Citations

In part one of this two-part paper, we present eight principles that we believe must be considered for more effective treatment of the currently incurable cancers. These are addressed by multidrug adjunctive cancer treatment (MDACT), which uses multiple repurposed non-oncology drugs, not primarily to kill malignant cells, but rather to reduce the malignant cells’ growth drives. Previous multidrug regimens have used MDACT principles, e.g., the CUSP9v3 glioblastoma treatment. MDACT is an amalgam of (1) the principle that to be effective in stopping a chain of events leading to an undesired outcome, one must break more than one link; (2) the principle of Palmer et al. of achieving fractional cancer cell killing via multiple drugs with independent mechanisms of action; (3) the principle of shaping versus decisive operations, both being required for successful cancer treatment; (4) an idea adapted from Chow et al., of using multiple cytotoxic medicines at low doses; (5) the idea behind CUSP9v3, using many non-oncology CNS-penetrant drugs from general medical practice, repurposed to block tumor survival paths; (6) the concept from chess that every move creates weaknesses and strengths; (7) the principle of mass—by adding force to a given effort, the chances of achieving the goal increase; and (8) the principle of blocking parallel signaling pathways. Part two gives an example MDACT regimen, gMDACT, which uses six repurposed drugs—celecoxib, dapsone, disulfiram, itraconazole, pyrimethamine, and telmisartan—to interfere with growth-driving elements common to cholangiocarcinoma, colon adenocarcinoma, glioblastoma, and non-small-cell lung cancer. gMDACT is another example of—not a replacement for—previous multidrug regimens already in clinical use, such as CUSP9v3. MDACT regimens are designed as adjuvants to be used with cytotoxic drugs.

Objective Hypercapnia, an elevated concentration of carbon dioxide (CO2) in the blood, is known to promote acute increases in cerebral blood flow (CBF). This pilot study aimed to investigate whether a novel training method involving repeated bouts of hypercapnia, would influence cerebrovascular reactivity response in healthy adults. Hypothesis Repeated bouts of hypercapnia (as interval training) may promote beneficial adaptation to increase cerebrovascular reactivity. Methods Adults over 40yrs old without known disease or cardiovascular risk factors, were recruited for a non‐randomized cross‐over design pilot study. Subjects completed a 2‐week control period followed by a 2‐week intervention. The intervention involved a progressive hypercapnia training program of six sessions, whereby subjects completed 4‐6 intervals of rebreathing oxygen until a target end‐tidal CO2 (up to 25mmHg above resting) was reached, separated by recovery intervals breathing room air. Cerebrovascular reactivity was measured during study testing visits at baseline, 2‐weeks (between control and intervention) and 4‐weeks (after intervention). During study visits subjects underwent a stepped CO2 protocol, involving 5‐min stages of inspired room air, 2% CO2, 4% CO2, and 6% CO2, while measuring middle cerebral artery velocity (CBFv) using transcranial doppler ultrasound, mean arterial pressure (MAP) by finger plethysmography, ventilation, and end‐tidal CO2. Cerebrovascular conductance (CVCi) was calculated as CBFv/MAP. The reactivity of CBFv (in cm/s/mmHg), CVCi (in cm/s/mmHg2), and MAP (in mmHg/mmHg) were calculated as the linear regression slope against end‐tidal CO2 during the stepped CO2 protocol. Chemosensitivity (in L/min/mmHg) is the linear regression slope of VE vs end‐tidal CO2. Results Six healthy adults (age: 56 ± 10; 2 females) completed the study. Study visit data are displayed in Table 1. Individual training data are presented in Table 2. Following the control period there was a large reduction from baseline in CBFv reactivity [2.81 ± 1.50 to 2.03 ± 1.03; effect size 0.9], CVCi reactivity [0.020 ± 0.015 to 0.015 ± 0.010; effect size 0.7], and MAP reactivity [0.95 ± 0.63 to 0.62 ± 0.42; effect size 0.6] with no change in chemosensitivity [0.99 ± 0.68 to 0.98 ± 0.51; effect size 0.0]. Following the intervention there was no change from the 2‐week study visit in CBFv reactivity [2.03 ± 1.03 to 2.01 ± 1.09; effect size 0.0], CVCi reactivity [0.015 ± 0.010 to 0.014 ± 0.010; effect size 0.1], and MAP reactivity [0.62 ± 0.42 to 0.72 ± 0.44; effect size 0.1] with a small increase in chemosensitivity [0.98 ± 0.51 to 1.04 ± 0.53; effect size 0.3]. Conclusion Preliminary findings suggest a very brief progressive hypercapnia training program does not increase or desensitize cerebrovascular reactivity in healthy adults. These data also suggest an exaggerated cerebrovascular reactivity response may occur to an initial exposure of a stepped CO2 protocol (without familiarization), which appears to be driven by blood pressure response not chemosensitivity. Further research, particularly in populations with impaired cerebrovascular reactivity, is of interest for CBF regulation.

The PRSS23 gene, encoding putative serine protease 23, has been associated with several diseases by correlative gene expression studies and genetic‐based comparative models. Our group has recently developed data implicating the expression of this gene as a potential driver of ovarian cancer malignancy. However, there have been no studies defining PRSS23 protein structure or demonstrating its hypothesized proteolytic function. We aim to elucidate PRSS23 protein structure and enzymatic activity. The first step to achieve this goal is to develop a robust expression system and purification protocol for recombinant PRSS23 protein. We hypothesize that developing a methodology to produce PRSS23 recombinant protein will enable us to determine its crystal structure, evaluate its biological and enzyme function, and ultimately target the enzyme therapeutically. We strategized to maximize chances of producing PRSS23 in its native form and with high yield by testing multiple systems and host species: human, yeast, and bacterial. We anticipate, based on the protein sequence, that PRSS23 is endogenously secreted and may be activated in the secretory pathway by furin, releasing the C‐terminal catalytic domain from a smaller N‐terminal domain. The protein is also predicted to be glycosylated. We generated expression plasmids for full‐length PRSS23, codon‐optimized for expression in human and Pichia pastoris expression systems, incorporating a His‐tag for detection and purification. In the human HEK 293F and HEK 293T cell systems, despite optimizing transfection protocols and testing multiple expression constructs, secretion signals, and promoters, the expression level remained very low and was judged unlikely to produce sufficient protein for structural and functional studies. Integration of codon‐optimized PRSS23 into the genome of P. pastoris produced integrants showing a spectrum of expression levels from very low to moderate. Experiments are ongoing to optimize expression conditions of the best clone and develop a purification workflow involving ammonium sulfate precipitation, immobilized nickel ion chromatography, and additional chromatographic steps as needed. In parallel, we cloned the catalytic domain of PRSS23, appropriately codon‐optimized and also containing a C‐terminal His‐tag, into an expression vector for Escherichia coli. High levels of protein were produced as insoluble inclusion bodies, and a protocol was developed for nickel ion affinity purification under denaturing conditions. Experiments are ongoing to identify suitable conditions for in vitro refolding of the PRSS23 catalytic domain. Additionally, we are evaluating a maltose binding protein fusion with the PRSS23 catalytic domain as an alternative strategy to improve soluble protein production in E. coli. Significant quantities of pure protein will be needed to enable crystal structure determination and enzymatic activity elucidation, to unravel the biological mechanism of action and identify endogenous substrates, and potentially lead to new therapeutic strategies targeting PRSS23. The expression systems and purification workflows developed here will be a step forward toward these long‐term goals.

Background and purpose Radiation therapy is an important component of treatment in patients with malignancies of the head, neck, and spine. However, radiation to these regions has well-known potential side effects, many of which can be encountered on imaging. In this manuscript, we review selected radiographic manifestations of therapeutic radiation to the head, neck, and spine that may be encountered in the practice of radiology. Methods We conducted an extensive literature review of known complications of radiation therapy in the head, neck, and spine. We excluded intracranial and pulmonary radiation effects from our search. We selected complications that had salient, recognizable imaging findings. We searched our imaging database for illustrative examples of these complications. Results Based on our initial literature search and imaging database review, we selected cases of radiation-induced tumors, radiation tissue necrosis (osteoradionecrosis and soft tissue necrosis), carotid stenosis and blowout secondary to radiation, enlarging thyroglossal duct cysts, radiation myelopathy, and radiation-induced vertebral compression fractures. Conclusions We describe the clinical and imaging features of selected sequelae of radiation therapy to the head, neck, and spine, with a focus on those with characteristic imaging findings that can be instrumental in helping to make the diagnosis. Knowledge of these entities and their imaging findings is crucial for accurate diagnosis. Not only do radiologists play a key role in early detection of these entities, but many of these entities can be misinterpreted if one is not familiar with them.

AbstractIntroductionAlthough letters of reference (LORs) are required for postgraduate year one (PGY1) residency applications and used to distinguish between candidates, an evaluation of residency program director (RPD) perceptions and values surrounding LORs has not been described.ObjectiveThe aim of the study was to describe PGY1 RPDs' processes, values, and perceptions surrounding LORs.MethodsThis was a cross‐sectional descriptive survey. After assessing content validity, the Education and Training Practice and Research Network (PRN) taskforce sent a 25‐item electronic survey to 1266 PGY1 RPDs. Survey questions captured program demographics, LOR requirements, processes for LOR review, and perceptions about the value of LORs. Two open‐ended questions solicited suggestions for LORs and the existing standardized form; responses were evaluated via thematic analysis.ResultsA total of 291 (24%) programs completed the survey. LORs were rated as extremely or quite valuable by 82% of respondents and moderately valuable by 16% of respondents. Scoring rubrics for LOR evaluation were used by 79% of programs, and performance ratings were reported to impact interview consideration by a majority of programs. Accuracy, detailed comments, and inclusion of specific candidate strengths and areas for improvement were rated as extremely or quite important characteristics by 90% or more of respondents. Specific strengths were reported to be present in LORs more than half of the time by 81% of programs; however, accuracy, detailed comments, and inclusion of specific areas for improvement were only reported to be present about half the time or less by 41%, 63%, and 63% of respondents. Among 207 suggestions submitted to improve LOR utility, common themes included a desire for LOR authors to have candid discussions with candidates prior to letter writing, to contextualize their relationship with the candidate, and provide honest and specific assessments.ConclusionLORs remain highly valued by PGY1 RPDs during application review. Several notable findings were observed, resulting in recommendations for LOR authors, residency applicants, and the standardized LOR form.

Background Availability of checkpoint inhibitors has created a paradigm shift in the management of patients with solid tumors. Despite this, most patients do not respond to immunotherapy, and there is considerable interest in developing combination therapies to improve response rates and outcomes. B7-H3 (CD276) is a member of the B7 family of cell surface molecules and provides an alternative immune checkpoint molecule to therapeutically target alone or in combination with programmed cell death-1 (PD-1)–targeted therapies. Enoblituzumab, an investigational anti-B7-H3 humanized monoclonal antibody, incorporates an immunoglobulin G1 fragment crystallizable (Fc) domain that enhances Fcγ receptor-mediated antibody-dependent cellular cytotoxicity. Coordinated engagement of innate and adaptive immunity by targeting distinct members of the B7 family (B7-H3 and PD-1) is hypothesized to provide greater antitumor activity than either agent alone. Methods In this phase I/II study, patients received intravenous enoblituzumab (3–15 mg/kg) weekly plus intravenous pembrolizumab (2 mg/kg) every 3 weeks during dose-escalation and cohort expansion. Expansion cohorts included non–small cell lung cancer (NSCLC; checkpoint inhibitor [CPI]–naïve and post-CPI, programmed death-ligand 1 [PD-L1] <1%), head and neck squamous cell carcinoma (HNSCC; CPI-naïve), urothelial cancer (post-CPI), and melanoma (post-CPI). Disease was assessed using Response Evaluation Criteria in Solid Tumors version 1.1 after 6 weeks and every 9 weeks thereafter. Safety and pharmacokinetic data were provided for all enrolled patients; efficacy data focused on HNSCC and NSCLC cohorts. Results Overall, 133 patients were enrolled and received ≥1 dose of study treatment. The maximum tolerated dose of enoblituzumab with pembrolizumab at 2 mg/kg was not reached. Intravenous enoblituzumab (15 mg/kg) every 3 weeks plus pembrolizumab (2 mg/kg) every 3 weeks was recommended for phase II evaluation. Treatment-related adverse events occurred in 116 patients (87.2%) and were grade ≥3 in 28.6%. One treatment-related death occurred (pneumonitis). Objective responses occurred in 6 of 18 (33.3% [95% CI 13.3 to 59.0]) patients with CPI-naïve HNSCC and in 5 of 14 (35.7% [95% CI 12.8 to 64.9]) patients with CPI-naïve NSCLC. Conclusions Checkpoint targeting with enoblituzumab and pembrolizumab demonstrated acceptable safety and antitumor activity in patients with CPI-naïve HNSCC and NSCLC. Trial registration number NCT02475213.

Cardiovascular disease surveillance involves quantifying the evolving population‐level burden of cardiovascular outcomes and risk factors as a data‐driven initial step followed by the implementation of interventional strategies designed to alleviate this burden in the target population. Despite widespread acknowledgement of its potential value, a national surveillance system dedicated specifically to cardiovascular disease does not currently exist in the United States. Routinely collected health care data such as from electronic health records (EHRs) are a possible means of achieving national surveillance. Accordingly, this article elaborates on some key strengths and limitations of using EHR data for establishing a national cardiovascular disease surveillance system. Key strengths discussed include the: (1) ubiquity of EHRs and consequent ability to create a more “national” surveillance system, (2) existence of a common data infrastructure underlying the health care enterprise with respect to data domains and the nomenclature by which these data are expressed, (3) longitudinal length and detail that define EHR data when individuals repeatedly patronize a health care organization, and (4) breadth of outcomes capable of being surveilled with EHRs. Key limitations discussed include the: (1) incomplete ascertainment of health information related to health care–seeking behavior and the disconnect of health care data generated at separate health care organizations, (2) suspect data quality resulting from the default information‐gathering processes within the clinical enterprise, (3) questionable ability to surveil patients through EHRs in the absence of documented interactions, and (4) the challenge in interpreting temporal trends in health metrics, which can be obscured by changing clinical and administrative processes.

Hodgkin lymphoma (HL) is an uncommon malignancy of B-cell origin. Classical HL (cHL) and nodular lymphocyte–predominant HL are the 2 main types of HL. The cure rates for HL have increased so markedly with the advent of modern treatment options that overriding treatment considerations often relate to long-term toxicity. These NCCN Guidelines Insights discuss the recent updates to the NCCN Guidelines for HL focusing on (1) radiation therapy dose constraints in the management of patients with HL, and (2) the management of advanced-stage and relapsed or refractory cHL.

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program ( n = 63,302) and UK Biobank ( n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.