Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

T-cell redirecting bispecific antibodies (bsAbs) or antibody-derived agents that combine tumor antigen recognition with CD3-mediated T cell recruitment are highly potent tumor-killing molecules. Despite the tremendous progress achieved in the last decade, development of such bsAbs still faces many challenges. This work aimed to develop a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) modeling framework that can be used to assist the development of T-cell redirecting bsAbs. A Target cell-Biologics-Effector cell (TBE) complex-based cell killing model was developed using in vitro and in vivo data, which incorporates information on binding affinities of bsAbs to CD3 and target receptors, expression levels of CD3 and target receptors, concentrations of effector and target cells, as well as respective physiological parameters. This TBE model can simultaneously evaluate the effect of multiple system-specific and drug-specific factors on the T-cell redirecting bsAb exposure–response relationship on a physiological basis; it reasonably captured multiple reported in vitro cytotoxicity data, and successfully predicted the effect of some key factors on in vitro cytotoxicity assays and the efficacious dose of blinatumomab in humans. The mechanistic nature of this model uniquely positions it as a knowledge-based platform that can be readily expanded to guide target selection, drug design, candidate selection and clinical dosing regimen projection, and thus support the overall discovery and development of T-cell redirecting bsAbs.     

Evidence-based methodology for obtaining commercial insurance coverage of stereotactic radiosurgery for intractable epilepsy

ObjectivesThe coverage policies of many commercial insurers in the United States do not include coverage of stereotactic radiosurgery (SRS) for intractable epilepsy despite recent Level I evidence supporting its efficacy. We sought to assess the efficacy of an evidence-based methodology in obtaining coverage approval of SRS for intractable epilepsy.Patients and MethodsThe clinical policy guidelines from five of the largest United States commercial insurers were reviewed for their language regarding coverage of SRS for epilepsy. An evidence-based questionnaire was created for temporal lobe epilepsy and extratemporal lobe epilepsy based on recent evidence. Telephone interviewers of Insurers assessed the likelihood of SRS coverage for an epilepsy patient meeting the clinical inclusion criteria in the questionnaire. This likelihood was assessed numerically based on interviewee response (2 = yes, 1 = dependent on peer-to-peer, 0 = no).ResultsOf the five policy guidelines, none included literature more recent than 2017. For TLE, 3/5 insurance companies indicated likely SRS coverage; 2/5 indicated peer-to-peer discussion dependence for patients meeting questionnaire criteria for a score of 8/10. For extratemporal TLE, 2/5 companies indicated likely SRS coverage and 3/5 indicated peer-to-peer discussion dependence for a total score of 7/10.ConclusionCreation of an evidence-based methodology in approaching commercial insurers greatly increased the likelihood of SRS coverage for an indication (intractable epilepsy) widely perceived as investigational. These results should pave the way for epilepsy patients to receive coverage should they be appropriate SRS candidates.     

Induction of type XVI collagen expression facilitates proliferation of oral cancer cells

Type XVI collagen belongs to the family of fibril-associated collagens with interrupted triple helices (FACIT). Recently, high affinity to integrin alpha1beta1 has been shown allowing cells expressing those integrins to attach and spread on recombinant type XVI collagen. Here, we show that type XVI collagen is overexpressed in dysplastic areas of mucosal epithelium from oral squamous cell carcinoma (OSCC) patients. Induction of its expression in OSCC cell lines (COLXVI cells) leads to an increased expression of Kindlin-1. Moreover, we demonstrate a significantly increased Kindlin-1/beta1-integrin interaction. Additionally, we detected a higher number of activated beta1-integrins in COLXVI cells and found a neo-expression of alpha1 integrin subunit on these cells. FACS analysis revealed a significantly higher amount of COLXVI cells in S-phase and G2/M-phase 6 h after synchronisation leading to a markedly higher proliferation activity. Blocking beta1-integrins with a specific antibody resulted in reduced proliferation of COLXVI cells. In summary, we demonstrate that overexpression of type XVI collagen in aberrant oral keratinocytes leads to Kindlin-1 induction, increased Kindlin-1/beta1-integrin interaction, integrin activation and subsequently to a proliferative cellular phenotype.     

Understanding the Fluid Nature of Personhood – the Ring Theory of Personhood

Familial determination, replete with its frequent usurping of patient autonomy, propagation of collusion, and circumnavigation of direct patient involvement in their own care deliberations, continues to impact clinical practice in many Asian nations. Suggestions that underpinning this practice, in Confucian‐inspired societies, is the adherence of the populace to the familial centric ideas of personhood espoused by Confucian ethics, provide a novel means of understanding and improving patient‐centred care at the end of life. Clinical experience in Confucian‐inspired Singapore, however, suggests that personhood is conceived in broader terms. This diverging view inspired a study of local conceptions of personhood and scrutiny of the influence of the family upon it. From the data gathered, a culturally appropriate, clinically relevant and ethically sensitive concept of personhood was proposed: the Ring Theory of Personhood (Ring Theory) that better captures the nuances of local conceptions of personhood. The Ring Theory highlights the fact that, far from being solely dependent upon familial centric ideals, local conceptions of personhood are dynamic, context dependent, evolving ideas delineated by four dimensions. Using the Ring Theory, the nature of familial influences upon the four dimensions of personhood – the Innate, Individual, Relational and Societal – are examined to reveal that, contrary to perceived knowledge, conceptions of personhood within Confucian societies are not the prime reason for the continued presence of this decision‐making model but remain present within local thinking and practices as a sociocultural residue and primarily because of inertia in updating ideas.     

Scheduling of anticancer drugs

Many cancer patients are treated with a combination of anticancer drugs. Here, we discuss the importance of drug scheduling and the need for studies that investigate the optimal timing of the various anticancer drugs. Positron emission tomography (PET) using radiolabeled anticancer drugs could be an important tool for those studies.     

The case for radiotherapy in a Value based environment

AimDescribe the Value proposition for radiotherapy (RT) in the United States.BackgroundIn the United States since 2005, two forces have worked to decrease RT cost per patient: Federal changes in reimbursement and hypofractionation of treatment courses. We theorize that these have driven stable reimbursement in the context of increasing technology of intensity modulation (IMRT) and image guidance (IGRT). This phenomenon provides increasing Value of the discipline to patients and systems.Materials and methodsWe searched the Medicare Physician/Supplier data for Program Payments per Person with Utilization for 2000 through 2016. This involves two databases: Enrollment Database (EDB) for 2000–2012 and Common Medicare Enrollment (CME) since 2013. RT payments to individual patients accessing services were retrieved.ResultsTaking into account the change of calculation algorithm used by CMS in 2013, costs per patient were similar in 2012 and 2003, and 2016 and 2013.ConclusionsIn the United States, stabilizing costs in the face of increasing work, better outcomes, and decreased toxicity contributes to increasing RT value over the past 10 years.     

Moral dilemmas in (not) treating patients who feel they are a burden

Working as clinical ethicists in an academic hospital, we find that practitioners tend to take a principle‐based approach to moral dilemmas when it comes to (not) treating patients who feel like a burden, in which respect for autonomy tends to trump other principles. We argue that this approach insufficiently deals with the moral doubts of professionals with regard to feeling that you are a burden as a motive to decline or withdraw from treatment. Neither does it take into adequately account the specific needs of the patient that might underlie their feeling of being a burden to others. We propose a care ethics approach as an alternative. It focuses on being attentive and responsive to the caring needs of those involved in the care process—which can be much more specific than either receiving or withdrawing from treatment. This approach considers these needs in the context of the patient's identity, biography and relationships, and regards autonomy as relational rather than as individual. We illustrate the difference between these two approaches by means of the case of Mrs K. Furthermore, we show that a care ethics approach is in line with interventions that are found to alleviate feeling a burden and maintain that facilitating moral case deliberation among practitioners can supports them in taking a care ethics approach to moral dilemmas in (not) treating patients who feel like a burden.     

Analysis of pre-residency research productivity,dual degree status,and gender distribution of underrepresented minorities among a current United States radiation oncology junior resident class

BackgroundAmong the most competitive medical subspecialties, representation of underrepresented minorities (African–American race and/or Hispanic ethnicity) among resident trainees has historically been low compared to their United States Census general population representation. Research productivity and dual degree status may impact residency applicant competitiveness. To date, such an analysis has yet to be performed in Radiation Oncology.MethodsA list of radiation oncology residents from the graduating class of 2022 was obtained through internet searches. Demographics included were gender and dual degree status. Research productivity was calculated using the number of pre-residency peer-reviewed publications (PRP). Fisher's exact test was used for statistical analysis.ResultsOf the 179 residents evaluated from the 2022 class, eleven (6.1%) were underrepresented minorities. Compared to the remainder of the class, underrepresented minorities had a lower proportion of men (63.6% versus 69.3%), a higher proportion of dual degrees (45.5% versus 28.6%), and a lower proportion of MD-PhD degrees (9.1% versus 17.2%). Underrepresented minorities had a higher proportion of residents with at least two PRP (72.7% versus 57.1%) and a lower proportion of residents with no PRP (18.2% versus 24.4%). None of these differences reached statistical significance (p > 0.05).ConclusionUnderrepresented minorities were comparable to the remainder of their Radiation Oncology resident class regarding gender distribution, dual degrees status, and likelihood of having at least two peer-reviewed publications cited in PubMed during the calendar year of residency application. Further studies will be needed to determine how these findings translate into future scholarly activity and post-graduate career choice.     

Current status of the organ replacement approach for malignancies and an overture for organ bioengineering and regenerative medicine

Significant achievements in the organ replacement approach for malignancies over the last 2 decades opened new horizons, and the age of “Transplant Oncology” has dawned. The indications of liver transplantation for malignancies have been carefully expanded by a strict patient selection to assure comparable outcomes with non-malignant diseases. Currently, the Milan criteria, gold standard for hepatocellular carcinoma, are being challenged by high-volume centers worldwide. Neoadjuvant chemoradiation therapy and liver transplantation for unresectable hilar cholangiocarcinoma has been successful in specialized institutions. For other primary and metastatic liver tumors, clinical evidence to establish standardized criteria is lacking. Intestinal and multivisceral transplantation is an option for low-grade neoplasms deemed unresectable by conventional surgery. However, the procedure itself is in the adolescent stage. Solid organ transplantation for malignancies inevitably suffers from “triple distress,” i.e., oncological, immunological, and technical. Organ bioengineering and regenerative medicine should serve as the “triple threat” therapy and revolutionize “Transplant Oncology.”