MIS are steadily increasing, it is important to identify potential risk factors which may be associated with this approach. This study evaluates the impact of local factors on the risk of disease recurrence. METHODS: A retrospective cohort study was conducted of patients diagnosed with high grade endometrial cancer (HGEC) who underwent MIS between 2012 and 2016 at eight Canadian centers. Data was collected from medical records. The 75th percentile was calculated for estimated uterine volume and weight. All recurrences were categorized into two groups; intra-abdominal vs. extra-abdominal. To search for significant covariates associated with recurrence-free survival a Cox proportional hazard model was performed. RESULTS: A total of 758 patients were included in the study. Intra-uterine manipulator was used in 497 (35.8%) of patients. Vaginal lacerations were documented in 9.1%. Median follow-up was 30.5 months (interquartile range 20-47). There were 157 who had disease recurrence (20.71%), including 92 (12.14%) intra-abdominal and 60 (7.92%) extra-abdominal only recurrences. In univariate analysis myometrial invasion, LVI, stage, uterine volume and weight > 75th percentile and chemotherapy were associated with increased risk of intra-abdominal recurrence. In multivariable analysis only stage, and specimen weight > 75th percentile (OR 2.207, CI 1.123-4.337) remained significant. Uterine volume, and weight were not associated with increased risk of extra-abdominal recurrences. CONCLUSION: For patients diagnosed with HGEC undergoing MIS, extracting a large uterus is associated with a significantly increased risk for intra-abdominal recurrence.

Ingestive behaviors in bearded capuchins (Sapajus libidinosus).

The biomechanical and adaptive significance of variation in craniodental and mandibular morphology in fossil hominins is not always clear, at least in part because of a poor understanding of how different feeding behaviors impact feeding system design (form-function relationships). While laboratory studies suggest that ingestive behaviors produce variable loading, stress, and strain regimes in the cranium and mandible, understanding the relative importance of these behaviors for feeding system design requires data on their use in wild populations. Here we assess the frequencies and durations of manual, ingestive, and masticatory behaviors from more than 1400 observations of feeding behaviors video-recorded in a wild population of bearded capuchins (Sapajus libidinosus) at Fazenda Boa Vista in Piauí, Brazil. Our results suggest that ingestive behaviors in wild Sapajus libidinosus were used for a range of food material properties and typically performed using the anterior dentition. Coupled with previous laboratory work indicating that ingestive behaviors are associated with higher mandibular strain magnitudes than mastication, these results suggest that ingestive behaviors may play an important role in craniodental and mandibular design in capuchins and may be reflected in robust adaptations in fossil hominins.

Positional behavior and substrate use in wild adult bearded capuchin monkeys (Sapajus libidinosus).

Natural selection for positional behavior (posture and locomotion) has at least partially driven the evolution of anatomical form and function in the order Primates. Examination of bipedal behaviors associated with daily activity patterns, foraging, and terrestrial habitat use in nonhuman primates, particularly those that adopt bipedal postures and use bipedal locomotion, allows us to refine hypotheses concerning the evolution of bipedalism in humans. This study describes the positional behavior of wild bearded capuchins (Sapajus libidinosus), a species that is known for its use of terrestrial substrates and its habitual use of stones as tools. Here, we test the association of terrestrial substrate use with bipedal posture and locomotion, and the influence of sex (which co-varies with body mass in adults of this species) on positional behavior and substrate use. Behavior and location of 16 wild adult bearded capuchins from two groups were sampled systematically at 15 s intervals for 2 min periods for 1 year (10,244 samples). Despite their different body masses, adult males (average 3.5 kg) and females (average 2.1 kg) in this study did not differ substantially in their positional behaviors, postures, or use of substrates for particular activities. The monkeys used terrestrial substrates in 27% of samples. Bipedal postures and behaviors, while not a prominent feature of their behavior, occurred in different forms on the two substrates. The monkeys crouched bipedally in trees, but did not use other bipedal postures in trees. While on terrestrial substrates, they also crouched bipedally but occasionally stood upright and moved bipedally with orthograde posture. Bearded capuchin monkeys' behavior supports the suggestion from anatomical analysis that S. libidinosus is morphologically better adapted than its congeners to adopt orthograde postures.

Evaluating the endometabolic and bone health effects of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukaemia: a systematic review protocol.

INTRODUCTION: Chronic Myeloid Leukaemia (CML) constitutes 15% of new adult leukaemia cases as well as 2%-3% of leukaemia in children under 15% and 9% of leukaemias in adolescents 15-19 years of age annually. The introduction of Tyrosine Kinase Inhibitors (TKI) therapy has dramatically improved survival in these patients, yet the off-target effects of this treatment may have long-term health impacts on CML survivors. The risk of adverse health outcomes is especially important in children, where TKI exposure may occur during critical windows of growth and puberty, and patients require treatment for prolonged periods of time. The aim of this systematic review protocol is to report on the methods used to conduct a systematic review to investigate the endometabolic and bone health effects of TKI therapy in CML. METHODS AND ANALYSIS: Searches will be conducted in the Cochrane Central Register of Controlled Trials, EMBASE and MEDLINE from inception on August 1st, 2019. Searches may be updated while performing the systematic review to ensure new evidence is included if applicable. Grey literature search will include ClinicalTrials.gov and ProQuest Dissertations and Theses A&I. We will perform a meta-analysis if there are at least two studies reporting similar populations, interventions, methods and tracking the same outcome measures. The studies should also have similar age and sex distributions. ETHICS AND DISSEMINATION: As this is a systematic review protocol, it does not include patient data; therefore, Research Ethics Board approval is not indicated. The systematic review will be published in a peer-reviewed journal and presented at international conferences. PROSPERO REGISTRATION NUMBER: CRD42018091175.

Taking a big bite: Working together to better understand the evolution of feeding in primates.

The study of adaptation requires the integration of an array of different types of data. A single individual can find such integration daunting, if not impossible. In an effort to clarify the role of diet in the evolution of the primate craniofacial and dental apparatus, we assembled a team of researchers that have various types and degrees of expertise. This interaction has provided a range of insights for all contributors, and this has helped to refine questions, clarify the possibilities and limitations that laboratory and field settings offer, and further explore the ways in which laboratory and field data can be suitably integrated. A complete and accurate picture of dietary adaptation cannot be gained in isolation. Collaboration provides the bridge to a more holistic view of primate biology and evolution.

Sister Chromatid Exchange and Genomic Instability in Soft Tissue Sarcomas: Potential Implications for Response to DNA-Damaging Treatments.

Sarcomas are rare heterogeneous malignancies of mesenchymal origin characterised by complex karyotypes but no specific abnormalities. Recurrence is common, and metastatic disease carries poor survival despite standard DNA-damaging radiotherapy or chemotherapy. DNA double-strand breaks (DSBs) are either repaired by mechanisms such as homologous recombination (HR) or result in cell death by apoptosis. Endogenous γH2AX formation and SCE formation are early and late events, respectively, and their levels are considered surrogate measures of genomic instability. Combined γH2AX and SCE analysis was used to evaluate endogenous DNA DSB levels (and their subsequent repair) in 9 primary sarcoma cell lines and compared with well-established commercial lines. All the sarcoma cell lines had elevated γH2AX and SCE levels, but there was no correlation between the DNA DSB frequency and subsequent SCE. Typically, radioresistant osteosarcoma cells had relatively low γH2AX frequency but high SCE counts suggestive of efficient DNA repair. Conversely, liposarcoma cells derived from a radiosensitive tumour had high H2AX but relatively lower SCE levels that may imply inefficient DNA DSB repair. To our knowledge, this is the first report that correlates H2AX and SCE levels in primary sarcoma cell lines and may provide insight into potential response to DNA-damaging treatments.

Kinetics of bipedal locomotion during load carrying in capuchin monkeys.

Facultative bipedalism during load transport in nonhuman primates has been argued to be an important behavior potentially leading to the evolution of obligate, extended limb bipedalism. Understanding the biomechanics of such behavior may lead to insights about associated morphology, which may translate to interpretation of features in the fossil record. Some populations of bearded capuchin monkeys (Sapajus libidinosus) spontaneously carry heavy loads bipedally during foraging activities. This study provides the first data on all three components of ground reaction force for spontaneous bipedalism during load carriage in a nonhuman primate. Five individual S. libidinosus (mean body mass = 2.4 kg ± 0.96) were videorecorded during bipedalism while carrying a stone (0.93 kg) under natural conditions. A force plate was embedded in the path of the monkeys. Spatiotemporal and force data for all three components of the ground reaction force were recorded for 28 steps. Capuchins exhibited a mean vertical peak force per total weight (Vpk) for the hindlimb of 1.19 (sd = 0.13), consistent with those of unloaded capuchins in the laboratory and for other bipedal primates, including humans. Vertical force records suggest that capuchins, along with most nonhuman primates, maintain a relatively compliant leg during both unloaded and loaded locomotion. Like all other primates, loaded capuchins maintained laterally (outward) directed medio-lateral forces, presumably to stabilize side-to-side movements of the center of mass. Medio-lateral forces suggest that at near-running speeds dynamic stability diminishes the need to generate high lateral forces. Vertical force traces exhibited a measurable impact spike at foot contact in 85% of the steps recorded. An impact spike is common in human walking and running but has not been reported in other bipedal primates. This spike in humans is thought to lead to bone and cartilage damage. The earliest biped may have experienced similar impact spikes during bipedal locomotion, requiring compensatory behaviors or anatomical features.

The effects of ecology and evolutionary history on robust capuchin morphological diversity.

Recent molecular work has confirmed the long-standing morphological hypothesis that capuchins are comprised of two distinct clades, the gracile (untufted) capuchins (genus Cebus, Erxleben, 1777) and the robust (tufted) capuchins (genus Sapajus Kerr, 1792). In the past, the robust group was treated as a single, undifferentiated and cosmopolitan species, with data from all populations lumped together in morphological and ecological studies, obscuring morphological differences that might exist across this radiation. Genetic evidence suggests that the modern radiation of robust capuchins began diversifying ∼2.5 Ma, with significant subsequent geographic expansion into new habitat types. In this study we use a morphological sample of gracile and robust capuchin craniofacial and postcranial characters to examine how ecology and evolutionary history have contributed to morphological diversity within the robust capuchins. We predicted that if ecology is driving robust capuchin variation, three distinct robust morphotypes would be identified: (1) the Atlantic Forest species (Sapajus xanthosternos, S. robustus, and S. nigritus), (2) the Amazonian rainforest species (S. apella, S. cay and S. macrocephalus), and (3) the Cerrado-Caatinga species (S. libidinosus). Alternatively, if diversification time between species pairs predicts degree of morphological difference, we predicted that the recently diverged S. apella, S. macrocephalus, S. libidinosus, and S. cay would be morphologically comparable, with greater variation among the more ancient lineages of S. nigritus, S. xanthosternos, and S. robustus. Our analyses suggest that S. libidinosus has the most derived craniofacial and postcranial features, indicative of inhabiting a more terrestrial niche that includes a dependence on tool use for the extraction of imbedded foods. We also suggest that the cranial robusticity of S. macrocephalus and S. apella are indicative of recent competition with sympatric gracile capuchin species, resulting in character displacement.

A retrospective study of the association between Fuchs' endothelial dystrophy and glaucoma.

OBJECTIVE: The goal of this study was to examine a possible clinical association between Fuchs' endothelial dystrophy (FED) and glaucoma suspect (GS)/ocular hypertension (OHT) or open angle glaucoma (OAG). METHODS: A retrospective chart review was carried out using data from electronic medical records and paper records from a private ophthalmology clinic in Kansas City, MO, USA. The review included 257 patients with FED and 584 randomly selected controls with no history of endothelial dystrophy. Binomial and multinomial regression using generalized estimating equations was used to create models to examine the correlation between FED diagnosis/severity and glaucoma diagnosis/type of glaucoma adjusted for age, sex, presence of diabetes, number of guttae, and intraocular pressure (IOP). RESULTS: No statistically significant increase in prevalence of either OHT or GS/OHT compared to controls was observed (P>0.3). There was a statistically significant positive correlation between increasing age and IOP with increased glaucoma prevalence (P<0.05). There was also a statistically significant positive correlation between increasing age, IOP and male sex, with increased prevalence of the more severe glaucoma subtype of OAG versus GS/OHT and controls (P<0.05). Increasing severity of FED divided into category 1 and 2 based upon number of guttae was not associated with any significant increase in glaucoma prevalence (P>0.09), and was actually significantly negatively correlated to worsening glaucoma subtype for category 2 FED patients (P<0.05). Diabetes was not associated with the prevalence of either glaucoma or its subtypes of GS/OHT or OAG. CONCLUSION: The correlation between FED and glaucoma has been controversial. This study showed no statistically significant association between FED and glaucoma by prevalence or severity of FED as measured by corneal guttae. Further study is needed to determine if a connection between FED and glaucoma does exist, and if so, whether this relationship may impact earlier the detection and treatment of disease.

Neonatal circumcision: is feeding behavior altered?

BACKGROUND: The effect of circumcision on feeding behavior in the newborn period is unknown. We hypothesized that circumcision would not have a significant effect on newborn feeding. METHODS: This prospective study analyzed the effect of circumcision on neonatal feeding behavior. Inclusion criteria were healthy male infants WHO were exclusively bottle-fed and underwent a circumcision before discharge from the newborn nursery. We collected data (N = 42) on gestational age, birth weight, Apgar scores, maternal age, gravid status, anesthesia used during delivery, analgesia used after circumcision, time of circumcision, and volume and frequency of feeding before and after circumcision. Data were analyzed by using paired t tests, multivariable regression analysis, and analysis of variance (with SPSS version 18). Significance was P < .05 (2-tailed α). RESULTS: Descriptive statistics for the entire group (N = 42) are as follows: mean ± SD gestational age: 38.7 ± 1.2 weeks; mean birth weight: 3.3 ± 0.4 kg; maternal age: 26.7 ± 6.3 years; baseline feeding (mean of first 2 feedings before circumcision): 24.5 ± 9.9 mL; mean first feeding after circumcision: 21.7 ± 11.9 mL; and mean second feeding: 26.7 ± 13.5 mL. Forty-eight percent of patients increased their feeding volume after circumcision compared with baseline, and 52% of patients decreased their feeding volume, which persisted with the second feeding. There was no statistical difference between the baseline and first feeding (P = .11) or second feeding (P = .22). CONCLUSIONS: Our data suggest that circumcision does not alter feeding after circumcision. This information will be useful in counseling families regarding circumcision in the newborn period.

Telehealth-delivered group smoking cessation for rural and urban participants: feasibility and cessation rates.

BACKGROUND: Large-group behavioral smoking cessation interventions are effective for helping people quit smoking, but have not been evaluated using videoconferencing technology for rural and remote participants who have no access to in-person cessation programs. The objectives of this study were to provide and evaluate an evidence-based group smoking cessation program for rural/remote smokers wishing to quit through a Telehealth videoconferencing link at their local Health Centre. METHODS: From September 2005 through April 2008, eight separate eight-session, 4 month long smoking cessation group programs were offered both in person to urban participants in Calgary and at up to six rural sites simultaneously via Telehealth videoconferencing. Quit rates were assessed at program completion, 6 and 12 month follow-up. Participants also provided evaluations of the program and technology. RESULTS: 554 smokers participated in the program: 370 in Calgary and 184 at various remote sites. Sixteen Telehealth sites participated from across Alberta and one site from the Northwest Territories. After program completion, continuous abstinence rates using the most conservative intent-to-treat method were 27.5% in Calgary and 25.5% for the rural Telehealth sites. Quit numbers were much higher using only Available Data at 39.2% for Calgary and 37.2% for the rural sites. Similar rates were maintained over the 12-month follow-up. Program evaluations were positive. CONCLUSIONS: It is possible to offer effective smoking cessation to small groups of patients in rural or remote locations through Telehealth videoconferencing technology, which produces quit rates similar to in-person groups.

Fallback foraging as a way of life: using dietary toughness to compare the fallback signal among capuchins and implications for interpreting morphological variation.

The genus Cebus is one of the best extant models for examining the role of fallback foods in primate evolution. Cebus includes the tufted capuchins, which exhibit skeletal features for the exploitation of hard and tough foods. Paradoxically, these seemingly "specialized" taxa belong to the most ubiquitous group of closely related primates in South America, thriving in a range of different habitats. This appears to be a consequence of their ability to exploit obdurate fallback foods. Here we compare the toughness of foods exploited by two tufted capuchin species at two ecologically distinct sites; C. apella in a tropical rainforest, and C. libidinosus in a cerrado forest. We include dietary data for one untufted species (C. olivaceus) to assess the degree of difference between the tufted species. These data, along with information on skeletal morphology, are used to address whether or not a fallback foraging species exhibits a given suite of morphological and behavioral attributes, regardless of habitat. Both tufted species ingest and masticate a number of exceedingly tough plant tissues that appear to be used as fallback resources, however, C. libidinosus has the toughest diet both in terms of median and maximal values. Morphologically, C. libidinosus is intermediate in absolute symphyseal and mandibular measurements, and in measures of postcranial robusticity, but exhibits a higher intermembral index than C. apella. We propose that this incongruence between dietary toughness and skeletal morphology is the consequence of C. libidinosus' use of tools while on the ground for the exploitation of fallback foods.

Change processes in couple therapy: an intensive case analysis of one couple using a common factors lens.

The article describes a research study that explored the process of how change occurred for one distressed couple and a specific therapist in a naturalistic setting. Quantitative and qualitative data were collected on the couple at multiple points in the therapy. A research team comprised of five members met regularly to analyze the data and collectively they arrived at a theory of change for the couple posttherapy. Conclusions are made related to how change occurred for the couple with an emphasis on the role of extratherapeutic events, client motivational factors, the therapeutic alliance, hope and expectancy factors, therapist factors, specific techniques and interventions, and other surprise factors that contributed to change.

The relationship between locomotor behavior and limb morphology in brown (Cebus apella) and weeper (Cebus olivaceus) capuchins.

This study is a comparison of locomotor behavior and postcranial form in two species of capuchin monkey, the brown capuchin (Cebus apella), and the weeper capuchin (Cebus olivaceus). Behavioral data from groups of wild C. apella and C. olivaceus in Guyana were collected during the period of December 1999 through November 2000. Postcranial variables including 40 measurements and three indices were taken from 43 adult and subadult specimens of C. apella and 14 adult and subadult specimens of C. olivaceus housed in American museums, as well as two wild-caught adult specimens of C. olivaceus from the Georgetown Zoo in Guyana. The results of this study indicate that these two capuchins exhibit similar patterns of locomotor behavior, but that there are important differences in how they move through their homerange, particularly with respect to quadrupedalism. These differences in behavior are reflected in their postcranial morphology and can be related to differences in foraging strategies. This study provides an example of the importance of using more exclusive categories of quadrupedal behaviors when comparing closely related arboreal quadrupeds, as well as an alternative explanation for some of the postcranial features of C. apella that may relate to foraging postures and foraging strategy rather than traditionally categorized patterns of locomotor behavior.