Correlation of immune fitness with response to teclistamab in relapsed/refractory multiple myeloma in MajesTEC-1.

Teclistamab, an off-the-shelf B-cell maturation antigen (BCMA) × CD3 bispecific antibody that mediates T-cell activation and subsequent lysis of BCMA-expressing myeloma cells, is approved for the treatment of patients with relapsed/refractory multiple myeloma (RRMM). As a T-cell redirection therapy, clinical outcomes with teclistamab may be influenced by patient immune fitness and tumor antigen expression. We correlated tumor characteristics and baseline immune profiles with clinical response and disease burden in patients with RRMM from the pivotal phase 1/2 MajesTEC-1 study, focusing on patients treated with 1.5 mg/kg of teclistamab (N = 165). Peripheral blood samples were collected at screening and bone marrow samples were collected at screening and cycle 3. Better clinical outcomes to teclistamab correlated with higher baseline total T-cell counts in the periphery. In addition, responders (partial response or better) had a lower proportion of immunosuppressive regulatory T cells, T cells expressing co-inhibitory receptors (CD38, PD-1, PD-1/TIM-3), and soluble BCMA, and a T-cell profile suggestive of a more cytolytic potential, compared with nonresponders. Neither frequency of baseline bone marrow BCMA expression nor BCMA receptor density were associated with clinical response to teclistamab. Improved progression-free survival was observed in patients with a lower frequency of T cells expressing exhaustion markers and immunosuppressive regulatory T cells. Overall, response to teclistamab was associated with baseline immune fitness; nonresponders had immune profiles suggestive of immune suppression and T-cell dysfunction. These findings illustrate the importance of the contribution of the immune landscape to T-cell redirection therapy response. This trial was registered at www.ClinicalTrials.gov, NCT03145181/NCT04557098.

Patient-centred learning in practice. A mixed methods study of supervision and learning in student clinics.

OBJECTIVE: Patient-centred learning (PCL) allows medical students to practice a patient-centred approach; however, didactic characteristics of PCL have yet to be fully elucidated. Clinical placements structured as a student clinic (SC) enable authentic student-patient learning relations through enhanced student responsibility and can serve as examples of PCL. We explored the didactic characteristics of supervision and learning in SCs to provide recommendations for PCL-oriented medical education. METHODS: Triangulation mixed methods study based on qualitative data collected from in-depth interviews with clinical teachers and quantitative data collected from student evaluations of supervision and learning in the SCs. RESULTS: Supervision and learning in SCs were characterized by 1) a focus on student-patient compatibility and patient needs and resources, which indicated PCL, 2) person-centred explorative supervision to adjust challenges to students' needs and resources, and 3) support of student autonomy to take responsibility for patient treatment. CONCLUSION: PCL was facilitated by clinical teachers through a dual person-centred didactic approach combined with autonomy-supportive didactic practice. This enabled the integration of patients' and students' needs and resources in clinical teaching. PRACTICE IMPLICATIONS: Clinical teachers can stimulate student-patient learning relations by selecting patients, exploring students' needs and resources, and supporting student autonomy through reflective practice and backup.

Embodied teacher identity: a qualitative study on 'practical sense' as a basic pedagogical condition in times of Covid-19.

Worldwide, the Covid-19 pandemic has transformed teaching contexts rapidly. Studies on the effects of the Covid-19 pandemic have largely focused on students' learning and well-being. In contrast, little is known about how emergency online teaching affects teachers. The aim of this study was to examine how disrupted teaching contexts during the Covid-19 pandemic affected academic teacher identities in health science education. Interviews were conducted with 19 experienced lecturers in health science education from two universities. Interview data were analysed using systematic text condensation. The established codes were compared across interviews to identify common themes and subsequently synthesized into descriptions of the emerging phenomena. Findings indicated that a form of embodied teacher identity, i.e. internalized teaching practices turned into dispositions, constituted a basic pedagogical condition and a resource for the teachers, and that the sudden change in the teaching context caused a loss of teacher identity. This identity loss was related to an incorporated understanding and use of the teacher's sense of the classroom (subtheme 1), non-verbal feedback from students (subtheme 2) and reciprocal visual contact (subtheme 3). Data also indicated that teachers' ability to adapt their teaching to students' needs while teaching and teachers' motivation and job satisfaction may have suffered. Universities should carefully consider how to cultivate sustainable and adaptive teacher identities compatible with the increasing digitalization of learning environments. Teaching is an embodied affair, and teacher identities are sensitive to structural changes in teaching contexts.

A Modular Approach to Light Capture and Synthetic Tuning of the Excited-State Properties of Fe(II)-Based Chromophores.

The development of chromophores based on earth-abundant transition metals whose photophysical properties are dominated by their charge-transfer excited states has inspired considerable research over the past decade. One challenge associated with this effort is satisfying the dual requirements of a strong ligand field and chemical tunability of the compound's absorptive cross-section. Herein we explore one possible approach using a heteroleptic compositional motif that combines both of these attributes into a single compound. With the parent complex [Fe(phen)3]2+ (1; where phen is 1,10-phenanthroline) as the starting material, replacement of one of the phen ligands for two cyanides to obtain Fe(phen)2(CN)2 (2) allows for conversion to [Fe(phen)2(C4H10N4)]2+ (3), a six-coordinate Fe(II) complex whose coordination sphere consists of two chelating polypyridyl ligands and one bidentate carbene-based donor. Ground-state absorption spectra of all three compounds exhibit 1A1 → 1MLCT transition(s) associated with the phen ligands that are relatively insensitive to the identity of the third counterligand(s). Ultrafast time-resolved electronic absorption measurements revealed lifetimes for the MLCT excited states of compounds 1 and 2 of 180 ± 30 and 250 ± 90 fs, respectively, values that are typical for iron(II)-based polypyridyl complexes. The corresponding kinetics for compound 3 were substantially slower at 7.4 ± 0.9 ps; the spectral evolution associated with these dynamics confirms that these kinetics are tracking the MLCT excited state and, more importantly, are coupled to ground-state recovery from this excited state. The data are interpreted in terms of a modulation of the relative energies of the MLCT and ligand-field states across the series, leading to a systematic destabilization of metal-localized ligand-field excited states such that the low-energy portions of the charge-transfer and ligand-field manifolds are at or near an energetic inversion point in compound 3. We believe these results illustrate the potential for a modular, orthogonal approach to chromophore design in which part of the coordination sphere can be targeted for light absorption while another can be used to tune electronic-state energetics.

Deep immune profiling of patients treated with lenalidomide and dexamethasone with or without daratumumab.

CD38-targeted antibody, daratumumab, is approved for the treatment of multiple myeloma (MM). Phase 1/2 studies GEN501/SIRIUS revealed a novel immunomodulatory mechanism of action (MOA) of daratumumab that enhanced the immune response, reducing natural killer (NK) cells without affecting efficacy or safety. We further evaluated daratumumab's effects on immune cells in whole blood samples of relapsed/refractory MM patients from both treatment arms of the phase 3 POLLUX study (lenalidomide/dexamethasone [Rd] or daratumumab plus Rd [D-Rd]) at baseline (D-Rd, 40; Rd, 45) and after 2 months on treatment (D-Rd, 31; Rd, 33) using cytometry by time-of-flight. We confirmed previous reports of NK cell reduction with D-Rd. Persisting NK cells were phenotypically distinct, with increased expression of HLA-DR, CD69, CD127, and CD27. The proportion of T cells increased preferentially in deep responders to D-Rd, with a higher proportion of CD8+ versus CD4+ T cells. The expansion of CD8+ T cells correlated with clonality, indicating generation of adaptive immune response with D-Rd. D-Rd resulted in a higher proportion of effector memory T cells versus Rd. D-Rd reduced immunosuppressive CD38+ regulatory T cells. This study confirms daratumumab's immunomodulatory MOA in combination with immunomodulatory drugs and provides further insight into immune cell changes and activation status following daratumumab-based therapy.

Blood-based gene expression signature associated with metastatic castrate-resistant prostate cancer patient response to abiraterone plus prednisone or enzalutamide.

BACKGROUND: Precision medicine approaches for managing patients with metastatic castrate-resistant prostate cancer (mCRPC) are lacking. Non-invasive approaches for molecular monitoring of disease are urgently needed, especially for patients suffering from bone metastases for whom tissue biopsy is challenging. Here we utilized baseline blood samples to identify mCRPC patients most likely to benefit from abiraterone plus prednisone (AAP) or enzalutamide. METHODS: Baseline blood samples were collected for circulating tumor cell (CTC) enumeration and qPCR-based gene expression analysis from 51 men with mCRPC beginning treatment with abiraterone or enzalutamide. RESULTS: Of 51 patients (median age 68 years [51-82]), 22 received AAP (abiraterone 1000 mg/day plus prednisone 10 mg/day) and 29 received enzalutamide (160 mg/day). The cohort was randomly divided into training (n = 37) and test (n = 14) sets. Baseline clinical variables (Gleason score, PSA, testosterone, and hemoglobin), CTC count, and qPCR-based gene expression data for 141 genes/isoforms in CTC-enriched blood were analyzed with respect to overall survival (OS). Genes with expression most associated with OS included MSLN, ARG2, FGF8, KLK3, ESRP2, NPR3, CCND1, and WNT5A. Using a Cox-elastic net model for our test set, the 8-gene expression signature had a c-index of 0.87 (95% CI [0.80, 0.94]) and was more strongly associated with OS than clinical variables or CTC count alone, or a combination of the three variables. For patients with a low-risk vs. high-risk gene expression signature, median OS was not reached vs. 18 months, respectively (HR 5.32 [1.91-14.80], p = 0.001). For the subset of 41 patients for whom progression-free survival (PFS) data was available, the median PFS for patients with a low-risk vs high-risk gene expression signature was 20 vs. 5 months, respectively (HR 2.95 [1.46-5.98], p = 0.003). CONCLUSIONS: If validated in a larger prospective study, this test may predict patients most likely to benefit from second-generation antiandrogen therapy.

The best way possible! A fieldwork study outlining expectations and needs for nursing of patients in endoscopy facilities for short-term stay.

This paper is a descriptive study of nursing in facilities for short-term stay, aiming to outline the expectations and needs for nursing of patients undergoing gastroscopy in outpatient endoscopy clinics. Existing research finds it important to meet patients' expectations and needs for help to get through a procedure in the best and safest way possible. Despite recent years' focus on patient expectations, little attention has been paid to understanding the patients' distinct expectations and needs for nursing in the context of facilities for short-term stay. A fieldwork study influenced by practical ethnographic principles was performed in high-technology endoscopy outpatient clinics during 2008 - 2010. Data were collected using triangulation of participant observation for 12 weeks including participant reports and semi-structured interviews with eight patients and four nurses. The expectations and needs for nursing of patients undergoing gastroscopy were related to two main areas, summarized by the categories: 'Nervousness and anxiety' and 'Maintaining control'. The former concerned how patients managed their nervousness and anxiety and was described differently in terms of 'Getting it over with', 'The meaning of words' and 'Taking precautions'. The latter 'Maintaining control' concerned how patients in different ways managed to maintain control over their situation and was described in terms of 'Being informed', 'Others are in the same "boat"' and 'Being proactive'. The study concludes that nervousness and anxiety are expressed differently in patients undergoing gastroscopy and that patients have individual ways of claiming their right to elements of control over the situation and the course of gastroscopy. In order for nursing in endoscopy settings to be tailored to the individual patient, it must be adapted to the individual patient's ways of managing nervousness and anxiety as well as ways of claiming control.

What to know and how to get to know? A fieldwork study outlining the understanding of knowing the patient in facilities for short-term stay.

AIM: To report a descriptive study of nursing in facilities for short-term stay aiming to outline what 'knowing the patient' means in an endoscopic outpatient clinic. BACKGROUND: 'Knowing the patient' is indispensable to the effort of tailoring nursing to the individual patient's needs. Structural changes in the practice environments, however, reduce the amount of time a nurse spends getting to know the patient. Despite recent years' focus on the subject, no uniform description of 'knowing the patient' in facilities for short-term stay exists. DESIGN: A fieldwork study influenced by practical ethnographic principles was performed in a high-technology endoscopic outpatient clinic during 2008-2010. METHODS: Data were collected using participant observation for 12 weeks and semi-structured interviews with eight patients and four nurses. FINDINGS: Findings were summarized into two categories 'What to know?' and 'How to get to know?' The former concerned practical issues in relation to gastroscopy and was described in terms of the patient's level of anxiety, wish for medication and previous experiences. The latter 'How to get to know?' concerned instruments employed in getting to know the patient and was described in terms of the use of communication and sensing. CONCLUSIONS: 'Knowing the patient' in the endoscopic outpatient clinic was understood in a very practical sense. Conversation and the use of the eyes and physical touch enabled a situational awareness. It helped tailor nursing to the patient's needs and allowed the nurse to treat every patient as a unique individual.

Calcium phosphate cement enhances primary stability of open-wedge high-tibial osteotomies.

We investigated if injectable calcium phosphate cement improves primary stability in open-wedge high-tibial osteotomy. A 10 mm open-wedge osteotomy was performed on eight pairs of preserved cadaver tibiae and seven pairs of composite (Sawbone) left tibiae. Osteosynthesis was performed with the Dynafix plate system. The gap resulting from surgery either was filled with 15 g injectable calcium phosphate cement in half the bones or was left untreated. The composite tibiae were loaded at a ramp speed of 20 mm/min up to 20 kN. The cadaver tibiae were exposed to 100 cycles with a maximum compressive force of 2,250 N. After 100 cycles of loading with 2,250 N, the final loaded displacement was 1.2 mm for the cadaver tibiae treated with injectable calcium phosphate cement as compared with 3.6 mm for the empty defects (P = 0.028). All the seven empty defect composite specimens failed prior to 20 kN (median 2.8 kN) as compared with five of the injectable calcium phosphate cement specimens (median 17 kN) (P = 0.005). The injection of injectable calcium phosphate cement following open-wedge osteotomy of the proximal tibia increases the initial stability of the bone as measured by load-to-failure and displacement after cyclic loading. Clinical studies are ongoing to investigate whether injectable calcium phosphate cement also has clinical advantage on wedge healing and stability.

Association of GUCY2C expression in lymph nodes with time to recurrence and disease-free survival in pN0 colorectal cancer.

CONTEXT: The established relationship between lymph node metastasis and prognosis in colorectal cancer suggests that recurrence in 25% of patients with lymph nodes free of tumor cells by histopathology (pN0) reflects the presence of occult metastases. Guanylyl cyclase 2C (GUCY2C) is a marker expressed by colorectal tumors that could reveal occult metastases in lymph nodes and better estimate recurrence risk. OBJECTIVE: To examine the association of occult lymph node metastases detected by quantifying GUCY2C messenger RNA, using the reverse transcriptase-polymerase chain reaction, with recurrence and survival in patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 257 patients with pN0 colorectal cancer enrolled between March 2002 and June 2007 at 9 US and Canadian centers (7 academic medical centers and 2 community hospitals) provided 2570 fresh lymph nodes measuring 5 mm or larger for histopathology and GUCY2C messenger RNA analysis. Patients were followed up for a median of 24 months (range, 2-63 months) for disease recurrence or death. MAIN OUTCOME MEASURES: Time to recurrence (primary outcome) and disease-free survival (secondary outcome) relative to expression of GUCY2C in lymph nodes. RESULTS: Thirty-two patients (12.5%) had lymph nodes negative for GUCY2C (pN0 [mol-]), and all but 2 remained free of disease during follow-up (recurrence rate, 6.3%; 95% confidence interval [CI], 0.8%-20.8%). Conversely, 225 patients (87.5%) had lymph nodes positive for GUCY2C (pN0 [mol+]), and 47 developed recurrent disease (20.9%; 95% CI, 15.8%-26.8%) (P = .006). Multivariate analyses revealed that GUCY2C in lymph nodes was an independent marker of prognosis. Patients who were pN0 (mol+) exhibited earlier time to recurrence (adjusted hazard ratio, 4.66; 95% CI, 1.11-19.57; P = .04) and reduced disease-free survival (adjusted hazard ratio, 3.27; 95% CI, 1.15-9.29; P = .03). CONCLUSION: Expression of GUCY2C in histologically negative lymph nodes appears to be independently associated with time to recurrence and disease-free survival in patients with pN0 colorectal cancer.

Bile acids initiate lineage-addicted gastroesophageal tumorigenesis by suppressing the EGF receptor-AKT axis.

While bile acids are a risk factor for tumorigenesis induced by reflux disease, the mechanisms by which they contribute to neoplasia remain undefined. Here, we reveal that in gastroesophageal junction (GEJ) cells bile acids activate a tissue-specific developmental program defining the intestinal epithelial cell phenotype characterizing GEJ metaplasia. Deoxycholic acid (DCA) inhibited phosphorylation of EGF receptors (EGFRs) suppressing the proto-oncogene AKT. Suppression of EGFRs and AKT by DCA actuated an intestine-specific cascade in which NF-kappaB transactivated the tissue-specific transcription factor CDX2. In turn, CDX2 orchestrated a lineage-specific differentiation program encompassing genes characterizing intestinal epithelial cells. Conversely, progression from metaplasia to invasive carcinoma in patients, universally associated with autonomous activation of EGFRs and/or AKT, was coupled with loss of this intestinal program. Thus, bile acids induce intestinal metaplasia at the GEJ by activating the lineage-specific differentiation program involving suppression of EGFR and AKT, activating the NF-kappaB-CDX2 axis. Induction of this axis provides the context for lineage-addicted tumorigenesis, in which autonomous activation of AKT corrupts adaptive intestinal NF-kappaB signaling, amplifying tumorigenic programs.

A validated quantitative assay to detect occult micrometastases by reverse transcriptase-polymerase chain reaction of guanylyl cyclase C in patients with colorectal cancer.

PURPOSE: Guanylyl cyclase C (GCC), a receptor for bacterial diarrheagenic enterotoxins, may be a prognostic and predictive marker to detect occult micrometastases in patients undergoing staging for colorectal cancer. However, quantification of GCC expression in tissues by the quantitative reverse transcription-PCR (qRT-PCR) has not undergone analytic and clinicopathologic validation. EXPERIMENTAL DESIGN: A technique to quantify GCC mRNA in tissues employing RT-PCR was developed and validated employing external calibration standards of RNA complementary to GCC. RESULTS: GCC qRT-PCR exhibited reaction efficiencies >92%, coefficients of variations <5%, linearity >6 orders of magnitude, and a limit of quantification of >25 copies of GCC cRNA. This assay confirmed that GCC mRNA was overexpressed by colorectal tumors from 41 patients, which correlated with increased GCC protein quantified by immunohistochemistry. Analyses obtained with 164 lymph nodes from patients free of cancer and 15 nodes harboring metastases established a threshold for metastatic disease of approximately 200 GCC mRNA copies/mug total RNA, with a sensitivity of 93% and specificity of 97%. GCC mRNA above that threshold was detected in 76 of 367 (approximately 21%) nodes free of disease by histopathology from 6 of 23 (26%) patients, suggesting the presence of occult micrometastases. CONCLUSIONS: Quantifying GCC mRNA in tissues by RT-PCR employing external calibration standards is analytically robust and reproducible, with high clinicopathologic sensitivity and specificity. This validated assay is being applied to approximately 10,000 lymph nodes in a prospective trial to define the sensitivity of GCC qRT-PCR for staging patients with colorectal cancer.

The putative tumor suppressor Cdx2 is overexpressed by human colorectal adenocarcinomas.

PURPOSE: The current paradigm suggests that the homeodomain transcription factor Cdx2, which directs the development and maintenance of the intestinal epithelium, is a tumor suppressor in the colon and rectum. Although a cardinal property of tumor suppressors is their inactivation during carcinogenesis, the expression of Cdx2 in colorectal tumors has not been compared with that in normal mucosa. Here, Cdx2 expression and function was quantified in tumors and matched normal mucosa from patients with colorectal cancer. EXPERIMENTAL DESIGN: Cdx2 expression was quantified by reverse transcription-PCR, immunoblot analysis, and immunohistochemistry. Transcriptional activity was explored by quantifying expression of an endogenous downstream target of Cdx2, guanylyl cyclase C (GCC), in tissues by quantitative reverse transcription-PCR and expression of exogenous Cdx2-specific luciferase promoter constructs in epithelial cells isolated from tumors and normal mucosa. RESULTS: Most (>80%) colorectal tumors overexpressed Cdx2 mRNA and protein compared with normal mucosa, with median fold increases of 3.6 and 1.4, respectively (P<0.002). Concomitantly, immunohistochemistry revealed elevated levels of Cdx2 in nuclei of tumor cells compared with normal epithelial cells. Further, tumors exhibited increased expression of GCC compared with normal mucosa. Moreover, cells isolated from tumors overexpressed a Cdx2-specific luciferase promoter construct compared with normal mucosal cells. CONCLUSION: These observations show, for the first time, the structural and functional overexpression of Cdx2 by human colorectal tumors compared with matched normal mucosa. They suggest that loss of Cdx2 expression or transcriptional activity is an infrequent event during tumorigenesis, which does not contribute to molecular mechanisms underlying initiation and progression of most colorectal tumors.