Search

Waste is endemic in the U.S. health care system. Operating rooms are a source of significant solid waste. Surgeons are integral to many decisions in the operating room.Online survey of surgeons at 2 major academic centers in the United States assessing perspectives on intraoperative waste and willingness to work to actively reduce intraoperative waste.We received responses from 219 surgeons: 90% agreed or strongly agreed that waste of sterile surgical items is an issue, and 95% agreed or strongly agreed to a willingness to change the operating room workflow to reduce waste. Surgeons estimated 26% of single-use, sterile supplies opened for surgery were unused at the end of the case. The barriers to waste reduction cited most frequently were: (1) lack of awareness of waste, (2) lack of concern for waste, and (3) lack of time to address the waste.Surgeons understand there is significant waste in the operating room and are willing to change their workflow to reduce waste. Changes in operating room practices that reduce waste will be beneficial to health systems' finances and their efforts to improve population health through a reduction in consumption and pollution. Efforts should be directed toward reducing operating room waste with an initial focus on the elimination of unnecessary waste of sterile surgical supplies. Further work is needed to determine the precise sources of perioperative waste and what initiatives can be implemented to reduce this burden while maintaining high-value patient care.

Therapy-resistant microenvironments represent a major barrier toward effective elimination of disseminated cancer. Many hematologic and solid tumors are resistant to therapeutic antibodies in the bone marrow (BM), but not in the periphery (e.g., spleen). We previously showed that cyclophosphamide (CTX) sensitizes the BM niche to antibody therapeutics. Here, we show that (i) BM resistance was induced not only by the tumor but also by the intrinsic BM microenvironment; (ii) CTX treatment overcame both intrinsic and extrinsic resistance mechanisms by augmenting macrophage activation and phagocytosis, including significant upregulation of activating Fcγ receptors (FcγRIII and FcγRIV) and downregulation of the inhibitory receptor, FcγRIIB; and (iii) CTX synergized with cetuximab (anti-EGFR) and trastuzumab (anti-Her2) in eliminating metastatic breast cancer in the BM of humanized mice. These findings provide insights into the mechanisms by which CTX synergizes with antibody therapeutics in resistant niche-specific organs and its applicability in treating BM-resident tumors.

Inhibitors targeting BRAF and its downstream kinase MEK produce robust response in patients with advanced BRAFV600-mutant melanoma. However, the duration and depth of response vary significantly between patients; therefore, predicting response a priori remains a significant challenge. Here, we utilized the Novartis collection of patient-derived xenografts to characterize transcriptional alterations elicited by BRAF and MEK inhibitors in vivo, in an effort to identify mechanisms governing differential response to MAPK inhibition. We show that the expression of an MITF-high, “epithelial-like” transcriptional program is associated with reduced sensitivity and adaptive response to BRAF and MEK inhibitor treatment. On the other hand, xenograft models that express an MAPK-driven “mesenchymal-like” transcriptional program are preferentially sensitive to MAPK inhibition. These gene-expression programs are somewhat similar to the MITF-high and -low phenotypes described in cancer cell lines, but demonstrate an inverse relationship with drug response. This suggests a discrepancy between in vitro and in vivo experimental systems that warrants future investigations. Finally, BRAFV600-mutant melanoma relies on either MAPK or alternative pathways for survival under BRAF and MEK inhibition in vivo, which in turn predicts their response to further pathway suppression using a combination of BRAF, MEK, and ERK inhibitors. Our findings highlight the intertumor heterogeneity in BRAFV600-mutant melanoma, and the need for precision medicine strategies to target this aggressive cancer.

BRAFV600 mutant melanoma PDXs exhibit varied degrees of MAPK pathway suppression upon BRAF and MEK inhibitor treatment

List of genes from the DEG clustering analysis.

Supplementary Table 4: List of cell lines evaluated for sensitivity to SHP099 (Tab 1) or an RTK-inhibitor (Tab 2) in 2D or 3D. Included is the lineage and the KRAS mutation status. Where data are blank, no viable data was available, or the cell line did not grow appropriately as a tumor spheroid.

This file describes supplementary material and methods used.

In vivo efficacy of SHP099 (100 mg/kg, daily) in the KYSE-520 esophageal cancer cell line model. Data are plotted as the treatment mean {plus minus} s.e.m (n=7) ( (B-I) In vivo efficacy data for cell line models represented in Fig. 3E. SHP099 and trametinib were orally administered at the doses, schedules and for the duration indicated. Data are plotted as the treatment mean {plus minus} s.e.m.

This file contains supplementary tables describing parameters for antitumor activity (T/C analyses), PK and protein crystallography.

Supplementary Materials and Methods, Tables

Supplementary Figures S1-S9 show CD32b mRNA vs protein expression, preclinical activity of NVS32b1 vs NVS32b2, differential activation of human vs mouse FcgRs, CD32b expression on cell lines and healthy immune cells.

Supplementary Material and Methods. File contains the following: Transcriptome sequencing and analysis, Soft agar assay, 2D and 3D Cell proliferation screen and compound characterization information.

This file contains the figure legends for supplementary figures S1-S7.

CSF1R-driven SHP2-dependent MAPK signaling in GDM-1 cells and SHP2 dependency of the viability in M-CSF-stimulated monocytes in the T cell co-culture assay, and the in vivo combination benefit in suppressing tumor associated macrophage by anti-PD-1 antibody and TNO155 in MC38 tumors.

Supplementary Figure Legend

The synergy in the MAPK pathway suppression and anti-proliferation effect by KRASG12C inhibitor and TNO155.

Patients with lung tumors harboring activating mutations in the EGF receptor (EGFR) show good initial treatment responses to the EGFR tyrosine kinase inhibitors (TKI) erlotinib or gefitinib. However, acquired resistance invariably develops. Applying a focused shRNA screening approach to identify genes whose knockdown can prevent and/or overcome acquired resistance to erlotinib in several EGFR-mutant non–small cell lung cancer (NSCLC) cell lines, we identified casein kinase 1 α (CSNK1A1, CK1α). We found that CK1α suppression inhibits the NF-κB prosurvival signaling pathway. Furthermore, downregulation of NF-κB signaling by approaches independent of CK1α knockdown can also attenuate acquired erlotinib resistance, supporting a role for activated NF-κB signaling in conferring acquired drug resistance. Importantly, CK1α suppression prevented erlotinib resistance in an HCC827 xenograft model in vivo. Our findings suggest that patients with EGFR-mutant NSCLC might benefit from a combination of EGFR TKIs and CK1α inhibition to prevent acquired drug resistance and to prolong disease-free survival. Cancer Res; 75(22); 4937–48. ©2015 AACR.

Fig. S1. Summary of EGFR status and sensitivity to erlotinib of NSCLC cell lines used in this study. Fig. S2. Knockdown of CK1α inhibits proliferation of PC9 cells more than proliferation of HCC827 or HCC4006 cells under DMSO treatment. Fig. S3. Performance of individual shRNAs against members of the CK1-family in shRNA screens. Fig. S4. Knockdown of CK1α does not sensitize NSCLC cells to doxorubicin or cisplatin. Fig. S5. Suppression of CK1α attenuates acquired resistance to erlotinib in EGFR-mutant NSCLC cells. Fig. S6. Suppression of CK1α attenuates the outgrowth of drug tolerant persisters (DTPs) to resistant clones and inhibits proliferation of resistant PC9 cells in the presence of erlotinib. Fig. S7. The CK1 inhibitor D4476 can attenuate acquired resistance to erlotinib in NSCLC cell lines. Fig. S8: Knockdown of CK1α does not influence EGFR signaling. Fig. S9: Knockdown of CK1α does not activate WNT-signaling. Fig. S10: Erlotinib treatment activates NF-κB-signaling and CK1α-knockdown decreases expression of NF-κB-target genes. Fig. S11: Inhibition of NF-κB-signaling attenuates resistance to erlotinib while only slightly affecting proliferation in the absence of erlotinib.

Identification of the feedback activated RTK and the synergy in anti-proliferation effect by the combination of respective RTK inhibitors and dabrafenib plus trametinib in RKO and MDST8 cells.

Purpose:SHP2 inhibitors offer an appealing and novel approach to inhibit receptor tyrosine kinase (RTK) signaling, which is the oncogenic driver in many tumors or is frequently feedback activated in response to targeted therapies including RTK inhibitors and MAPK inhibitors. We seek to evaluate the efficacy and synergistic mechanisms of combinations with a novel SHP2 inhibitor, TNO155, to inform their clinical development.Experimental Design:The combinations of TNO155 with EGFR inhibitors (EGFRi), BRAFi, KRASG12Ci, CDK4/6i, and anti–programmed cell death-1 (PD-1) antibody were tested in appropriate cancer models in vitro and in vivo, and their effects on downstream signaling were examined.Results:In EGFR-mutant lung cancer models, combination benefit of TNO155 and the EGFRi nazartinib was observed, coincident with sustained ERK inhibition. In BRAFV600E colorectal cancer models, TNO155 synergized with BRAF plus MEK inhibitors by blocking ERK feedback activation by different RTKs. In KRASG12C cancer cells, TNO155 effectively blocked the feedback activation of wild-type KRAS or other RAS isoforms induced by KRASG12Ci and greatly enhanced efficacy. In addition, TNO155 and the CDK4/6 inhibitor ribociclib showed combination benefit in a large panel of lung and colorectal cancer patient–derived xenografts, including those with KRAS mutations. Finally, TNO155 effectively inhibited RAS activation by colony-stimulating factor 1 receptor, which is critical for the maturation of immunosuppressive tumor-associated macrophages, and showed combination activity with anti–PD-1 antibody.Conclusions:Our findings suggest TNO155 is an effective agent for blocking both tumor-promoting and immune-suppressive RTK signaling in RTK- and MAPK-driven cancers and their tumor microenvironment. Our data provide the rationale for evaluating these combinations clinically.

Supplementary Figure Legends 1-11 Lantermann et al.

Supplementary Table 1: Hit list shRNA screen

The activity of nazartinib, TNO155, and their combination in EGFR mutant NSCLC cell lines.

Supplementary Figure 6 from CD44posCD49fhiCD133/2hi Defines Xenograft-Initiating Cells in Estrogen Receptor–Negative Breast Cancer

Supplementary Figure 3 from CD44posCD49fhiCD133/2hi Defines Xenograft-Initiating Cells in Estrogen Receptor–Negative Breast Cancer

Supplementary Figure 8 from CD44posCD49fhiCD133/2hi Defines Xenograft-Initiating Cells in Estrogen Receptor–Negative Breast Cancer

Supplementary Figure 2 from CD44posCD49fhiCD133/2hi Defines Xenograft-Initiating Cells in Estrogen Receptor–Negative Breast Cancer

Defining the populations of tumor-initating cells that are present in tumors is a first step in developing therapeutics to target these cells. We show here that both CD44posCD24neg and CD44posCD24pos cell populations in estrogen receptor (ER) α–negative breast tumors are tumorigenic in murine xenograft models. We also describe a third population of xenograft-initiating cells (XIC) enriched in CD44posCD49fhiCD133/2hi cells that display heightened tumorigenicity, self-renewal in vivo, and the capacity to give rise to functional and molecular heterogeneity. Consistent with their capacity for self-renewal, these cells express elevated levels of Sox2, Bmi-1, and/or Nanog and their CpG islands are hypermethylated relative to nontumorigenic cells. These differences in methylome regulation may be responsible for the dramatic functional differences between the two populations. The identification of CD44posCD49fhiCD133/2hi XIC in ER-negative tumors may lead to expanded understanding of these tumors and ultimately the development of therapeutics designed to specifically target the cells. Cancer Res; 70(11); 4624–33. ©2010 AACR.

Supplementary Figure 9 from CD44posCD49fhiCD133/2hi Defines Xenograft-Initiating Cells in Estrogen Receptor–Negative Breast Cancer

Supplementary Tables 1-4 from CD44posCD49fhiCD133/2hi Defines Xenograft-Initiating Cells in Estrogen Receptor–Negative Breast Cancer

Supplementary Figure 5 from CD44posCD49fhiCD133/2hi Defines Xenograft-Initiating Cells in Estrogen Receptor–Negative Breast Cancer

Supplementary Figure 7 from CD44posCD49fhiCD133/2hi Defines Xenograft-Initiating Cells in Estrogen Receptor–Negative Breast Cancer

Supplementary Figure 4 from CD44posCD49fhiCD133/2hi Defines Xenograft-Initiating Cells in Estrogen Receptor–Negative Breast Cancer

Purpose: SHP2 inhibitors offer an appealing and novel approach to inhibit receptor tyrosine kinase (RTK) signaling, which is the oncogenic driver in many tumors or is frequently feedback activated in response to targeted therapies including RTK inhibitors and MAPK inhibitors. We seek to evaluate the efficacy and synergistic mechanisms of combinations with a novel SHP2 inhibitor, TNO155, to inform their clinical development. Experimental Design: The combinations of TNO155 with EGFR inhibitors (EGFRi), BRAFi, KRASG12Ci, CDK4/6i, and anti–programmed cell death-1 (PD-1) antibody were tested in appropriate cancer models in vitro and in vivo, and their effects on downstream signaling were examined. Results: In EGFR-mutant lung cancer models, combination benefit of TNO155 and the EGFRi nazartinib was observed, coincident with sustained ERK inhibition. In BRAFV600E colorectal cancer models, TNO155 synergized with BRAF plus MEK inhibitors by blocking ERK feedback activation by different RTKs. In KRASG12C cancer cells, TNO155 effectively blocked the feedback activation of wild-type KRAS or other RAS isoforms induced by KRASG12Ci and greatly enhanced efficacy. In addition, TNO155 and the CDK4/6 inhibitor ribociclib showed combination benefit in a large panel of lung and colorectal cancer patient–derived xenografts, including those with KRAS mutations. Finally, TNO155 effectively inhibited RAS activation by colony-stimulating factor 1 receptor, which is critical for the maturation of immunosuppressive tumor-associated macrophages, and showed combination activity with anti–PD-1 antibody. Conclusions: Our findings suggest TNO155 is an effective agent for blocking both tumor-promoting and immune-suppressive RTK signaling in RTK- and MAPK-driven cancers and their tumor microenvironment. Our data provide the rationale for evaluating these combinations clinically.

Statement of problem Intraoral scanners (IOSs), facial scanners (FSs), and computer-aided design (CAD) software programs have become powerful tools for treatment planning. However, discrepancies in perception regarding 2-dimensional (2D) or 3-dimensional (3D) simulations by dentists, dental students, and laypeople have not been analyzed. Purpose The purpose of this observational study was to analyze the perceptions of laypersons, dental students, and dentists regarding disparities of the maxillary dental midline and the occlusal plane when analyzing the dental discrepancies on 2D- and 3D-clinical simulations. Material and methods A female model was digitized by using an FS, IOS, and a full-face smile photograph. Dental discrepancies were simulated by using a 2D photograph (2D group) and 3D scan (3D group) of the model. In both simulation groups, 2 subgroups were produced. The occlusal plane of the first subgroup was modified in 1-degree increments without changing the dental midline or the position of the maxillary dental incisors. In the second subgroup, the occlusal plane was modified by using the same increments, but the maxillary central incisors and dental midline were altered to match the inclination of the occlusal plane. A total of 300 participants (N=300) were asked to rate the 2D images (N=12) and 3D videos (N=12) on a 1-to-6 scale and answer a questionnaire. Ordinal logistic regression was used to analyze the ratings. Results The ratings decreased with the increased tilt of the occlusal plane, and the layperson group gave consistently higher ratings than the other 2 groups. For dentists, the odds of giving a higher versus lower rating decreased by almost a half for each degree of tilt. However, for students, that effect was diminished by a positive interaction term, and for laypersons, the effect was even less. Students gave similar ratings to dentists, but laypersons gave higher ratings. As the age of the participants increased, however, the ratings also increased. The use of 3D versus 2D images had a positive effect on the ratings, but the effect decreased for the student observers and decreased even further for laypersons. Furthermore, midline alteration led to higher ratings but also resulted in worsening of the odds ratio for the tilt. Seventy percent of the dentists, 57% of the dental students, and 52% of the laypersons preferred 2D simulations to 3D simulations. Conclusions Dentists, dental students, and laypersons decreased their ratings with increased inclination of the occlusal plane; however, laypersons still graded all the 2D and 3D images as esthetically pleasant, giving consistently higher ratings than the dentists and dental students. Overall, 3D simulations obtained higher ratings than 2D images, but the positive effect decreased for the student observers and decreased even further for laypersons.

Objective The relationship between ketamine's hallucinogenic- and dissociative-type effects and antidepressant mechanism of action is poorly understood. This paper reviewed the correlation between subjective effects defined by various psychometric scales and observed clinical outcomes in the treatment of patients with Major Depressive Disorder ( MDD ). Methods Based on PRISMA guidelines, we reviewed the dissociative and psychotomimetic mental state induced with ketamine during MDD treatment. Our selected studies correlated depression rating with validated scales collected at regular intervals throughout the study period such as the Clinician-Administered Dissociative States Scale (CADSS), Brief Psychiatric Rating Scale (BPRS), and the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC). We excluded studies with bipolar depression or with repeated dosing and no single-dose phase. We included 8 of 556 screened reports. Results Two of five CADSS studies found significant negative correlations between increases in CADSS scores and depression scores. One of six BPRS studies demonstrated correlations between BPRS scores and depression scores. The 5D-ASC's one study found no correlation with the MADRS. Conclusions Ketamine's dissociative and psychotomimetic effects were correlated with depression changes in 37.5% of studies, but most studies did not examine this relationship and future studies should consider this association since it appears important for MDMA and psilocybin therapies.

Background High-quality shared decision-making for patients undergoing elective surgical procedures includes eliciting patient goals and treatment preferences. This is particularly important, should complications occur and life-sustaining therapies be considered. Our objective was to determine the preoperative care preferences of older higher-risk patients undergoing elective procedures and to determine any factors associated with a preference for limitations to life-sustaining treatments. Methods Cross-sectional survey conducted between May and December 2018. Patients ≥55 years of age presenting for a preprocedural evaluation in a high-risk anesthesia clinic were queried on their desire for life-sustaining treatments (cardiopulmonary resuscitation, mechanical ventilation, dialysis, and artificial nutrition) as well as tolerance for declines in health states (physical disability, cognitive disability, and daily severe pain). Results One hundred patients completed the survey. The median patient age was 68. Most patients were Caucasian (87%) and had an American Society of Anesthesiologists (ASA) score of III (88%). The majority of patients (89%) desired cardiopulmonary resuscitation. However, most patients would not accept mechanical ventilation, dialysis, or artificial nutrition for an indefinite period of time. Similarly, most patients (67%-81%) indicated they would not desire treatments to sustain life in the event of permanent physical disability, cognitive disability, or daily severe pain. Conclusions Among older, higher-risk patients presenting for elective procedures, most patients chose limitations to life-sustaining treatments. This work highlights the need for an in-depth goals of care discussion and establishment of advance care preferences before a procedure or operative intervention.

KRAS, an oncogene mutated in nearly one third of human cancers, remains a pharmacologic challenge for direct inhibition except for recent advances in selective inhibitors targeting the G12C variant. Here, we report that selective inhibition of the protein tyrosine phosphatase, SHP2, can impair the proliferation of KRAS-mutant cancer cells in vitro and in vivo using cell line xenografts and primary human tumors. In vitro, sensitivity of KRAS-mutant cells toward the allosteric SHP2 inhibitor, SHP099, is not apparent when cells are grown on plastic in 2D monolayer, but is revealed when cells are grown as 3D multicellular spheroids. This antitumor activity is also observed in vivo in mouse models. Interrogation of the MAPK pathway in SHP099-treated KRAS-mutant cancer models demonstrated similar modulation of p-ERK and DUSP6 transcripts in 2D, 3D, and in vivo, suggesting a MAPK pathway–dependent mechanism and possible non-MAPK pathway–dependent mechanisms in tumor cells or tumor microenvironment for the in vivo efficacy. For the KRASG12C MIAPaCa-2 model, we demonstrate that the efficacy is cancer cell intrinsic as there is minimal antiangiogenic activity by SHP099, and the effects of SHP099 is recapitulated by genetic depletion of SHP2 in cancer cells. Furthermore, we demonstrate that SHP099 efficacy in KRAS-mutant models can be recapitulated with RTK inhibitors, suggesting RTK activity is responsible for the SHP2 activation. Taken together, these data reveal that many KRAS-mutant cancers depend on upstream signaling from RTK and SHP2, and provide a new therapeutic framework for treating KRAS-mutant cancers with SHP2 inhibitors.

Inhibitors targeting BRAF and its downstream kinase MEK produce robust response in patients with advanced BRAFV600-mutant melanoma. However, the duration and depth of response vary significantly between patients; therefore, predicting response a priori remains a significant challenge. Here, we utilized the Novartis collection of patient-derived xenografts to characterize transcriptional alterations elicited by BRAF and MEK inhibitors in vivo, in an effort to identify mechanisms governing differential response to MAPK inhibition. We show that the expression of an MITF-high, “epithelial-like” transcriptional program is associated with reduced sensitivity and adaptive response to BRAF and MEK inhibitor treatment. On the other hand, xenograft models that express an MAPK-driven “mesenchymal-like” transcriptional program are preferentially sensitive to MAPK inhibition. These gene-expression programs are somewhat similar to the MITF-high and -low phenotypes described in cancer cell lines, but demonstrate an inverse relationship with drug response. This suggests a discrepancy between in vitro and in vivo experimental systems that warrants future investigations. Finally, BRAFV600-mutant melanoma relies on either MAPK or alternative pathways for survival under BRAF and MEK inhibition in vivo, which in turn predicts their response to further pathway suppression using a combination of BRAF, MEK, and ERK inhibitors. Our findings highlight the intertumor heterogeneity in BRAFV600-mutant melanoma, and the need for precision medicine strategies to target this aggressive cancer.

The sole inhibitory Fcγ receptor CD32b (FcγRIIb) is expressed throughout B and plasma cell development and on their malignant counterparts. CD32b expression on malignant B cells is known to provide a mechanism of resistance to rituximab that can be ameliorated with a CD32b-blocking antibody. CD32b, therefore, represents an attractive tumor antigen for targeting with a monoclonal antibody (mAb). To this end, two anti-CD32b mAbs, NVS32b1 and NVS32b2, were developed. Their complementarity-determining regions (CDR) bind the CD32b Fc binding domain with high specificity and affinity while the Fc region is afucosylated to enhance activation of FcγRIIIa on immune effector cells. The NVS32b mAbs selectively target CD32b+ malignant cells and healthy B cells but not myeloid cells. They mediate potent killing of opsonized CD32b+ cells via antibody-dependent cellular cytotoxicity and phagocytosis (ADCC and ADCP) as well as complement-dependent cytotoxicity (CDC). In addition, NVS32b CDRs block the CD32b Fc–binding domain, thereby minimizing CD32b-mediated resistance to therapeutic mAbs including rituximab, obinutuzumab, and daratumumab. NVS32b mAbs demonstrate robust antitumor activity against CD32b+ xenografts in vivo and immunomodulatory activity including recruitment of macrophages to the tumor and enhancement of dendritic cell maturation in response to immune complexes. Finally, the activity of NVS32b mAbs on CD32b+ primary malignant B and plasma cells was confirmed using samples from patients with B-cell chronic lymphocytic leukemia (CLL) and multiple myeloma. The findings indicate the promising potential of NVS32b mAbs as a single agent or in combination with other mAb therapeutics for patients with CD32b+ malignant cells.