What's important in a contract beyond the salary? A primer for pain physicians and trainees.

This manuscript is designed to complement the previously published primer on salary structures for new pain physicians. The previous manuscript "Employment Contract Financial Models for the Pain Physician: A Primer" had a goal of increasing understanding of financial models by pain fellows when preparing for contract negotiations. This manuscript illustrates the many equally important considerations of "non-monetary" values that are a significant part of contract negotiation outside of salary. It contributes to the overall education for trainees and pain physicians on benefits and job responsibilities.

Indoor and ambient black carbon and fine particulate matter associations with blood biomarkers in COPD patients.

BACKGROUND: Systemic inflammation contributes to cardiovascular risk and chronic obstructive pulmonary disease (COPD) pathophysiology. Associations between systemic inflammation and exposure to ambient fine particulate matter (PM ≤ 2.5 µm diameter; PM2.5), and black carbon (BC), a PM2.5 component attributable to traffic and other sources of combustion, infiltrating indoors are not well described. METHODS: Between 2012 and 2017, COPD patients completed in-home air sampling over one-week intervals, up to four times (seasonally), followed by measurement of plasma biomarkers of systemic inflammation, C-reactive protein (CRP) and interleukin-6 (IL-6), and endothelial activation, soluble vascular adhesion molecule-1 (sVCAM-1). Ambient PM2.5, BC and sulfur were measured at a central site. The ratio of indoor/ambient sulfur in PM2.5, a surrogate for fine particle infiltration, was used to estimate indoor BC and PM2.5 of ambient origin. Linear mixed effects regression with a random intercept for each participant was used to assess associations between indoor and indoor of ambient origin PM2.5 and BC with each biomarker. RESULTS: 144 participants resulting in 482 observations were included in the analysis. There were significant positive associations between indoor BC and indoor BC of ambient origin with CRP [%-increase per interquartile range (IQR);95 % CI (13.2 %;5.2-21.8 and 11.4 %;1.7-22.1, respectively)]. Associations with indoor PM2.5 and indoor PM2.5 of ambient origin were weaker. There were no associations with IL-6 or sVCAM-1. CONCLUSIONS: In homes of patients with COPD without major sources of combustion, indoor BC is mainly attributable to the infiltration of ambient sources of combustion indoors. Indoor BC of ambient origin is associated with increases in systemic inflammation in patients with COPD, even when staying indoors.

Carotid cavernous fistula masquerading as orbital inflammation on noninvasive imaging in a peripartum patient.

A carotid cavernous fistula (CCF) is a pathological connection between the internal or external carotid artery and the cavernous sinus venous system. Pregnancy has been proposed as a risk factor for spontaneous CCF, but the exact mechanism of risk is unknown. Overall, there are few published reports describing CCF in pregnancy. Study of this risk factor relationship is further complicated by potential ambiguity in diagnosing CCF, which may present as subtle, nonspecific findings on initial workup. We report a case of CCF during pregnancy in which the diagnostic process was notable for misleading, noninvasive, imaging studies.

Family physicians' questions about the COVID-19 pandemic: a content analysis of 2,272 helpline calls.

BACKGROUND: During the COVID-19 pandemic, family physicians faced challenges including travel restrictions for patients, lockdowns, diagnostic testing delays, and changing public health guidelines. Given that 95% of Canadian physicians are members of the Canadian Medical Protective Association (CMPA), the CMPA's telephone helpline - which offers peer-to-peer support - provides valuable insights into family physicians' experiences during the pandemic. METHODS: We used a content analysis approach to identify and understand family physicians' questions and concerns related to the COVID-19 pandemic expressed during calls to the Canadian Medical Protective Association (CMPA) telephone helpline. Calls were classified with preliminary codes and subsequently organized into themes. We collected aggregated data on calls, including province, call date, and whether the physician self-identified having hospital-based activities as part of their practice. Findings from the analysis were explored alongside family physician calls per month (call volume). RESULTS: Between 01 and 2020 and 31 December 2021, 2,272 family physician calls related to the pandemic were included for content analysis. We identified six major themes across these calls: challenging patient interactions; COVID-related care; the impact of the pandemic on the healthcare system; virtual care; physician obligations and rights; and public health matters. COVID-related call volumes were highest early in the pandemic especially among physicians without major hospital affiliation when family physicians practiced with little guidance on how to balance patient care and scarce resources in the face of a novel pandemic. CONCLUSIONS: This research provides unique insight on the effects the COVID-19 pandemic had on family medicine in Canada. These results provide insights on the needs and information gaps of family physicians in a public health crisis and can inform preparedness efforts by public health agencies, professional organizations, educators, and practitioners.

Medico-Legal Cases in Breast Imaging in Canada: A Trend Analysis.

Purpose: Breast imaging accounts for a large proportion of medico-legal cases involving radiologists in several countries and may be a disincentive to breast imaging. As this has not been well studied in Canada, we evaluated the key medico-legal issues of breast imaging in Canada and their implications for health care providers and patient safety. Methods: In collaboration with Canadian Medical Protective Association (CMPA), we obtained information from the medico-legal repository, including civil-legal, medical regulatory authority (College) and hospital complaints occurring between 2002-2021. Canadian Classification of Health Interventions (CCI) codes were used for breast imaging and biopsy. Trend analysis was done comparing cases involving breast imaging/biopsy to all cases where a radiologist was named. Results: Radiologists were named in 3108 medico-legal cases, 188 (6%, 188/3108) of which were CCI coded for breast imaging or biopsy. Factors related to radiologists were most frequent (64%, 120/188), followed by team (23.4%, 44/188) and system (6.9%, 13/188). Equal representation of male and female radiologists was found (IRR = 1.22; 95% CI: .89, 1.56). In a 10-year test window from 2006 - 2015 we identified an increasing trend for all cases involving radiologists (P = 0,0128) but a decreasing trend for cases coded with breast imaging or biopsy (P = 0,0099). Conclusions: A significant decrease in cases involving breast imaging were found from 2006-2015, accounting for 6% of the medico-legal cases. The lower risk of breast imaging medico-legal issues may encourage more radiologists in breast imaging.

Targeting Novel LPXTG Surface Proteins with Monoclonal Antibodies for Immunomagnetic Separation of Listeria monocytogenes.

The Gram-positive bacterium Listeria monocytogenes causes a significantly high percentage of fatalities among human foodborne illnesses. Surface proteins, specifically expressed from a wide range of L. monocytogenes serotypes under selective enrichment culture conditions, can serve as targets for the isolation of this pathogen using antibody-based methods to facilitate molecular detection. In this study, monoclonal antibodies (MAbs), previously raised against the L. monocytogenes LPXTG surface proteins LMOf2365_0639 and LMOf2365_0148, were investigated for their ability to isolate L. monocytogenes from bacterial samples with immunomagnetic separation (IMS). Only 1 out of 35 MAbs against LMOf2365_0639, M3644, was capable of capturing L. monocytogenes. Among all the 24 MAbs examined against LMOf2365_0148, 4 MAbs, M3686, M3697, M3699, and M3700, were capable of capturing L. monocytogenes cells specifically from abbreviated primary selective enrichment cultures in either Palcam or LEB/UVM1 media or from mixed samples containing target and nontarget bacteria. MAb M3686 showed a unique specificity with the capability to capture strains of seven L. monocytogenes serotypes (1/2a, 1/2b, 1/2c, 3a, 4a, 4b, and 4d). These promising MAbs were subsequently characterized by quantitative measurements of antigen-binding affinity using surface plasmon resonance analysis and epitope mapping using overlapping recombinant polypeptides. The usefulness of these MAbs to LMOf2365_0148 in bacterial capture was consistent with their high affinities with KD constants in the nanomolar range and can be explored further for the development of an automated IMS method suitable for routine isolation of L. monocytogenes from food and environmental samples.

Second Generation of Cata-Annulated Azaacene Bisimides: Towards Electron-Accepting Materials.

This work presents the 2nd generation of cata-annulated azaacene bisimides with increased electron affinities (up to -4.38 eV) compared to their consaguine conventional azaacenes. These compounds were synthesized via Buchwald-Hartwig coupling followed by oxidation with MnO2 . Crystal structure engineering through variation of the bisimide substituents furnished crystalline derivatives suitable for proof of concept organic field effect transistors with electron mobilities up to 2.2×10-4  cm2 (Vs)-1 . Moreover, we were able to characterize the charge carrying species, the radical anion, using electron paramagnetic resonance and absorption measurements.

Design of medical tympanostomy conduits with selective fluid transport properties.

Implantable tubes, shunts, and other medical conduits are crucial for treating a wide range of conditions from ears and eyes to brain and liver but often impose serious risks of device infection, obstruction, migration, unreliable function, and tissue damage. Efforts to alleviate these complications remain at an impasse because of fundamentally conflicting design requirements: Millimeter-scale size is required to minimize invasiveness but exacerbates occlusion and malfunction. Here, we present a rational design strategy that reconciles these trade-offs in an implantable tube that is even smaller than the current standard of care. Using tympanostomy tubes (ear tubes) as an exemplary case, we developed an iterative screening algorithm and show how unique curved lumen geometries of the liquid-infused conduit can be designed to co-optimize drug delivery, effusion drainage, water resistance, and biocontamination/ingrowth prevention in a single subcapillary-length-scale device. Through extensive in vitro studies, we demonstrate that the engineered tubes enabled selective uni- and bidirectional fluid transport; nearly eliminated adhesion and growth of common pathogenic bacteria, blood, and cells; and prevented tissue ingrowth. The engineered tubes also enabled complete eardrum healing and hearing preservation and exhibited more efficient and rapid antibiotic delivery to the middle ear in healthy chinchillas compared with current tympanostomy tubes, without resulting in ototoxicity at up to 24 weeks. The design principle and optimization algorithm presented here may enable tubes to be customized for a wide range of patient needs.

Improved Syntheses of Halogenated Benzene-1,2,3,4-Tetracarboxylic Diimides.

The preparation of halogenated benzene-1,2,3,4-tetracarboxylic diimide derivatives is challenging because of the possibility of competitive incorrect cyclizations and SNAr reactivity. Here, we demonstrate that bypassing traditional cyclic anhydrides and instead directly reacting dihalobenzene-1,2,3,4-tetracarboxylic acids with primary amines in acetic acid solvent successfully provides a range of desirable ortho-diimide products in good yields. Furthermore, we demonstrate that sterically challenging N-derivatizations can be readily achieved under microwave reactor conditions. The halogenated diimides described here are attractive building blocks for organic materials chemistry.

Patterns and trends among physicians-in-training named in civil legal cases: a retrospective analysis of Canadian Medical Protective Association data from 1993 to 2017.

BACKGROUND: Medico-legal data show opportunities to improve safe medical care; little is published on the experience of physicians-in-training with medical malpractice. The purpose of this study was to examine closed civil legal cases involving physicians-in-training over time and provide novel insights on case and physicians characteristics. METHODS: We conducted a retrospective descriptive study of closed civil legal cases at the Canadian Medical Protective Association (CMPA), a mutual medico-legal defence organization for more than 105 000 physicians, representing an estimated 95% of physicians in Canada. Eligible cases involved at least 1 physician-in-training and were closed between 1993 and 2017 (for time trends) or 2008 and 2017 (for descriptive analyses). We analyzed case rates over time using Poisson regression and the annualized change rate. Descriptive analyses addressed case duration, medico-legal outcome and patient harm. We explored physician specialties and practice characteristics in a subset of cases. RESULTS: Over a 25-year period (1993-2017), 4921 physicians-in-training were named in 2951 closed civil legal cases, and case rates decreased significantly (ß = -0.04, 95% confidence interval -0.05 to -0.03, where ß was the 1-year difference in log case rates). The annualized change rate was -1.1% per year. Between 2008 and 2017, 1901 (4.1%) of 45 967 physicians-in-training were named in 1107 civil legal cases. Cases with physicians-in-training generally involved more severe patient harm than cases without physicians-in-training. In a subgroup with available information (n = 951), surgical specialties were named most often (n = 531, 55.8%). INTERPRETATION: The rate of civil legal cases involving physicians-in-training has diminished over time, but more recent cases featured severe patient harm and death. Efforts to promote patient safety may enhance medical care and reduce the frequency and severity of malpractice issues for physicians-in-training.

Comparative biomarker analysis of PALOMA-2/3 trials for palbociclib.

While cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including palbociclib, combined with endocrine therapy (ET), are becoming the standard-of-care for hormone receptor-positive/human epidermal growth factor receptor 2‒negative metastatic breast cancer, further mechanistic insights are needed to maximize benefit from the treatment regimen. Herein, we conducted a systematic comparative analysis of gene expression/progression-free survival relationship from two phase 3 trials (PALOMA-2 [first-line] and PALOMA-3 [≥second-line]). In the ET-only arm, there was no inter-therapy line correlation. However, adding palbociclib resulted in concordant biomarkers independent of initial ET responsiveness, with shared sensitivity genes enriched in estrogen response and resistance genes over-represented by mTORC1 signaling and G2/M checkpoint. Biomarker patterns from the combination arm resembled patterns observed in ET in advanced treatment-naive patients, especially patients likely to be endocrine-responsive. Our findings suggest palbociclib may recondition endocrine-resistant tumors to ET, and may guide optimal therapeutic sequencing by partnering CDK4/6 inhibitors with different ETs. Pfizer (NCT01740427; NCT01942135).

Control over emergence and alignment of transient blisters in thermo-responsive gels using hierarchically patterned substrates.

Surfaces with tunable microscale textures are vital in a large variety of technological applications, including heat transfer, antifouling and adhesion. To facilitate such broad-scale use, there is a need to create surfaces that undergo reconfigurable changes in topology and thus, enable switchable functionality. To date, there is a relative dearth of methods for engineering surfaces that can be actuated to change topography over a range of length scales, and hence, form tunable hierarchically structured layers. Combining modeling and experiments, we design a geometrically patterned, thermo-responsive poly (N-isopropylacrylamide) gel film that undergoes controllable hierarchical changes in topology with changes in temperature. At the bottom, the film is covalently bound to a solid, curved substrate; at the top, the film encompasses longitudinal rectangular ridges that are oriented perpendicular to the underlying cylindrical curves. At temperatures below lower critical solution temperature (LCST), the swollen gel exhibits 3D variations in polymer density and thickness defined by the gel's top and bottom topography. As the temperature rises above LCST, the interplay between the upper ridges and lower curves in the gel drives non-uniform, directional solvent transport, the nucleation and propagation of a phase-separated higher-density skin layer, and the resulting pressure buildup within the film. These different, interacting kinetic processes lead to an instability, which produces transient microscopic blisters in the film. Through simulations, we show how tuning the width of the ridges modifies the propagation of a skin layer and creates localized pressure build-up points, which enables control over the emergence, distribution, and alignment of the microscopic blisters. Additionally, we provide a simple argument to predict the size of such microscopic features. Experiments confirm our predictions and further highlight how our computational model enables the rational design of topographical transitions in these tunable films. The development of actuatable, hierarchically structured films provides new routes for achieving switchable functionality in actuators, drug release systems and adhesives.

Physician questions and concerns related to COVID-19: a content analysis of advice calls to a medico-legal helpline.

BACKGROUND: With the onset of the COVID-19 pandemic, physicians have had concerns related to the impact of the pandemic on their practice of medicine. Our objective was to evaluate physician questions and concerns related to the COVID-19 pandemic by studying physician calls made to a medico-legal telephone helpline, and explore associations between the pattern of these calls and the temporal progression of the pandemic. METHODS: We conducted a descriptive study of calls related to the COVID-19 pandemic to the Canadian Medical Protective Association (CMPA) from Jan. 1, 2020, to June 30, 2021. Using content analysis, we classified calls into themes. Using a Poisson regression model, we tested for associations between the weekly numbers of physician calls related to COVID-19 and national rates of COVID-19 cases and deaths. RESULTS: We analyzed 3810 COVID-19-related calls. The highest call volume was observed during the pandemic's early months and was widely distributed across the country. Call volume correlated with rates of SARS-CoV-2 infection during the pandemic's first wave (p = 0.002) but not across the entire study period. Call themes included virtual care (826 calls), the pandemic's effect on health care (1160 calls) and challenging patient interactions (1091 calls). INTERPRETATION: We observed high volumes of physician calls to a medico-legal helpline during the first 18 months of the COVID-19 pandemic in Canada. Our data provide insight into the questions and concerns of Canadian physicians, and serve as a contemporaneous account of the adaptability and resilience of physicians during this challenging time.

Assessment of Listeria monocytogenes Surface Proteins Identified from Proteomics Analysis for Use as Diagnostic Biomarkers.

The Gram-positive bacterium Listeria monocytogenes is an important pathogen that causes a foodborne illness with a high percentage of fatalities. Surface proteins, specifically expressed from a wide range of L. monocytogenes serotypes under selective enrichment culture conditions, can serve as targets for the detection and isolation of this pathogen using antibody-based methods. Among a number of surface proteins identified by mass spectrometry in a previous proteomic study, six candidates (annotated as LMOf2365_0148, LMOf2365_0312, LMOf2365_0546, LMOf2365_1883, LMOf2365_2111, and LMOf2365_2742) were selected here for investigating their expression in the bacterial cells cultured in vitro by raising rabbit polyclonal antibodies (PAbs) against the recombinant form of each candidate. These protein candidates contained regions conserved among various L. monocytogenes isolates but variable in other Listeria species. LMOf2365_0148, an uncharacterized protein with a LPXTG motif accountable for covalent linkage to the cell wall peptidoglycan, exhibited a strong reaction signal from anti-LMOf2365_0148 PAb binding to the cell surface, as detected by immunofluorescence microscopy. Further study, through the generation of a panel of mouse monoclonal antibodies (MAbs) to the recombinant LMOf2365_0148, showed that one of the MAbs, M3686, reacted to bacterial isolates belonging to all three lineages of L. monocytogenes under Health Canada's standard enrichment culture conditions (MFHPB-07 and MFHPB-30). These results demonstrated the potential of using LMOf2365_0148 as a surface biomarker, in conjunction with specific MAbs developed here, for the isolation and detection of L. monocytogenes from foods and food processing environments. IMPORTANCE Strains of Listeria monocytogenes are differentiated serologically into at least 13 serotypes and grouped phylogenetically into 4 distinct lineages (I, II, III, and IV). No single monoclonal antibody (MAb) reported to date is capable of binding to the surface of L. monocytogenes strains representing all the serotypes. This study assessed the expression of six surface proteins selected from a previous proteomic study and demonstrated that surface protein LMOf2365_0148 has the greatest potential as a surface biomarker. A panel of 24 MAbs to LMOf2365_0148 were assessed extensively, revealing that one of the MAbs, M3686, reacted to a wide range of L. monocytogenes isolates (lineage I, II, and III isolates) grown under standard enrichment culture conditions and thus led to the conclusion that LMOf2365_0148 is a useful novel surface biomarker for identifying, detecting, and isolating the pathogen from food and environmental samples.

Trends and Contributing Factors in Medicolegal Cases Involving Spine Surgery.

STUDY DESIGN: Retrospective descriptive study. OBJECTIVE: The aim of this study was to describe closed medicolegal cases involving physicians and spine surgery in Canada from a trend and patient safety perspective. SUMMARY OF BACKGROUND DATA: Spine surgery is a source of medicolegal complaints against surgeons partly owing to the potential severity of associated complications. In previous medicolegal studies, researchers applied a medicolegal lens to their analyses without applying a quality improvement or patient safety lens. METHODS: The study comprised a 15-year medicolegal trend analysis and a 5-year contributing factors analysis of cases (civil legal and regulatory authority matters) from the Canadian Medical Protective Association (CMPA), representing an estimated 95% of physicians in Canada. Included cases were closed by the CMPA between 2004 and 2018 (trends) or 2014 and 2018 (contributing factors). We fit a linear trend line to the annual rates of spine surgery cases per 1000 physician-years of CMPA membership for physicians in a neurosurgery or orthopedic surgery specialty. We then applied an ANOVA type III sum of squares test to determine the statistical significance of the annualized change rate over time. For the contributing factors analysis, we reported descriptive statistics for patient and physician characteristics, patient harm, and peer expert criticisms in each case. RESULTS: Our trend analysis included 340 cases. Case rates decreased significantly at an annualized change rate of -4.7% (P  = 0.0017). Our contributing factors analysis included 81 civil legal and 19 regulatory authority cases. Most patients experienced health care-related harm (89/100, 89.0%). Peer experts identified intraoperative injuries (29/89, 32.6%), diagnostic errors (14/89, 15.7%), and wrong site surgeries (16/89, 18.0%) as the top patient safety indicators. The top factor contributing to medicolegal risk was physician clinical decision-making. CONCLUSION AND RELEVANCE: Although case rates decreased, patient harm was attributable to health care in the majority of recently closed cases. Therefore, crucial opportunities remain to enhance patient safety in spine surgery.Level of Evidence: 4.

Pressurized interfacial failure of soft adhesives.

Interfacial separation of soft, often viscoelastic, materials typically cause the onset of instabilities, such as cavitation and fingering. These instabilities complicate the pathways for interfacial separation, and hence hinder the quantitative characterization of bulk and interfacial contributions to soft material adhesion. To overcome these challenges, we developed a method termed pressurized interfacial failure (PIF), in which the interfacial separation is controlled by applying a positive pressure at the contact interface between a rigid, annular probe and a thin adhesive. We conducted experiments on model and commercially-available acrylic adhesives. Surprisingly, all the materials studied here fail by an inside-out growth of an interfacial cavity and show similar trends in the interrelationship between the cavity radius, applied pressure and change of contact force. In contrast, the force-displacement relationships of the same materials measured by conventional tack tests vary significantly. Accordingly, we conclude that the PIF method allows for controlling the interfacial failure mechanism. Furthermore, we have applied a linear elastic fracture mechanics framework and conducted finite element analysis to develop analytical models to calculate the critical energy release rate for interfacial separation, Gc. For model acrylic adhesives and commercially available adhesives, the values of Gc are similar to values determined by sphere-probe tack tests. Collectively, the herein introduced PIF method and analysis work provide a new foundation for quantitatively decoupling the interfacial and bulk contributions to soft polymer adhesion.

Corneal perforation in ocular graft-versus-host disease.

PURPOSE: Corneal perforation is a rare, vision-threatening complication of ocular graft-versus-host disease (GVHD) and is not well understood. Our objective was to examine the clinical disease course and histopathologic correlation in patients who progressed to this outcome. METHODS: This study is a retrospective case series from four academic centers in the United States. All patients received a hematopoietic stem cell transplant (HSCT) prior to developing ocular GVHD. Variables of interest included patient demographics, time interval between HSCT and ocular events, visual acuity throughout clinical course, corticosteroid and infection prophylaxis regimens at time of corneal perforation, medical/surgical interventions, and histopathology. RESULTS: Fourteen eyes from 14 patients were analyzed. Most patients were male (86%) and Caucasian (86%), and average age at time of hematopoietic stem cell transplant was 47 years. The mean interval between hematopoietic stem cell transplant and diagnosis of ocular graft-versus-host disease was 9.5 months, and between hematopoietic stem cell transplant and corneal perforation was 37 months. Initial best-corrected visual acuity was 20/40 or better in 9 eyes, and all eyes had moderate or poor visual outcomes despite aggressive management, including corneal gluing in all patients followed by keratoplasty in 8 patients. The mean follow-up after perforation was 34 months (range 2-140 months). Oral prednisone was used prior to perforation in 11 patients (79%). On histopathology, representative specimens in the acute phase demonstrated ulcerative keratitis with perforation but minimal inflammatory cells and no microorganisms, consistent with sterile corneal "melt" in the setting of immunosuppression; and in the healed phase, filling in of the perforation site with fibrous scar. CONCLUSIONS: In these patients, an extended time interval was identified between the diagnosis of ocular graft-versus-host disease and corneal perforation. This represents a critical window to potentially prevent this devastating outcome. Further study is required to identify those patients at greatest risk as well as to optimize prevention strategies.

Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor.

The CDK4/6 inhibitor, palbociclib (PAL), significantly improves progression-free survival in HR+/HER2- breast cancer when combined with anti-hormonals. We sought to discover PAL resistance mechanisms in preclinical models and through analysis of clinical transcriptome specimens, which coalesced on induction of MYC oncogene and Cyclin E/CDK2 activity. We propose that targeting the G1 kinases CDK2, CDK4, and CDK6 with a small-molecule overcomes resistance to CDK4/6 inhibition. We describe the pharmacodynamics and efficacy of PF-06873600 (PF3600), a pyridopyrimidine with potent inhibition of CDK2/4/6 activity and efficacy in multiple in vivo tumor models. Together with the clinical analysis, MYC activity predicts (PF3600) efficacy across multiple cell lineages. Finally, we find that CDK2/4/6 inhibition does not compromise tumor-specific immune checkpoint blockade responses in syngeneic models. We anticipate that (PF3600), currently in phase 1 clinical trials, offers a therapeutic option to cancer patients in whom CDK4/6 inhibition is insufficient to alter disease progression.