Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has ...increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.
The proliferation of computer-aided design and additive manufacturing enables on-demand fabrication of complex, three-dimensional structures. However, combining the versatility of cell-laden ...hydrogels within the 3D printing process remains a challenge. Herein, we describe a facile and versatile method that integrates polymer networks (including hydrogels) with 3D-printed mechanical supports to fabricate multicomponent (bio)materials. The approach exploits surface tension to coat fenestrated surfaces with suspended liquid films that can be transformed into solid films. The operating parameters for the process are determined using a physical model, and complex geometric structures are successfully fabricated. We engineer, by tailoring the window geometry, scaffolds with anisotropic mechanical properties that compress longitudinally (~30% strain) without damaging the hydrogel coating. Finally, the process is amenable to high cell density encapsulation and co-culture. Viability (>95%) was maintained 28 days after encapsulation. This general approach can generate biocompatible, macroscale devices with structural integrity and anisotropic mechanical properties.
Abstract Introduction Identification of some somatic molecular alterations in non-small-cell lung cancer (NSCLC) has become evidence-based practice. The success and failure rate of using commercially ...available tumor genotyping techniques in routine day-to-day NSCLC pathology samples is not well described. We sought to evaluate the success and failure rate of EGFR mutation, KRAS mutation, and ALK FISH in a cohort of lung cancers subjected to routine clinical tumor genotype. Methods Clinicopathologic data, tumor genotype success and failure rates were retrospectively compiled and analyzed from 381 patient-tumor samples. Results From these 381 patients with lung cancer, the mean age was 65 years, 61.2% were women, 75.9% were white, 27.8% were never smokers, 73.8% had advanced NSCLC and 86.1% had adenocarcinoma histology. The tumor tissue was obtained from surgical specimens in 48.8%, core needle biopsies in 17.9%, and as cell blocks from aspirates or fluid in 33.3% of cases. Anatomic sites for tissue collection included lung (49.3%), lymph nodes (22.3%), pleura (11.8%), bone (6.0%), brain (6.0%), among others. The overall success rate for EGFR mutation analysis was 94.2%, for KRAS mutation 91.6% and for ALK FISH 91.6%. The highest failure rates were observed when the tissue was obtained from image-guided percutaneous transthoracic core-needle biopsies (31.8%, 27.3%, and 35.3% for EGFR , KRAS , and ALK tests, respectively) and bone specimens (23.1%, 15.4%, and 23.1%, respectively). In specimens obtained from bone, the failure rates were significantly higher for biopsies than resection specimens (40% vs. 0%, p = 0.024 for EGFR ) and for decalcified compared to non-decalcified samples (60% vs. 5.5%, p = 0.021 for EGFR ). Conclusions Tumor genotype techniques are feasible in most samples, outside small image-guided percutaneous transthoracic core-needle biopsies and bone samples from core biopsies with decalcification, and therefore expansion of routine tumor genotype into the care of patients with NSCLC may not require special tissue acquisition or manipulation.
•Review of biomarker testing on over 1000 patients with non-small cell lung cancer.•Biomarker testing patterns evolve with approval of new targeted therapies.•Smoking status affects the frequency of ...targetable oncogenic drivers.
Although a growing list of essential genomic/immune-based biomarkers are linked to approved non-small-cell lung cancer (NSCLC) therapies worldwide, few reports have detailed the evolution of NSCLC predictive biomarker assessment in routine clinical practice.
We retrospectively reviewed the first one thousand plus NSCLC patient specimens from our institution analyzed for predictive biomarkers from 2004 to 2017 and evaluated patterns of testing as well as correlation with clinical-pathologic characteristics.
The majority of 1009 NSCLC patients had advanced stages of adenocarcinoma with most tissues obtained from the lung, mediastinal/hilar nodes, or pleura. The majority of testing was performed on cytology or small biopsy specimens. All were tested for EGFR mutations, 895 for ALK rearrangement, 841 for KRAS mutation, 537 for ROS1 rearrangement, and 179 using comprehensive genomic profiling. Implementation of near-universal genomic biomarker testing at our institution for EGFR, ALK, ROS1 and PD-L1 all occurred within the first year following evidence of clinical activity or regulatory body approval of an associated inhibitor. The overall testing failure rate after use of the best specimen for the most common tests was ≤5.5%. A quarter of tumors had a driver oncogene identified (EGFR/ALK/ROS1/BRAF V600E) with an approved oral targeted therapy, with the highest prevalence in those patients with no or light (≤15 pack-years) history of tobacco use.
Tumor biomarker testing using clinical NSCLC specimens in routine oncologic care evolves rapidly following approval of targeted therapies linked to diagnostic assays. Our practice’s decade plus experience highlights the rapid evolution of biomarker testing and confirms the therapeutic relevance of such testing in all patients—particularly those patients with light/no history of tobacco use.
Adequate tumor acquisition is essential to identify somatic molecular alterations in non–small-cell lung cancer (NSCLC), such as epidermal growth factor receptor (EGFR) mutations and anaplastic ...lymphoma kinase (ALK) translocations. The success and failure rates for tumor genotyping of tissue obtained from fine-needle aspirates of nodal tissue using a convex probe endobronchial ultrasound (CP-EBUS) and other diagnostic modalities in routine NSCLC care have not been described.
Clinicopathologic data, tumor genotype success and failure rates were retrospectively compiled and analyzed from 207 patient-tumor samples sent for routine tumor genotype in clinical practice, including 42 patient-tumor samples obtained from hilar or mediastinal lymph nodes using CP-EBUS.
The median age of the patients was 65 years, 62.3% were women, 77.8% were white, 26.6% were never smokers, 73.9% had advanced NSCLC, and 84.1% had adenocarcinoma histology. Tumor tissue was obtained from CP-EBUS–derived hilar or mediastinal nodes in 42 cases (20.2% of total). In this latter cohort, the overall success rate for EGFR mutation analysis was 95.2%, for Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation 90.5%, and for ALK fluorescence in situ hybridization 90.5%. In the complete 207 tumors, the success rate for EGFR was 92.3%, for KRAS 91.8%, and for ALK 89.9%. The failure rates were not significantly different when comparing CP-EBUS–derived nodal tissue versus all other samples or versus surgical biopsies of mediastinal nodes, but were significantly lower than image-guided percutaneous transthoracic core-needle biopsies.
The success rate of multiple tumor genomic analyses techniques for EGFR, KRAS, and ALK gene abnormalities using routine lung cancer tissue samples obtained from hilar or mediastinal lymph nodes by means of CP-EBUS exceeds 90%, and this method of tissue acquisition is not inferior to other specimen types. Tumor genotype techniques are feasible in most CP-EBUS–derived samples and therefore further expansion of routine tumor genotype for the care of patients with NSCLC may be possible using targeted sample acquisition through CP-EBUS.
Highlights • EGFR mutations occur in some high-grade neuroendocrine lung cancers. • EGFR protein is not expressed in EGFR mutated neuroendocrine lung cancers. • Patients with neuroendocrine lung ...cancers don’t respond to EGFR inhibitors.
Abstract Background Mistreatment has potential downstream effects on students. General surgery rotations tend to have a higher incidence of mistreatment reports. This study was undertaken to identify ...dominant themes contributing to a negative learning environment. Methods A qualitative study was performed using Delphi consensus technique to develop a discussion guide. Four focus groups were performed (n = 30 participants) with medical students, residents, nurses, and attending surgeons. Participants were selected using purposive-stratified criterion-based sampling. Results Multiple themes emerged: 1) unclear expectations for medical students; 2) passive mistreatment (neglect); 3) failure to integrate students into surgical team; 4) witnessed or experienced active mistreatment, 5) negative attitude of residents towards medical students' lack of knowledge. Conclusions Medical student mistreatment persists and is a threat to the learning environment and individual learning process. Passive mistreatment (neglect) represents the most distressing component of mistreatment. These findings suggest a need for education aimed at surgical residents and others in the learning environment.
Abstract Introduction The identification of somatic genomic aberrations in non-small-cell lung cancer (NSCLC) is part of evidence-based practice guidelines for care of patients with NSCLC. We sought ...to establish the frequency and correlates with these changes in routine patient–tumor sample pairs. Methods Clinicopathologic data and tumor genotype were retrospectively compiled and analyzed from an overall cohort of 381 patient–tumor samples. Results Of these patients, 75.9% self-reported White race, 13.1% Asian, 6.5% Black, 27.8% were never-smokers, 54.9% former-smokers and 17.3% current-smokers. The frequency of EGFR mutations was 23.9% (86/359), KRAS mutations 34.2% (71/207) and ALK FISH positivity 9.1% (23/252) in tumor samples, and almost all had mutually exclusive results for these oncogenes. In tumors from White, Black and Asian patients, the frequencies of EGFR mutations were 18.4%, 18.2% and 62%, respectively; of ALK FISH positivity 7.81%, 0% and 14.8%, respectively; and of KRAS mutations 41.6%, 20% and 0%. These patterns changed significant with increasing pack-year history of smoking. In White patients, the frequencies of EGFR mutations and ALK FISH positivity decreased with increasing pack-year cohorts; while the frequencies of KRAS mutations increased. Interestingly, in Asian patients the frequencies of EGFR mutations were similar in never smokers and in the cohorts with less than 45pack-year histories of smoking and only decreased in the 45pack-year plus cohort. Conclusions The frequencies of somatic EGFR , KRAS , and ALK gene abnormalities using routine lung cancer tissue samples from our United States-based academic medical practice reflect the diverse ethnicity (with a higher frequency of EGFR mutations in Asian patients) and smoking patterns (with an inverse correlation between EGFR mutation and ALK rearrangement) of our tested population. These results may help other medical practices appreciate the expected results from introduction of routine tumor genotyping techniques into their day-to-day care of NSCLC.
An excessive amount of nonurgent pages may disrupt patient care, reduce efficiency, and contribute to burnout. We present detailed paging data to analyze frequency, content, and urgency of pages ...received by surgery residents to provide recommendations to reduce resident distractions and fatigue.
Prospective review of pages received by surgery residents over 15 weeks in 2019. Pages were analyzed by content and urgency (routine, important, emergent) by author consensus and compared among day and night shifts, and page senders’ profession.
University tertiary-care hospital
Seventeen junior surgery residents (PGY-1 and PGY-2)
Total 1,740 resident-hours yielded 1,871 pages. Residents working day and night shift received a median of 11 (IQR 7-14) and 13 (IQR 6-22) pages, respectively. Pages from nurses were most common for both shifts but constituted a significantly increased proportion at night (71.3% vs 36.7%, p < 0.00005). Most pages during day shift were routine (74.4%) and pertained to plan of care and order request (38.4% and 15.7%, respectively). Emergent and important pages were more common at night (8.9% and 24.7% vs 1.8 and 14.8%, p < 0.00005) which paralleled an increase in pages reporting change in patient condition compared to day shift (19.7 from 6.7%, p < 0.00005). Routine pages pertaining care plan and order requests remained common at night (26.5 and 28%, respectively).
Over half of pages received by residents contain routine communications about care plan and request for non-urgent orders, even during night shift. Resident-nurse collaboration and support from technology services might optimizing communication pathways.
A nonintrusive e-mail reminder incorporating teaching tips and manuscripts was developed to supplement resident-as-teacher curricula.
Ten high-yield manuscripts and 10 teaching tips exemplifying the ...themes of mentorship or role modeling, teaching methods, adult learning theory, feedback, and the resident role of teaching were distributed to general surgery house staff through a weekly e-mail series. House staff completed surveys before and after the 20-week e-mail series.
Thirty (43%) and 28 (40%) respondents completed the pre-e-mail and post-e-mail survey, respectively. Residents found teaching tips to be more helpful than manuscripts. Weekly e-mail reminders were “just right” in frequency according to 74% of respondents. Forty percent of residents felt the weekly e-mails helped them teach more often and 50% of residents changed their teaching style.
Weekly reminders are an easy way to encourage resident teaching without a significant resident time commitment. Residents typically find teaching tips to be more useful than manuscripts.
•A weekly e-mail series consisting of teaching tips and education manuscripts was e-mailed to general surgery residents.•Surgical residents stated they taught more frequently and differently following the e-mail series.•Surgical residents preferred teaching tips to reading education manuscripts.•Weekly e-mailed teaching tips are an easy, nonintrusive method to encourage teaching among surgical residents.
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