Clinician Perspectives Regarding the Impact of Information Technology on Multidisciplinary Tumor Boards: A National Comprehensive Cancer Network Survey.

PURPOSE: Multidisciplinary tumor boards (MTBs) support high-quality cancer care. Little is known about the impact of information technology (IT) tools on the operational and technical aspects of MTBs. The National Comprehensive Cancer Network EHR Oncology Advisory Group formed a workgroup to investigate the impact of IT tools such as EHRs and virtual conferencing on MTBs. METHODS: The workgroup created a cross-sectional survey for oncology clinicians (eg, pathology, medical, surgical, radiation, etc) participating in MTBs at 31 National Comprehensive Cancer Network member institutions. A standard invitation e-mail was shared with each EHR Advisory Group Member with a hyperlink to the survey, and each member distributed the survey to MTB participants at their institution or identified the appropriate person at their institution to do so. The survey was open from February 26, 2022, to April 26, 2022. Descriptive statistics were applied in the analysis of responses, and a qualitative thematic analysis of open-ended responses was completed. RESULTS: Individuals from 27 institutions participated. Almost all respondents (99%, n = 764 of 767) indicated that their MTBs had participants attending virtually. Most indicated increased attendance (69%, n = 514 of 741) after virtualization with the same or improved quality of discussion (75%, n = 557 of 741) compared with in-person MTBs. Several gaps between the current and ideal state emerged regarding EHR integration: 57% (n = 433 of 758) of respondents noted the importance of adding patients for MTB presentation via the EHR, but only 40% (n = 302 of 747) reported being able to do so most of the time. Similarly, 87% (n = 661 of 760) indicated the importance of documenting recommendations in the EHR, but only 53% (n = 394 of 746) reported this occurring routinely. CONCLUSION: Major gaps include the lack of EHR integration for MTBs. Clinical workflows and EHR functionalities could be improved to further optimize EHRs for MTB management and documentation.

Preferences in Oncology History Documentation Styles Among Clinical Practitioners.

PURPOSE: Clinical notes function as the de facto handoff between providers and assume great importance during unplanned medical encounters. An organized and thorough oncology history is essential in care coordination. We sought to understand reader preferences for oncology history organization by comparing between chronologic and narrative formats. METHODS: A convenience sample of 562 clinicians from 19 National Comprehensive Cancer Network Member Institutions responded to a survey comparing two formats of oncology histories, narrative and chronologic, for the same patient. Both histories were consensus-derived real-world examples. Each history was evaluated using semantic differential attributes (thorough, useful, organized, comprehensible, and succinct). Respondents choose a preference between the two styles for history gathering and as the basis of a new note. Open-ended responses were also solicited. RESULTS: Respondents preferred the chronologic over the narrative history to prepare for a visit with an unknown patient (66% preference) and as a basis for their own note preparation (77% preference) (P < .01). The chronologic summary was preferred in four of the five measured attributes (useful, organized, comprehensible, and succinct); the narrative summary was favored for thoroughness (P < .01). Open-ended responses reflected the attribute scoring and noted the utility of content describing social determinants of health in the narrative history. CONCLUSION: Respondents of this convenience sample preferred a chronologic oncology history to a concise narrative history. Further studies are needed to determine the optimal structure and content of chronologic documentation for oncology patients and the provider effort to use this format.

Oncologist Perspectives on Telemedicine for Patients With Cancer: A National Comprehensive Cancer Network Survey.

PURPOSE: The use of telemedicine expanded dramatically in March 2020 following the COVID-19 pandemic. We sought to assess oncologist perspectives on telemedicine's present and future roles (both phone and video) for patients with cancer. METHODS: The National Comprehensive Cancer Network (NCCN) Electronic Health Record (EHR) Oncology Advisory Group formed a Workgroup to assess the state of oncology telemedicine and created a 20-question survey. NCCN EHR Oncology Advisory Group members e-mailed the survey to providers (surgical, hematology, gynecologic, medical, and radiation oncology physicians and clinicians) at their home institution. RESULTS: Providers (N = 1,038) from 26 institutions responded in Summer 2020. Telemedicine (phone and video) was compared with in-person visits across clinical scenarios (n = 766). For reviewing benign follow-up data, 88% reported video and 80% reported telephone were the same as or better than office visits. For establishing a personal connection with patients, 24% and 7% indicated video and telephone, respectively, were the same as or better than office visits. Ninety-three percent reported adverse outcomes attributable to telemedicine visits never or rarely occurred, whereas 6% indicated they occasionally occurred (n = 801). Respondents (n = 796) estimated 46% of postpandemic visits could be virtual, but challenges included (1) lack of patient access to technology, (2) inadequate clinical workflows to support telemedicine, and (3) insurance coverage uncertainty postpandemic. CONCLUSION: Telemedicine appears effective across a variety of clinical scenarios. Based on provider assessment, a substantial fraction of visits for patients with cancer could be effectively and safely conducted using telemedicine. These findings should influence regulatory and infrastructural decisions regarding telemedicine postpandemic for patients with cancer.

Yttrium-90 Anti-CD45 Immunotherapy Followed by Autologous Hematopoietic Cell Transplantation for Relapsed or Refractory Lymphoma.

Autologous hematopoietic cell transplantation (AHCT) is a standard of care for several subtypes of high-risk lymphoma, but durable remissions are not achieved in the majority of patients. Intensified conditioning using CD45-targeted antibody-radionuclide conjugate (ARC) preceding AHCT may improve outcomes in lymphoma by permitting the delivery of curative doses of radiation to disease sites while minimizing toxicity. We performed sequential phase I trials of escalating doses of yttrium-90 (90Y)-labeled anti-CD45 antibody with or without BEAM (carmustine, etoposide, cytarabine, melphalan) chemotherapy followed by AHCT in adults with relapsed/refractory or high-risk B cell non-Hodgkin lymphoma (NHL), T cell NHL (T-NHL), or Hodgkin lymphoma (HL). Twenty-one patients were enrolled (16 NHL, 4 HL, 1 T-NHL). Nineteen patients received BEAM concurrently. No dose-limiting toxicities were observed; therefore, the maximum tolerated dose is estimated to be ≥34 Gy to the liver. Nonhematologic toxicities and engraftment kinetics were similar to standard myeloablative AHCT. Late myeloid malignancies and 100-day nonrelapse deaths were not observed. At a median follow-up of 5 years, the estimates of progression-free and overall survival of 19 patients were 37% and 68%, respectively. Two patients did not receive BEAM; one had stable disease and the other progressive disease post-transplant. The combination of 90Y-anti-CD45 with BEAM and AHCT was feasible and tolerable in patients with relapsed and refractory lymphoma. The use of anti-CD45 ARC as an adjunct to hematopoietic cell transplantation regimens or in combination with novel therapies/immunotherapies should be further explored based on these and other data.

Bendamustine with rituximab, etoposide and carboplatin (T(R)EC) in relapsed or refractory aggressive lymphoma: a prospective multicentre phase 1/2 clinical trial.

We sought to develop a safe and effective outpatient salvage regimen by replacing ifosfamide within the (R)ICE (rituximab, ifosfomide, carboplatin, etoposide) regimen with bendamustine (T(R)EC) via a multicentre phase I/II study for patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) and classic Hodgkin lymphoma (HL). Therapy consisted of 60-120 mg/m2 per day bendamustine on days 1 and 2 in combination with carboplatin, etoposide and rituximab (only for CD20+ lymphoma) used in the (R)ICE regimen for up to 2 cycles. The objectives were to define a maximally tolerated dose (MTD) of bendamustine, determine safety and toxicity, assess efficacy, and evaluate impact on stem cell collection. Forty-eight patients were treated of which 71% had refractory disease. No dose-limiting toxicities were observed. The recommended phase II dose of bendamustine was 120 mg/m2 per day on days 1 and 2. Response rates were 85% (70% complete response, CR) in HL, and 65% (40% CR) in DLBCL. Stem cell collection was successful in 30 of 32 patients. The most common non-haematological toxicities ≥grade 3 were febrile neutropenia (8%) and dehydration (8%). The T(R)EC regimen safely yields high response rates, successfully mobilizes peripheral blood stem cells and compares favourably to RICE, offering an effective outpatient treatment option for patients with relapsed or refractory DLBCL and HL.

Use of a computer-based provider order entry (CPOE) intervention to optimize laboratory testing in patients with suspected heparin-induced thrombocytopenia.

INTRODUCTION: Heparin-induced thrombocytopenia (HIT) is a rare but frequently considered diagnosis in hospitalized patients. Despite the availability of clinical prediction tools, HIT is often over-diagnosed and patients can be subjected to unnecessary and expensive testing. METHODS: A decision-support tool requiring providers to calculate the 4Ts (HIT risk) score prior to ordering laboratory-based tests for anti-PF4/heparin antibody enzyme-linked immunosorbent assay (ELISA) testing was implemented at our institution in January 2014. Charts of adult patients who underwent ELISA or serotonin release assay (SRA) testing during the 8-month time periods prior to and following this intervention were reviewed and 4Ts scores at the time of ELISA or SRA testing were calculated. RESULTS: A total of 443 ELISA and SRA tests were sent for 411 patients during the time periods studied. We observed a significant decrease from 43 tests/month before to 22 tests/month (p < 0.001) after the intervention. A total of 337 charts were reviewed. We observed a trend toward decrease in the proportion of tested patients with low 4Ts scores (66% vs 56%, p = 0.069), as well as an increase in the average 4Ts score of tested patients (3.0 vs 3.4, p = 0.010) following our intervention. DISCUSSION: Over-testing and treatment for HIT are frequent and potentially harmful occurrences in hospitalized patients. Our study demonstrates that a clinical decision support tool embedded within the electronic ordering process can decrease unnecessary testing for HIT.

Development of a hematology/oncology ICD-10 documentation job aid.

Conversion to the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) was mandated for October 1, 2014, but was delayed by one year. ICD-10 accommodates newly developed diagnoses and procedures and is expected to help measure quality of care. When implemented, it will impact oncology practices because of conversion costs, loss of productivity, and billing problems. Clinical documentation must meet the specificity required by ICD-10 codes or risk denial of payments, which are projected to dramatically increase. In preparation for the now delayed conversion, the ICD-10 transition team at the Seattle Cancer Care Alliance (SCCA) examined the ICD-10 codes for primary hematology/oncology diagnoses and comorbidities of cancer and therapy seen at our institution to identify the need for and feasibility of developing a printable job aid to guide clinical documentation. We found that the variable complexity of ICD-10 codes in hematology/oncology frequently requires nonintuitive specificity likely to be overlooked without prompting. We were able to develop a succinct and facile documentation aid usable in both electronic and printed forms that includes all hematology/oncology diagnoses and the comorbidities most frequently seen in our multidisciplinary institution. This document is organized in a notebook format for easy review and will be continuously improved with feedback from practitioners. It is available for free download from the SCCA Web site.

IQcat: multiplexed protein quantification by isoelectric QconCAT.

Expression of isotopically labeled peptide standards as artificial concatamers (QconCATs) allows for the multiplex quantification of proteins in unlabeled samples by mass spectrometry. We have developed a generalizable QconCAT design strategy, which we term IQcat, wherein concatenated peptides are binned by pI to facilitate MS-sample enrichment by isoelectric focusing. Our method utilizes a rapid (∼2 weeks), inexpensive and scalable purification of arg/lys labeled IQcat standards in the Escherichia coli auxotroph AT713. With this pipeline, we assess the fidelity of IQcat-based absolute quantification for ten yeast proteins over a broad concentration range in a single information-rich isoelectric fraction. The technique is further employed for a quantitative study of androgen-dependent protein expression in cultured prostate cancer cells.

Integrative analysis of N-linked human glycoproteomic data sets reveals PTPRF ectodomain as a novel plasma biomarker candidate for prostate cancer.

In an attempt to identify prostate cancer biomarkers with greater diagnostic and prognostic capabilities, we have developed an integrative proteomic discovery workflow focused on N-linked glycoproteins that refines the target selection process. In this work, hydrazide-based chemistry was used to identify N-linked glycopeptides from 22Rv1 prostate cancer cells cultured in vitro, which were compared with glycopeptides identified from explanted 22Rv1 murine tumor xenografts. One hundred and four human glycoproteins were identified in the former analysis and 75 in the latter, with 40 proteins overlapping between data sets. Of the 40 overlapping proteins, 80% have multiple literature references to the neoplastic process and ∼40% to prostatic neoplasms. These include a number of well-known prostate cancer-associated biomarkers, such as prostate-specific membrane antigen (PSMA). By integrating gene expression data and available literature, we identified members of the overlap data set that deserve consideration as potential prostate cancer biomarkers. Specifically, the identification of the extracellular domain of protein tyrosine phosphatase receptor type F (PTPRF) was of particular interest due to the direct involvement of PTPRF in the control of ß-catenin signaling, as well as dramatically elevated gene expression levels in the prostate compared to other tissues. In this investigation, we demonstrate that the PTPRF E-subunit is more abundant in human prostate tumor tissue compared to normal control and also detectable in murine plasma by immunoblot and ELISA. Specifically, PTPRF distinguishes between animals xenografted with the 22Rv1 cells and control animals as early as 14 days after implantation. This result suggests that the ectodomain of PTPRF has the potential to function as a novel plasma or tissue-based biomarker for prostate cancer. The workflow described adds to the literature of potential biomarker candidates for prostate cancer and demonstrates a pathway to developing new diagnostic assays.

Proteomic analysis of the androgen receptor via MS-compatible purification of biotinylated protein on streptavidin resin.

The strength of the streptavidin/biotin interaction poses challenges for the recovery of biotinylated molecules from streptavidin resins. As an alternative to high-temperature elution in urea-containing buffers, we show that mono-biotinylated proteins can be released with relatively gentle heating in the presence of biotin and 2% SDS/Rapigest, avoiding protein carbamylation and minimizing streptavidin dissociation. We demonstrate the utility of this mild elution strategy in two studies of the human androgen receptor (AR). In the first, in which formaldehyde cross-linked complexes are analyzed in yeast, a mass spectrometry-based comparison of the AR complex using SILAC reveals an association between the androgen-activated AR and the Hsp90 chaperonin, while Hsp70 chaperonins associate specifically with the unliganded complex. In the second study, the endogenous AR is quantified in the LNCaP cell line by absolute SILAC and MRM-MS showing approximately 127,000 AR copies per cell, substantially more than previously measured using radioligand binding.

SILAC compatible strain of Pichia pastoris for expression of isotopically labeled protein standards and quantitative proteomics.

The methylotrophic yeast Pichia pastoris is a powerful eukaryotic platform for the production of heterologous protein. Recent publication of the P. pastoris genome has facilitated strain development toward biopharmaceutical and environmental science applications and has advanced the organism as a model system for the study of peroxisome biogenesis and methanol metabolism. Here we report the development of a P. pastoris arg-/lys- auxotrophic strain compatible with SILAC (stable isotope labeling by amino acids in cell culture) proteomic studies, which is capable of generating large quantities of isotopically labeled protein for mass spectrometry-based biomarker measurements. We demonstrate the utility of this strain to produce high purity human serum albumin uniformly labeled with isotopically heavy arginine and lysine. In addition, we demonstrate the first quantitative proteomic analysis of methanol metabolism in P. pastoris, reporting new evidence for a malate-aspartate NADH shuttle mechanism in the organism. This strain will be a useful model organism for the study of metabolism and peroxisome generation.

Fast parallel tandem mass spectral library searching using GPU hardware acceleration.

Mass spectrometry-based proteomics is a maturing discipline of biologic research that is experiencing substantial growth. Instrumentation has steadily improved over time with the advent of faster and more sensitive instruments collecting ever larger data files. Consequently, the computational process of matching a peptide fragmentation pattern to its sequence, traditionally accomplished by sequence database searching and more recently also by spectral library searching, has become a bottleneck in many mass spectrometry experiments. In both of these methods, the main rate-limiting step is the comparison of an acquired spectrum with all potential matches from a spectral library or sequence database. This is a highly parallelizable process because the core computational element can be represented as a simple but arithmetically intense multiplication of two vectors. In this paper, we present a proof of concept project taking advantage of the massively parallel computing available on graphics processing units (GPUs) to distribute and accelerate the process of spectral assignment using spectral library searching. This program, which we have named FastPaSS (for Fast Parallelized Spectral Searching), is implemented in CUDA (Compute Unified Device Architecture) from NVIDIA, which allows direct access to the processors in an NVIDIA GPU. Our efforts demonstrate the feasibility of GPU computing for spectral assignment, through implementation of the validated spectral searching algorithm SpectraST in the CUDA environment.

Collision energy optimization of b- and y-ions for multiple reaction monitoring mass spectrometry.

Multiple reaction monitoring (MRM) is a highly sensitive and increasingly popular method of targeted mass spectrometry (MS) that can be used to selectively detect and quantify peptides and their corresponding proteins of interest within biological samples. The sensitivity of MRM-MS is highly dependent upon the tuning of transition-specific parameters, especially the collision energy (CE) applied during peptide fragmentation. Currently, empirical equations for CE work best for y-type ions and are much less effective for other types of transitions, such as b-type ions and small y-type transitions across particular amide bonds, which could also be useful for MRM-MS if optimized for maximum signal transmission. In this work, we have performed a CE optimization of all transitions for 80 doubly charged peptides, the results of which were used to define separate CE equations for b-ions and y-ions, as well as for small y-type ions derived from the fragmentation of amide bonds bounded on the amino-terminal side by aspartic or glutamic acid residues (D/E-X transitions). This analysis yielded four major observations: (1) b-ions tend to require lower collision energies than y-ions for optimal fragmentation, while D/E-X transitions tend to require more; (2) CE equations predict the optimal CEs more closely when product ion m/z dependence is included, in addition to the current standard of precursor ion m/z dependence; (3) separate CE equations for y-ions, b-ions, and D/E-X transitions are more effective than the previous one-size-fits-all equations, but best results are achieved by optimizing transitions individually; and (4) while b-ions gain substantial signal from CE optimization-often increases of several-fold-they still tend to rank lower than y-ions from the same peptide. These results confirm the notion that y-ions are usually the first-choice transitions for MRM experiments but also demonstrate, for the first time, that b-ions can be viable targets as well, if the proper collision energies are used.

Integrative proteomic analysis of serum and peritoneal fluids helps identify proteins that are up-regulated in serum of women with ovarian cancer.

BACKGROUND: We used intensive modern proteomics approaches to identify predictive proteins in ovary cancer. We identify up-regulated proteins in both serum and peritoneal fluid. To evaluate the overall performance of the approach we track the behavior of 20 validated markers across these experiments. METHODOLOGY: Mass spectrometry based quantitative proteomics following extensive protein fractionation was used to compare serum of women with serous ovarian cancer to healthy women and women with benign ovarian tumors. Quantitation was achieved by isotopically labeling cysteine amino acids. Label-free mass spectrometry was used to compare peritoneal fluid taken from women with serous ovarian cancer and those with benign tumors. All data were integrated and annotated based on whether the proteins have been previously validated using antibody-based assays. FINDINGS: We selected 54 quantified serum proteins and 358 peritoneal fluid proteins whose case-control differences exceeded a predefined threshold. Seventeen proteins were quantified in both materials and 14 are extracellular. Of 19 validated markers that were identified all were found in cancer peritoneal fluid and a subset of 7 were quantified in serum, with one of these proteins, IGFBP1, newly validated here. CONCLUSION: Proteome profiling applied to symptomatic ovarian cancer cases identifies a large number of up-regulated serum proteins, many of which are or have been confirmed by immunoassays. The number of currently known validated markers is highest in peritoneal fluid, but they make up a higher percentage of the proteins observed in both serum and peritoneal fluid, suggesting that the 10 additional markers in this group may be high quality candidates.

ChromEval: a software application for the rapid evaluation of HPLC system performance in proteomic applications.

Mass spectrometry-based proteomics is typically performed using high performance liquid chromatography (HPLC) to introduce peptides into the instrument via electrospray ionization. A variety of configurations exist with varying degrees of precision and cost, but the ultimate goal is the reproducible delivery of peptides in well-separated elution peaks. It is well-known that the quality of chromatography can have a dramatic effect on sample identification as well as run-to-run reproducibility, which is especially important for quantitative analyses. Despite the importance of the HPLC system for both shotgun and targeted proteomics, there are few tools available to monitor HPLC performance. In this paper, we describe a new open-source software application, named ChromEval, to allow rapid assessment of HPLC performance, as well as to provide other metrics of mass spectrometer performance, including mass accuracy calibration. ChromEval permits the user to visually monitor the elution of a set of standard peptides in quality control runs interspersed among a regular workflow. To perform these tasks, ChromEval searches mzXML files using Tandem and presents the peptide results in a graphical user interface (GUI) that allows fast assessment of chromatography by visualization of superimposed elution peaks. This tool facilitates the identification and troubleshooting of chromatography problems such as retention time shifts and variance in sample loading due to autosampler error. It also provides crude but consistent metrics of instrument performance including mass accuracy calibration and number of peptides identified from the standard mixture. ChromEval generates easily interpretable data quickly and thereby enables go/no-go decision making during intensive instrument operation.

A guided tour of the Trans-Proteomic Pipeline.

The Trans-Proteomic Pipeline (TPP) is a suite of software tools for the analysis of MS/MS data sets. The tools encompass most of the steps in a proteomic data analysis workflow in a single, integrated software system. Specifically, the TPP supports all steps from spectrometer output file conversion to protein-level statistical validation, including quantification by stable isotope ratios. We describe here the full workflow of the TPP and the tools therein, along with an example on a sample data set, demonstrating that the setup and use of the tools are straightforward and well supported and do not require specialized informatic resources or knowledge.

Correlation between y-type ions observed in ion trap and triple quadrupole mass spectrometers.

Multiple reaction monitoring mass spectrometry (MRM-MS) is a technique for high-sensitivity targeted analysis. In proteomics, MRM-MS can be used to monitor and quantify a peptide based on the production of expected fragment peaks from the selected peptide precursor ion. The choice of which fragment ions to monitor in order to achieve maximum sensitivity in MRM-MS can potentially be guided by existing MS/MS spectra. However, because the majority of discovery experiments are performed on ion trap platforms, there is concern in the field regarding the generalizability of these spectra to MRM-MS on a triple quadrupole instrument. In light of this concern, many operators perform an optimization step to determine the most intense fragments for a target peptide on a triple quadrupole mass spectrometer. We have addressed this issue by targeting, on a triple quadrupole, the top six y-ion peaks from ion trap-derived consensus library spectra for 258 doubly charged peptides from three different sample sets and quantifying the observed elution curves. This analysis revealed a strong correlation between the y-ion peak rank order and relative intensity across platforms. This suggests that y-type ions obtained from ion trap-based library spectra are well-suited for generating MRM-MS assays for triple quadrupoles and that optimization is not required for each target peptide.

MaRiMba: a software application for spectral library-based MRM transition list assembly.

Multiple reaction monitoring mass spectrometry (MRM-MS) is a targeted analysis method that has been increasingly viewed as an avenue to explore proteomes with unprecedented sensitivity and throughput. We have developed a software tool, called MaRiMba, to automate the creation of explicitly defined MRM transition lists required to program triple quadrupole mass spectrometers in such analyses. MaRiMba creates MRM transition lists from downloaded or custom-built spectral libraries, restricts output to specified proteins or peptides, and filters based on precursor peptide and product ion properties. MaRiMba can also create MRM lists containing corresponding transitions for isotopically heavy peptides, for which the precursor and product ions are adjusted according to user specifications. This open-source application is operated through a graphical user interface incorporated into the Trans-Proteomic Pipeline, and it outputs the final MRM list to a text file for upload to MS instruments. To illustrate the use of MaRiMba, we used the tool to design and execute an MRM-MS experiment in which we targeted the proteins of a well-defined and previously published standard mixture.