Construct validation of a novel synthetic tendon model used for assessing surgeon performance in a simulated core suture tendon repair technique.

BACKGROUND: The strength of tendon repair is dependent on the quality of the core suture. Organic and synthetic materials have been used to simulate tendon repair for training; however, no model has undergone construct validation. OBJECTIVES: To determine the construct validity of a novel synthetic tendon repair model. METHODS: Synthetic silicone tendon models were used to simulate adult Achilles tendon (AT) and digital flexor tendon (FT). Participants were categorised into novice, intermediate, and advanced groups based on prior surgical experience. Participants repaired tendons using the modified Kessler technique. A validated motion analysis system was used to measure the duration, path length, and movement count during the simulated task. A global rating score was also used to assess the performance. RESULTS: All participants in the novice (n = 12), intermediate (n = 8) and advanced (n = 11) groups completed the tasks. The results (mean±standard deviation) were duration (872 ± 335, 492 ± 257 and 357 ± 40 s), path length (9493 ± 3173, 6668 ± 1740 and 4672 ± 1228 cm), movement count (4974 ± 673, 4228 ± 259 and 3962 ± 69) and global rating (39 ± 13, 61 ± 14, 81 ± 5), respectively. The Kruskal-Wallis test was significant for all outcome measures (p < 0.01). Significant differences in duration and movement count were identified post-hoc in the AT model for each experience group (p < 0.05), and between novice and intermediate participants for FT repair (p < 0.04). Global rating was significantly different between all groups and was highly correlated with motion metrics (p < 0.01). CONCLUSION: The results support construct validity of this novel simulated tendon repair model. The global rating scores may allow wide utility of this simulation. This model provides a valid and safe environment for surgical trainees to practice tendon repair with several cost, ethical and logistical benefits over animal tendon use. 248/250.

INX-315, a Selective CDK2 Inhibitor, Induces Cell Cycle Arrest and Senescence in Solid Tumors.

Cyclin-dependent kinase 2 (CDK2) is thought to play an important role in driving proliferation of certain cancers, including those harboring CCNE1 amplification and breast cancers that have acquired resistance to CDK4/6 inhibitors (CDK4/6i). The precise impact of pharmacologic inhibition of CDK2 is not known due to the lack of selective CDK2 inhibitors. Here we describe INX-315, a novel and potent CDK2 inhibitor with high selectivity over other CDK family members. Using cell-based assays, patient-derived xenografts (PDX), and transgenic mouse models, we show that INX-315 (i) promotes retinoblastoma protein hypophosphorylation and therapy-induced senescence (TIS) in CCNE1-amplified tumors, leading to durable control of tumor growth; (ii) overcomes breast cancer resistance to CDK4/6i, restoring cell cycle control while reinstating the chromatin architecture of CDK4/6i-induced TIS; and (iii) delays the onset of CDK4/6i resistance in breast cancer by driving deeper suppression of E2F targets. Our results support the clinical development of selective CDK2 inhibitors. SIGNIFICANCE: INX-315 is a novel, selective inhibitor of CDK2. Our preclinical studies demonstrate activity for INX-315 in both CCNE1-amplified cancers and CDK4/6i-resistant breast cancer. In each case, CDK2 inhibition induces cell cycle arrest and a phenotype resembling cellular senescence. Our data support the development of selective CDK2 inhibitors in clinical trials. See related commentary by Watts and Spencer, p. 386. This article is featured in Selected Articles from This Issue, p. 384.

The RoboCOS Study: Development of an international core outcome set for the comprehensive evaluation of patient, surgeon, organisational and population level impacts of robotic assisted surgery.

BACKGROUND: The introduction of robot-assisted surgery is costly and requires whole system transformation, which makes the assessment of benefits (or drawbacks) complex. To date, there has been little agreement on which outcomes should be used in this regard. The aim of the RoboCOS study was to develop a core outcome set for the evaluation of robot-assisted surgery that would account for its impact on the whole system. METHODS: Identification of a long-list of potentially relevant outcomes through systematic review of trials and health technology assessments; interviews with individuals from a range of stakeholder groups (surgeons, service managers, policy makers and evaluators) and a focus group with patients and public; prioritisation of outcomes via a 2-round online international Delphi survey; consensus meeting. RESULTS: 721 outcomes were extracted from the systematic reviews, interviews and focus group which were conceptualised into 83 different outcome domains across four distinct levels (patient, surgeon, organisation and population) for inclusion in the international Delphi prioritisation survey (128 completed both rounds). The consensus meeting led to the agreement of a 10-item core outcome set including outcomes at: patient level (treatment effectiveness; overall quality of life; disease-specific quality of life; complications (including mortality); surgeon level (precision/accuracy; visualisation); organisation (equipment failure; standardisation of operative quality; cost-effectiveness); and population (equity of access). CONCLUSION: The RoboCOS core outcome set, which includes the outcomes of importance to all stakeholders, is recommended for use in all future evaluations of robot-assisted surgery to ensure relevant and comparable reporting of outcomes.

Clinicopathological Factors Affecting Breast Cancer Survival in Jamaican Women: A Retrospective Review.

OBJECTIVE: Breast cancer is the leading cause of cancer affecting women worldwide. The survival rate is primarily affected by the stage of the disease and several other demographic and clinicopathological factors. METHODS: This study is a retrospective cohort study of female patients of the University Hospital of the West Indies diagnosed with breast cancer between 2011 and 2016. The age, tumor size, SBR/Nottingham grade, tumor histologic subtype, tumor molecular subtype, and survival status of the cohort on November 1, 2019, were determined. The data were summarized. Survival across each variable was compared using univariate log-rank tests, Cox proportional hazard models, and crude and adjusted models. A second wave analysis was performed excluding patients whose survival status was presumed. RESULTS: A total of 503 patients were analyzed. The overall survival rate at 1, 3, and 5 years were 96.4%, 84.9%, and 79.0%, respectively, for the entire cohort. The molecular subtype was the most significant clinicopathological factor affecting overall survival. A younger age < 40 years, higher histologic grade, estrogen receptor-negative breast cancers, invasive ductal type breast cancers, and T1 lesions were associated with poorer survival outcomes at 5 years. The findings were reproduced after a second wave analysis excluding patients who were presumed alive was applied. CONCLUSIONS: Breast cancer overall survival in Jamaica is consistent with that of other developing countries in the literature. This study is an important contribution to the growing body of literature available and aids to the overall understanding of the behavior of breast cancer locally.

Comparison of Mg/Ca concentration series from Patella depressa limpet shells using CF-LIBS and LA-ICP-MS.

The elemental composition of marine mollusk shells can offer valuable information about environmental conditions experienced by a mollusk during its lifespan. Previous studies have shown significant correlations between Mg/Ca concentration ratios measured on biogenic carbonate of mollusk shells and sea surface temperature (SST). Here we propose the use of Laser-Induced Breakdown Spectroscopy (LIBS) and the validation of the Calibration-Free LIBS (CF-LIBS) approach for the rapid measurement and estimation of Mg/Ca molar concentration profiles within Patella depressa Pennant, 1777 limpet shells. To achieve these objectives, results derived from CF-LIBS methodology are compared with those obtained from an established analytical technique for this purpose, such as Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS). Concentration series obtained with both methodologies show defined temporal patterns and reflect the season-of-capture in each specimen. The results evidence a significant correlation (R2 = 0.63-0.81) between CF-LIBS and LA-ICP-MS Mg/Ca molar concentration profiles within four live-collected P. depressa shells. Averaged error for the molar concentration estimated with CF-LIBS was lower than 10% in every specimen. The comparison between the results obtained from two techniques used in this study has allowed us to demonstrate for the first time that Mg/Ca molar concentration measured in biogenic carbonates were accurately inferred using CF-LIBS technique. The CF-LIBS approach validation represents great potential for the rapid and large-scale paleoenvironmental and archaeological analysis of this mollusk species, which is frequently found in archaeological sites.

Validating the accuracy of a novel virtual reality platform for determining implant orientation in simulated primary total hip replacement.

Introduction: Accurate acetabular cup and femoral stem component orientation are critical for optimising patient outcomes, reducing complications and increasing component longevity following total hip replacement (THR). This study aimed to determine the accuracy of a novel virtual reality (VR) platform in assessing component orientation in a simulated THR model. Methods: The VR platform (HTC Vive Pro® system hardware) was compared against the validated Vicon® optical motion capture (MoCap) system. An acetabular cup and femoral stem were manually implanted across a range of orientations into pelvic and femur sawbones, respectively. Simultaneous readings of the acetabular cup operative anteversion (OA) and inclination (OI) and femoral stem alignment (FSA) and neck anteversion (FNA) were obtained from the VR and MoCap systems. Statistical analysis was performed using Pearson product-moment correlation coefficient (PPMCC) (Pearson's r) and linear regression (R2). Results: A total of 55 readings were obtained for the acetabular cup and 68 for the femoral stem model. The mean average differences in OA, OI, FSA and FNA between the systems were 3.44°, -0.01°, 0.01° and -0.04°, respectively. Strong positive correlations were demonstrated between both systems in OA, OI, FSA and FNA, with Pearson's r = 0.92, 0.94, 0.99 and 0.99, and adjusted R2 = 0.82, 0.9, 0.98 and 0.98, respectively. Conclusion: The novel VR platform is highly accurate and reliable in determining both acetabular cup and femoral stem component orientations in simulated THR models. This adaptable and cost-effective digital tracking platform may be modified for use in a range of simulated surgical training and educational purposes, particularly in orthopaedic surgery.

Re-evaluating Scythian lifeways: Isotopic analysis of diet and mobility in Iron Age Ukraine.

The Scythians are frequently presented, in popular and academic thought alike, as highly mobile warrior nomads who posed a great economic risk to growing Mediterranean empires from the Iron Age into the Classical period. Archaeological studies provide evidence of first millennium BCE urbanism in the steppe while historical texts reference steppe agriculture, challenging traditional characterizations of Scythians as nomads. However, there have been few direct studies of the diet and mobility of populations living in the Pontic steppe and forest-steppe during the Scythian era. Here, we analyse strontium, oxygen, and carbon isotope data from human tooth enamel samples, as well as nitrogen and carbon isotope data of bone collagen, at several Iron Age sites across Ukraine commonly associated with 'Scythian' era communities. Our multi-isotopic approach demonstrates generally low levels of human mobility in the vicinity of urban locales, where populations engaged in agro-pastoralism focused primarily on millet agriculture. Some individuals show evidence for long-distance mobility, likely associated with significant inter-regional connections. We argue that this pattern supports economic diversity of urban locales and complex trading networks, rather than a homogeneous nomadic population.

Trilaciclib dose selection: an integrated pharmacokinetic and pharmacodynamic analysis of preclinical data and Phase Ib/IIa studies in patients with extensive-stage small cell lung cancer.

PURPOSE: Trilaciclib is a first-in-class CDK4/6 inhibitor that transiently arrests hematopoietic stem and progenitor cells (HSPCs) in the G1 phase of the cell cycle to preserve them from chemotherapy-induced damage (myelopreservation). We report integrated analyses of preclinical and clinical data that informed selection of the recommended Phase II dose (RP2D) used in trilaciclib trials in extensive-stage small cell lung cancer (ES-SCLC). METHODS: A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model developed from preclinical data guided selection of an optimal dose for G1 bone marrow arrest in a first-in-human Phase I study (G1T28-1-01). PK, PD, safety, and efficacy data from G1T28-1-01 and two Phase Ib/IIa studies (G1T28-02/-03) in ES-SCLC were analyzed to support RP2D selection. RESULTS: Model simulation of bone marrow arrest based on preclinical data predicted that a ≥ 192 mg/m2 dose would induce a 40-50% decrease in total bone marrow proliferation in humans and almost 100% cell cycle arrest of cycling HSPCs. Consistent with this model, analysis of bone marrow aspirates in healthy volunteers after trilaciclib 192 mg/m2 administration demonstrated almost 100% G1 arrest in HSPCs and 40% decrease in total bone marrow proliferation, with minimal toxicity. G1T28-02/-03 reported similar PK parameters with trilaciclib 200 mg/m2 but slightly lower exposures than expected compared with healthy volunteers; consequently, 240 and 280 mg/m2 doses were also tested to match healthy volunteer exposures. Based on PK and relevant safety data, 240 mg/m2 was selected as the RP2D, which was also favored by myelopreservation endpoints in G1T28-02/-03. CONCLUSION: Integrated PK/PD, safety, and efficacy data support 240 mg/m2 as the RP2D for trilaciclib. CLINICALTRIALS. GOV IDENTIFIERS: NCT02243150; NCT02499770; NCT02514447.

CDK4/6 inhibition enhances antitumor efficacy of chemotherapy and immune checkpoint inhibitor combinations in preclinical models and enhances T-cell activation in patients with SCLC receiving chemotherapy.

BACKGROUND: Combination treatment with chemotherapy and immune checkpoint inhibitors (ICIs) has demonstrated meaningful clinical benefit to patients. However, chemotherapy-induced damage to the immune system can potentially diminish the efficacy of chemotherapy/ICI combinations. Trilaciclib, a highly potent, selective and reversible cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor in development to preserve hematopoietic stem and progenitor cells and immune system function during chemotherapy, has demonstrated proof of concept in recent clinical trials. Furthermore, CDK4/6 inhibition has been shown to augment T-cell activation and antitumor immunity in preclinical settings. Therefore, addition of trilaciclib has the potential to further enhance the efficacy of chemotherapy and ICI combinations. METHODS: In murine syngeneic tumor models, a schedule of 3 weekly doses of trilaciclib was combined with chemotherapy/ICI regimens to assess the effect of transient CDK4/6 inhibition on antitumor response and intratumor T-cell proliferation and function. Peripheral T-cell status was also analyzed in patients with small cell lung cancer (SCLC) treated with chemotherapy with or without trilaciclib to gain insights into the effect of transient exposure of trilaciclib on T-cell activation. RESULTS: Preclinically, the addition of trilaciclib to chemotherapy/ICI regimens enhanced antitumor response and overall survival compared with chemotherapy and ICI combinations alone. This effect is associated with the modulation of the proliferation and composition of T-cell subsets in the tumor microenvironment and increased effector function. Transient exposure of trilaciclib in patients with SCLC during chemotherapy treatment both preserved and increased peripheral lymphocyte counts and enhanced T-cell activation, suggesting that trilaciclib not only preserved but also enhanced immune system function. CONCLUSIONS: Transient CDK4/6 inhibition by trilaciclib was sufficient to enhance and prolong the duration of the antitumor response by chemotherapy/ICI combinations, suggesting a role for the transient cell cycle arrest of tumor immune infiltrates in remodeling the tumor microenvironment. These results provide a rationale for combining trilaciclib with chemotherapy/ICI regimens to improve antitumor efficacy in patients with cancer.

Isotopic and microbotanical insights into Iron Age agricultural reliance in the Central African rainforest.

The emergence of agriculture in Central Africa has previously been associated with the migration of Bantu-speaking populations during an anthropogenic or climate-driven 'opening' of the rainforest. However, such models are based on assumptions of environmental requirements of key crops (e.g. Pennisetum glaucum) and direct insights into human dietary reliance remain absent. Here, we utilise stable isotope analysis (δ13C, δ15N, δ18O) of human and animal remains and charred food remains, as well as plant microparticles from dental calculus, to assess the importance of incoming crops in the Congo Basin. Our data, spanning the early Iron Age to recent history, reveals variation in the adoption of cereals, with a persistent focus on forest and freshwater resources in some areas. These data provide new dietary evidence and document the longevity of mosaic subsistence strategies in the region.

Chemotherapy and CDK4/6 Inhibitors: Unexpected Bedfellows.

Cyclin-dependent kinases 4 and 6 (CDK4/6) have emerged as important therapeutic targets. Pharmacologic inhibitors of these kinases function to inhibit cell-cycle progression and exert other important effects on the tumor and host environment. Because of their impact on the cell cycle, CDK4/6 inhibitors (CDK4/6i) have been hypothesized to antagonize the antitumor effects of cytotoxic chemotherapy in tumors that are CDK4/6 dependent. However, there are multiple preclinical studies that illustrate potent cooperation between CDK4/6i and chemotherapy. Furthermore, the combination of CDK4/6i and chemotherapy is being tested in clinical trials to both enhance antitumor efficacy and limit toxicity. Exploitation of the noncanonical effects of CDK4/6i could also provide an impetus for future studies in combination with chemotherapy. Thus, while seemingly mutually exclusive mechanisms are at play, the combination of CDK4/6 inhibition and chemotherapy could exemplify rational medicine.

Pathologic Factors Affecting Colorectal Cancer Survival in a Jamaican Population-the UHWI Experience.

OBJECTIVE: Colorectal carcinoma (CRC) is the third most common cancer and a leading cause of cancer-related deaths in Jamaica. Globally, CRC mortality rates have been decreasing in developed countries; however, CRC mortality rates are trending upwards in low-income or developing countries. Our objectives are to estimate the overall 5-year survival and to determine the pathologic factors associated with overall survival of colorectal adenocarcinoma after surgery at the University Hospital of the West Indies (UHWI). METHODS: Retrospective, observational (cross-sectional) study on CRC patients. We summarized and analyzed demographic, clinical data, histopathological data, and survival rates. Single predictor Cox regression models were used to establish associations between survival and specified clinicopathological characteristics. RESULTS: A total of 217 patients who underwent operative resection of colorectal adenocarcinoma from January 2004 to December 2013. Median survival time post-therapeutic intervention was 48 months. Late stage at diagnosis, positive circumferential resection margins, neural and vascular invasion, as well as three or more nodal metastases were all associated with statistically significant worsened outcome. CONCLUSIONS: Despite surgical quality meeting USA standards, CRC survival rates in Jamaica are 13% lower than survival of CRC in non-Hispanic Blacks in the USA. The survival trends found by our study support the application of international indices for CRC prognostication to Jamaican patients.

Patient outcomes after radiofrequency ablation stratified by Clinical, Etiology, Anatomy, and Pathophysiology classification.

OBJECTIVE: Venous insufficiency is a prevalent and potentially debilitating disease. Treatment guidelines and techniques such as radiofrequency ablation (RFA) developed in the United States and Europe have been shown to provide significant improvements in quality of life; however, these have not been clearly assessed in the populations of developing nations. This study examined quality of life outcomes after RFA of patients treated at a single Jamaican vein center. METHODS: In this study, 100 patients who underwent RFA from 2007 to 2012 were evaluated. Patients answered the Venous Insufficiency Epidemiological and Economic Study on Quality of Life/Symptoms (VEINES-QOL/Sym) questionnaire assessing quality of life before and after RFA. Improvements in specific categories, such as venous symptoms, work limitations, social limitations, and cosmetic concerns, were evaluated. Cumulative VEINES-Sym and VEINES-QOL scores were also assessed. RESULTS: Patients' quality of life responses were significantly improved in every individual VEINES question. Average cumulative VEINES-Sym t score improved 9.96 points (P < .01), and VEINES-QOL t score improved 11.15 points (P < .01). For patients with Clinical, Etiology, Anatomy, and Pathophysiology (CEAP) C5 and C6 disease, the only questions that did not show significant improvement were limitations to daily workplace activity and impact on clothing after RFA. However, in this subset, the average VEINES-Sym t score improved 11.83 points (P < .01), and the VEINES-QOL t score improved 11.96 points (P < .01) after RFA. CONCLUSIONS: Venous disease is often overlooked, and access to treatment can be limited in developing nations. This study demonstrated that venous treatment guidelines and RFA techniques developed in the United States and Europe could be successfully applied to a Jamaican population, resulting in significant improvements in quality of life.

Growth rings of Brazil nut trees (Bertholletia excelsa) as a living record of historical human disturbance in Central Amazonia.

The Brazil nut tree (Bertholletia excelsa) is an iconic and economically valuable species that dominates vast swathes of the Amazon Basin. This species seems to have been an important part of human subsistence strategies in the region from at least the Early Holocene, and its current distribution may be a legacy of past human settlement. Because B. excelsa is a long-lived pioneer tree it requires natural or human disturbances to increase light availability in the understory for a successful establishment. However, it remains unclear how the long-term population dynamics of this species have been shaped by pre-colonial and post-colonial human practices. Here, we use tree-ring analyses to look at changes in growing conditions over the past 400 years in a Brazil nut tree population in Central Amazonia. We identify changes in tree recruitment and growth rates associated not only with regional climatic variability, but also major political and socio-economic activities recorded by historical documents in the vicinity of Manaus. We demonstrate that the expansion of a post-colonial political center (Manaus) from the middle of the 18th century onwards coincided with a reduction in recruitment of B. excelsa. We argue that this hiatus suggests the interruption of indigenous management practices, probably due to the collapse of pre-Columbian societies. A second recruitment pulse, and unprecedented cycles of growth release and suppression, aligns with a shift to modern exploitation of the forest into the 20th century. Our findings shed light on how past histories of human-forest interactions can be revealed by the growth rings of trees in Amazonia. Future interdisciplinary analysis of these trees should enable more detailed investigation of how human forest management has changed in this part of the world, through pre-colonial, colonial, and industrial periods of human activity, with potential implications for conservation.

Objectively Assessing Intraoperative Arthroscopic Skills Performance and the Transfer of Simulation Training in Knee Arthroscopy: A Randomized Controlled Trial.

PURPOSE: To objectively investigate the transfer validity of simulation training using wireless elbow-worn motion sensors intraoperatively to assess whether surgical simulation leads to improvements in intraoperative arthroscopic performance. METHODS: In this randomized controlled trial, postgraduate year 2 to 3 trainees in nationally approved orthopaedic surgery posts were randomized to standard junior residency training (control group) or standard training plus additional weekly simulation training (intervention group). Both groups performed a supervised real-life diagnostic knee arthroscopy in the operating room at 13 weeks. Performance was measured using wireless elbow-worn motion sensors recording objective surgical performance metrics: number of hand movements, smoothness, and time taken. A participant-supervisor performance ratio was used to adjust for variation in case mix and difficulty. The study took place in a surgical simulation suite and the orthopaedic operating rooms of a university teaching hospital. RESULTS: The intervention group objectively outperformed the control group in all outcome metrics. Procedures performed by the intervention group required fewer hand movements (544 [interquartile range (IQR), 465-593] vs 893 [IQR, 747-1,242]; P < .001), had smoother movements (25,842 ms-3 [IQR, 20,867-27,468 ms-3] vs 36,846 ms-3 [IQR, 29,840-53,949 ms-3]; P < .001), and took less time (320 seconds [IQR, 294-392 seconds] vs 573 seconds [IQR, 477-860 seconds]; P < .001) than those performed by the control group. The cases were comparable between the groups. Standardized to the supervisor's performance, the intervention group required fewer hand movements (1.9 [IQR, 1.5-2.1] vs 3.3 [IQR, 2.2-4.8]; P = .0091), required less time (1.2 [IQR, 1.1-1.7] vs 2.6 [IQR, 1.6-3.0]; P = .0037), and were smoother (2.1 [IQR, 1.8-2.8] vs 4.3 [IQR, 2.8-5.4]; P = .0037) than the control group, but they did not perform as well as their supervisors. CONCLUSIONS: This study uses intraoperative motion-analysis technology to objectively show that surgical simulation training improves actual intraoperative technical skills performance. CLINICAL RELEVANCE: The described wireless objective assessment method complements the subjective observational performance assessments commonly used. Further studies are required to assess how these measures of intraoperative performance correlate to patient outcomes. Intraoperative motion analysis is translatable across surgical specialties, offering potential for objective assessment of progression through competency-based training, revalidation, and talent selection for specialist training.

CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation.

Immune checkpoint blockade, exemplified by antibodies targeting the PD-1 receptor, can induce durable tumor regressions in some patients. To enhance the efficacy of existing immunotherapies, we screened for small molecules capable of increasing the activity of T cells suppressed by PD-1. Here, we show that short-term exposure to small-molecule inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) significantly enhances T-cell activation, contributing to antitumor effects in vivo, due in part to the derepression of NFAT family proteins and their target genes, critical regulators of T-cell function. Although CDK4/6 inhibitors decrease T-cell proliferation, they increase tumor infiltration and activation of effector T cells. Moreover, CDK4/6 inhibition augments the response to PD-1 blockade in a novel ex vivo organotypic tumor spheroid culture system and in multiple in vivo murine syngeneic models, thereby providing a rationale for combining CDK4/6 inhibitors and immunotherapies.Significance: Our results define previously unrecognized immunomodulatory functions of CDK4/6 and suggest that combining CDK4/6 inhibitors with immune checkpoint blockade may increase treatment efficacy in patients. Furthermore, our study highlights the critical importance of identifying complementary strategies to improve the efficacy of immunotherapy for patients with cancer. Cancer Discov; 8(2); 216-33. ©2017 AACR.See related commentary by Balko and Sosman, p. 143See related article by Jenkins et al., p. 196This article is highlighted in the In This Issue feature, p. 127.

Development of a surgical trainer assessment questionnaire.

BACKGROUND: The assessment of surgical trainees has become well-established in practice; however, this is not yet the case for surgical trainers. The aim of this study was to develop a trainer assessment questionnaire (OxTrAQ) based on the 12 key trainer attributes identified by a previous systematic review, to then explore this questionnaire's potential domains and test its reliability. METHODS: The OxTrAQ was piloted at two surgical training centres in two surgical sub-specialities. At each centre, every trainee assessed every trainer while under their clinical supervision. RESULTS: Internal consistency (Cronbach's alpha) was calculated for this 12-item questionnaire as 0.958. Factor analysis revealed two domains which accounted for 77.997% of the variance; these were the general domain (nine items) and the independence domain (three items). Inter-observer reliability was shown by the intraclass correlation coefficients (ICCs) (average measures) for the overall OxTrAQ score, general domain score and independence domain score which were 0.951, 0.945 and 0.955 for centre 1 and 0.857, 0.819 and 0.883 for centre 2, respectively. Intra-observer reliability was shown by the ICCs (average measures) for the overall OxTrAQ score, general domain score and independence domain score which were 0.925, 0.913 and 0.940, respectively. Construct validity was demonstrated by a high correlation (Spearman rho = 0.886, P = 0.019) between trainer scores and the scores predicted by the trainers themselves. CONCLUSIONS: The OxTrAQ is a simple trainer assessment questionnaire which has demonstrated both high inter- and intra-observer reliability.

Preclinical development of G1T38: A novel, potent and selective inhibitor of cyclin dependent kinases 4/6 for use as an oral antineoplastic in patients with CDK4/6 sensitive tumors.

Inhibition of the p16INK4a/cyclin D/CDK4/6/RB pathway is an effective therapeutic strategy for the treatment of estrogen receptor positive (ER+) breast cancer. Although efficacious, current treatment regimens require a dosing holiday due to severe neutropenia potentially leading to an increased risk of infections, as well as tumor regrowth and emergence of drug resistance. Therefore, a next generation CDK4/6 inhibitor that can inhibit proliferation of CDK4/6-dependent tumors while minimizing neutropenia could reduce both the need for treatment holidays and the risk of inducing drug resistance.Here, we describe the preclinical characterization and development of G1T38; a novel, potent, selective, and orally bioavailable CDK4/6 inhibitor. In vitro, G1T38 decreased RB1 (RB) phosphorylation, caused a precise G1 arrest, and inhibited cell proliferation in a variety of CDK4/6-dependent tumorigenic cell lines including breast, melanoma, leukemia, and lymphoma cells. In vivo, G1T38 treatment led to equivalent or improved tumor efficacy compared to the first-in-class CDK4/6 inhibitor, palbociclib, in an ER+ breast cancer xenograft model. Furthermore, G1T38 accumulated in mouse xenograft tumors but not plasma, resulting in less inhibition of mouse myeloid progenitors than after palbociclib treatment. In larger mammals, this difference in pharmacokinetics allowed for 28 day continuous dosing of G1T38 in beagle dogs without producing severe neutropenia. These data demonstrate G1T38 has unique pharmacokinetic and pharmacodynamic properties, which result in high efficacy against CDK4/6 dependent tumors while minimizing the undesirable on-target bone marrow activity, thus potentially allowing G1T38 to be used as a continuous, daily oral antineoplastic agent.

Transient CDK4/6 inhibition protects hematopoietic stem cells from chemotherapy-induced exhaustion.

Conventional cytotoxic chemotherapy is highly effective in certain cancers but causes dose-limiting damage to normal proliferating cells, especially hematopoietic stem and progenitor cells (HSPCs). Serial exposure to cytotoxics causes a long-term hematopoietic compromise ("exhaustion"), which limits the use of chemotherapy and success of cancer therapy. We show that the coadministration of G1T28 (trilaciclib), which is a small-molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), contemporaneously with cytotoxic chemotherapy protects murine hematopoietic stem cells (HSCs) from chemotherapy-induced exhaustion in a serial 5-fluorouracil treatment model. Consistent with a cell-intrinsic effect, we show directly preserved HSC function resulting in a more rapid recovery of peripheral blood counts, enhanced serial transplantation capacity, and reduced myeloid skewing. When administered to healthy human volunteers, G1T28 demonstrated excellent in vivo pharmacology and transiently inhibited bone marrow (BM) HSPC proliferation. These findings suggest that the combination of CDK4/6 inhibitors with cytotoxic chemotherapy should provide a means to attenuate therapy-induced BM exhaustion in patients with cancer.

What is Known About the Attributes of a Successful Surgical Trainer? A Systematic Review.

BACKGROUND: Surgical training has been subject to significant upheaval in recent years with an increasingly rigorous assessment regimen for trainees. The assessment of surgical trainers is less well evolved by comparison. Recent proposals from the Royal College of Surgeons of England recommend "professionalising the trainers." However, they do not suggest any accepted or validated methods of trainer assessment, nor do they indicate how these might be implemented and monitored in a real-world training program to determine their effect on trainee outcomes. AIM: To determine what is known about the attributes of successful surgical trainers. METHODS: We conducted a systematic review of the scientific literature using the preferred reporting items for systematic reviews and meta-analyses and Cochrane guidelines of the Medline database using specific search criteria. The qualitative analysis involved grouping trainer attributes together into "themes" within 4 "super-themes." Each theme needed to be mentioned by a minimum of 5 studies. RESULTS: After review of the full study texts a total of 14 studies met the inclusion criteria. Thirteen studies involved the views of trainees, whereas only 1 study solely assessed the views of trainers. There was a wide variety of study designs and types of participants. The attribute themes are listed in brackets after each super-theme: "character" (approachability, patience, enthusiasm, encouraging/supportiveness), "procedural" (willingness to let trainee operate, balance between supervision and independence), "teamwork and communication" (sets educational aims and objectives, ability to use appropriate feedback, communication skills, and time availability to train) and "clinical" (capable, good relationships with patients, and the health care team). CONCLUSIONS: This detailed review describes several perceived important themes for the positive attributes of surgical trainers. The identification of these key attributes is only of value if their presence is confirmed by effective and feasible evaluation, and if the possession of such attributes in trainers is proven to have a positive effect on training. In times of reduced training opportunities, exploring the topics raised by this review through future education research is warranted.