Effectiveness of routine provision of feedback from patient-reported outcome measurements for cancer care improvement: a systematic review and meta-analysis.

BACKGROUND: Research shows that feeding back patient-reported outcome information to clinicians and/or patients could be associated with improved care processes and patient outcomes. Quantitative syntheses of intervention effects on oncology patient outcomes are lacking. OBJECTIVE: To determine the effects of patient-reported outcome measure (PROM) feedback intervention on oncology patient outcomes. DATA SOURCES: We identified relevant studies from 116 references included in our previous Cochrane review assessing the intervention for the general population. In May 2022, we conducted a systematic search in five bibliography databases using predefined keywords for additional studies published after the Cochrane review. STUDY SELECTION: We included randomized controlled trials evaluating the effects of PROM feedback intervention on processes and outcomes of care for oncology patients. DATA EXTRACTION AND SYNTHESIS: We used the meta-analytic approach to synthesize across studies measuring the same outcomes. We estimated pooled effects of the intervention on outcomes using Cohen's d for continuous data and risk ratio (RR) with a 95% confidence interval for dichotomous data. We used a descriptive approach to summarize studies which reported insufficient data for a meta-analysis. MAIN OUTCOME(S) AND MEASURES(S): Health-related quality of life (HRQL), symptoms, patient-healthcare provider communication, number of visits and hospitalizations, number of adverse events, and overall survival. RESULTS: We included 29 studies involving 7071 cancer participants. A small number of studies was available for each metanalysis (median = 3 studies, ranging from 2 to 9 studies) due to heterogeneity in the evaluation of the trials. We found that the intervention improved HRQL (Cohen's d = 0.23, 95% CI 0.11-0.34), mental functioning (Cohen's d = 0.14, 95% CI 0.02-0.26), patient-healthcare provider communication (Cohen's d = 0.41, 95% CI 0.20-0.62), and 1-year overall survival (OR = 0.64, 95% CI 0.48-0.86). The risk of bias across studies was considerable in the domains of allocation concealment, blinding, and intervention contamination. CONCLUSIONS AND RELEVANCE: Although we found evidence to support the intervention for highly relevant outcomes, our conclusions are tempered by the high risk of bias relating mainly to intervention design. PROM feedback for oncology patients may improve processes and outcomes for cancer patients but more high-quality evidence is required.

Appraisal of International Guidelines for Cutaneous Melanoma Management using the AGREE II assessment tool.

BACKGROUND: The evidence base behind new melanoma treatments is rapidly accumulating. This is not necessarily reflected in current guidance. A recent UK-based expert consensus statement, published in JPRAS, has called for updates to the widely accepted 2015 National Institute for Health and Care Excellence (NICE) guideline for melanoma (NG14). We aimed to compare the quality of NG14 to all other melanoma guidelines published since. METHODS: We conducted a systematic search of PubMed, Medline, and online clinical practice guideline databases to identify melanoma guidelines published between 29th July 2015 and 23rd August 2021 providing recommendations for adjuvant treatment, radiotherapy, surgical management, or follow-up care. Three authors independently assessed the quality of identified guidelines using the Appraisal of Guidelines for Research & Evaluation Instrument II (AGREE II) assessment tool, which measures six domains of guideline development. Inter-rater reliability was assessed by Kendall's coefficient of concordance (W). RESULTS: Twenty-nine guidelines were included and appraised with excellent concordance (Kendall's W for overall guideline score 0.88, p<0.001). Overall, melanoma guidelines scored highly in the domains of 'Scope and purpose' and 'Clarity of presentation', but poorly in the 'Applicability' domain. The NICE guideline on melanoma (NG14) achieved the best overall scores. CONCLUSION: Melanoma treatment has advanced since NG14 was published, however, the NICE melanoma guideline is of higher quality than more recent alternatives. The planned update of NG14 in 2022 is in demand.

Construct validity of the anglicised FACE-Q skin cancer module.

OBJECTIVES: The FACE-Q Skin Cancer module is a patient-reported outcome measure (PROM) for facial skin cancer. It has been anglicised for the UK population and undergone psychometric testing using classical test theory. In this study, further evaluation of construct validity using Rasch measurement theory and hypothesis testing was performed. METHODS: Patients were prospectively recruited to the Patient-Reported Outcome Measures In Skin Cancer Reconstruction (PROMISCR) study and asked to complete the anglicised FACE-Q Skin Cancer module. The scalability and unidimensionality of the data were assessed with a Mokken analysis prior to Rasch analysis. Response thresholds, targeting, fit statistics, local dependency, and internal consistency were examined for all items and subscales. Four a priori hypotheses were tested to evaluate the convergent and divergent validity. We additionally hypothesised that the median 'cancer worry' score would be lower in post-operative than pre-operative patients. RESULTS: 239 patients self-completed the questionnaire between August 2017 and May 2019. Of the ten subscales assessed, five showed relative fit to the Rasch model. Unidimensionality was present for all five subscales, with most demonstrating ordered item thresholds and appropriate fit statistics. Two items in the 'cancer worry' subscale had either disordered or very close response thresholds. Subscales of the FACE-Q Skin Cancer module demonstrated convergent and divergent validity with relevant Skin Cancer Index comparators (p < 0.001). Median 'cancer worry' was lower in post-operative patients (44 vs 39, p < 0.001). CONCLUSION: The anglicised FACE-Q Skin Cancer module shows psychometric validity through hypothesis testing, and both classical and modern test theory.

Automated conversational agents for post-intervention follow-up: a systematic review.

BACKGROUND: Advances in natural language processing and other machine learning techniques have led to the development of automated agents (chatbots) that mimic human conversation. These systems have mainly been used in commercial settings, and within medicine, for symptom checking and psychotherapy. The aim of this systematic review was to determine the acceptability and implementation success of chatbots in the follow-up of patients who have undergone a physical healthcare intervention. METHODS: A systematic review of MEDLINE, MEDLINE In-process, EMBASE, PsychINFO, CINAHL, CENTRAL and the grey literature using a PRISMA-compliant methodology up to September 2020 was conducted. Abstract screening and data extraction were performed in duplicate. Risk of bias and quality assessments were performed for each study. RESULTS: The search identified 904 studies of which 10 met full inclusion criteria: three randomised control trials, one non-randomised clinical trial and six cohort studies. Chatbots were used for monitoring after the management of cancer, hypertension and asthma, orthopaedic intervention, ureteroscopy and intervention for varicose veins. All chatbots were deployed on mobile devices. A number of metrics were identified and ranged from a 31 per cent chatbot engagement rate to a 97 per cent response rate for system-generated questions. No study examined patient safety. CONCLUSION: A range of chatbot builds and uses was identified. Further investigation of acceptability, efficacy and mechanistic evaluation in outpatient care pathways may lend support to implementation in routine clinical care.

Emergence of Parechovirus A4 Central Nervous System Infections among Infants in Kansas City, Missouri, USA.

Among known parechovirus (PeV) types infecting humans, PeV-A3 (formerly HPeV3) and PeV-A1 (formerly HPeV1) are associated with pediatric central nervous system (CNS) infections. The prevalence of PeV-A3 among hospitalized infants with sepsis-like illness and viral CNS infection is well described; however, the contribution of PeV-A4 to infant CNS infection is relatively unexplored. We report the first 11 U.S. cases of PeV-A4 CNS infections occurring in Kansas City infants during 2010 to 2016 and compare the clinical presentation with that of PeV-A3. PeV-positive cerebrospinal fluid (CSF) specimens from 2010 to 2016 underwent sequencing for genotyping. Among all PeV-CSF positives, PeV-A4 was detected in 11 CSF samples from 2010 to 2016. PeV-A4 was first detected in 2010 (n = 1/4), followed by detections in 2014 (n = 1/39), 2015 (n = 6/9), and 2016 (n = 3/33). The median age of PeV-A4-infected infants in weeks (median, 4; range, 1 to 8) was similar to that of infants infected with PeV-A3 (median, 4; range, 0.25 to 8). Clinical characteristics of PeV-A4 (n = 11) were compared with those of select PeV-A3-infected children (n = 34) with CNS infections and found to be mostly similar, although maximum temperature was higher (P = 0.017) and fever duration was shorter (P = 0.03) for PeV-A4 than for PeV-A3. Laboratory test results were also similar between genotypes, although they showed significantly lower peripheral white blood cell (P = 0.014) and absolute lymphocyte (P = 0.04) counts for PeV-A4 infants. Like PeV-A3, PeV-A4 caused summer-fall seasonal clusters of CNS infections in infants, with mostly similar presentations. Further surveillance is necessary to confirm potential differences in laboratory findings and in fever intensity/duration.

Single-cell analysis identifies CRLF2 rearrangements as both early and late events in Down syndrome and non-Down syndrome acute lymphoblastic leukaemia.

Deregulated expression of the type I cytokine receptor, CRLF2, is observed in 5-15% of precursor B-cell acute lymphoblastic leukaemia (B-ALL). We have previously reported the genomic landscape of patients with CRLF2 rearrangements (CRLF2-r) using both whole genome and exome sequencing, which identified a number of potential clonal and sub-clonal genomic alterations. In this study, we aimed to assess when the CRLF2-r; IGH-CRLF2 or P2RY8-CRLF2, arose during the evolution of both Down syndrome-ALL (DS-ALL) and non-DS-ALL. Using fluorescence in situ hybridisation, we were able to track up to four structural variants in single cells from 47 CRLF2-r B-ALL patients, which in association with our multiplex single-cell analysis of a further four patients, permitted simultaneous tracking of copy number alterations, structural and single nucleotide variants within individual cells. We observed CRLF2-r arising as both early and late events in DS and non-DS-ALL patients. Parallel evolution of discrete clones was observed in the development of CRLF2-r B-ALL, either involving the CRLF2-r or one of the other tracked abnormalities. In-depth single-cell analysis identified both linear and branching evolution with early clones harbouring a multitude of abnormalities, including the CRLF2-r in DS-ALL patients.

Evaluation of RIDA®GENE norovirus GI/GII real time RT-PCR using stool specimens collected from children and adults with acute gastroenteritis.

BACKGROUND: Norovirus is the leading cause of epidemic and sporadic acute gastroenteritis (AGE) in the United States. Widespread prevalence necessitates implementation of accurate norovirus detection assays in clinical diagnostic laboratories. OBJECTIVE: To evaluate RIDA®GENE norovirus GI/GII real-time RT-PCR assay (RGN RT-PCR) using stool samples from patients with sporadic AGE. STUDY DESIGN: Patients between 14 days to 101 years of age with symptoms of AGE were enrolled prospectively at four sites across the United States during 2014-2015. Stool specimens were screened for the presence of norovirus RNA by the RGN RT-PCR assay. Results were compared with a reference method that included conventional RT-PCR and sequencing of a partial region of the 5'end of the norovirus ORF2 gene. RESULTS: A total of 259 (36.0%) of 719 specimens tested positive for norovirus by the reference method. The RGN RT-PCR assay detected norovirus in 244 (94%) of these 259 norovirus positive specimens. The sensitivity and specificity (95% confidence interval) of the RGN RT-PCR assay for detecting norovirus genogroup (G) I was 82.8% (63.5-93.5) and 99.1% (98.0-99.6) and for GII was 94.8% (90.8-97.2) and 98.6% (96.9-99.4), respectively. Seven specimens tested positive by the RGN-RT PCR that were negative by the reference method. The fifteen false negative samples were typed as GII.4 Sydney, GII.13, GI.3, GI.5, GI.2, GII.1, and GII.3 in the reference method. CONCLUSIONS: The RGN RT-PCR assay had a high sensitivity and specificity for the detection of norovirus in stool specimens from patients with sporadic AGE.

The T-cell leukemia-associated ribosomal RPL10 R98S mutation enhances JAK-STAT signaling.

Several somatic ribosome defects have recently been discovered in cancer, yet their oncogenic mechanisms remain poorly understood. Here we investigated the pathogenic role of the recurrent R98S mutation in ribosomal protein L10 (RPL10 R98S) found in T-cell acute lymphoblastic leukemia (T-ALL). The JAK-STAT signaling pathway is a critical controller of cellular proliferation and survival. A proteome screen revealed overexpression of several Jak-Stat signaling proteins in engineered RPL10 R98S mouse lymphoid cells, which we confirmed in hematopoietic cells from transgenic Rpl10 R98S mice and T-ALL xenograft samples. RPL10 R98S expressing cells displayed JAK-STAT pathway hyper-activation upon cytokine stimulation, as well as increased sensitivity to clinically used JAK-STAT inhibitors like pimozide. A mutually exclusive mutation pattern between RPL10 R98S and JAK-STAT mutations in T-ALL patients further suggests that RPL10 R98S functionally mimics JAK-STAT activation. Mechanistically, besides transcriptional changes, RPL10 R98S caused reduction of apparent programmed ribosomal frameshifting at several ribosomal frameshift signals in mouse and human Jak-Stat genes, as well as decreased Jak1 degradation. Of further medical interest, RPL10 R98S cells showed reduced proteasome activity and enhanced sensitivity to clinical proteasome inhibitors. Collectively, we describe modulation of the JAK-STAT cascade as a novel cancer-promoting activity of a ribosomal mutation, and expand the relevance of this cascade in leukemia.

A genome-wide association study identifies risk loci for childhood acute lymphoblastic leukemia at 10q26.13 and 12q23.1.

Genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of childhood acute lymphoblastic leukemia (ALL). To identify new susceptibility loci for the largest subtype of ALL, B-cell precursor ALL (BCP-ALL), we conducted a meta-analysis of two GWASs with imputation using 1000 Genomes and UK10K Project data as reference (totaling 1658 cases and 7224 controls). After genotyping an additional 2525 cases and 3575 controls, we identify new susceptibility loci for BCP-ALL mapping to 10q26.13 (rs35837782, LHPP, P=1.38 × 10-11) and 12q23.1 (rs4762284, ELK3, P=8.41 × 10-9). We also provide confirmatory evidence for the existence of independent risk loci at 9p21.3, but show that the association marked by rs77728904 can be accounted for by linkage disequilibrium with the rare high-impact CDKN2A p.Ala148Thr variant rs3731249. Our data provide further insights into genetic susceptibility to ALL and its biology.

A phase I/II trial of AT9283, a selective inhibitor of aurora kinase in children with relapsed or refractory acute leukemia: challenges to run early phase clinical trials for children with leukemia.

Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies.

The role of the RAS pathway in iAMP21-ALL.

Intrachromosomal amplification of chromosome 21 (iAMP21) identifies a high-risk subtype of acute lymphoblastic leukaemia (ALL), requiring intensive treatment to reduce their relapse risk. Improved understanding of the genomic landscape of iAMP21-ALL will ascertain whether these patients may benefit from targeted therapy. We performed whole-exome sequencing of eight iAMP21-ALL samples. The mutation rate was dramatically disparate between cases (average 24.9, range 5-51) and a large number of novel variants were identified, including frequent mutation of the RAS/MEK/ERK pathway. Targeted sequencing of a larger cohort revealed that 60% (25/42) of diagnostic iAMP21-ALL samples harboured 42 distinct RAS pathway mutations. High sequencing coverage demonstrated heterogeneity in the form of multiple RAS pathway mutations within the same sample and diverse variant allele frequencies (VAFs) (2-52%), similar to other subtypes of ALL. Constitutive RAS pathway activation was observed in iAMP21 samples that harboured mutations in the predominant clone (⩾35% VAF). Viable iAMP21 cells from primary xenografts showed reduced viability in response to the MEK1/2 inhibitor, selumetinib, in vitro. As clonal (⩾35% VAF) mutations were detected in 26% (11/42) of iAMP21-ALL, this evidence of response to RAS pathway inhibitors may offer the possibility to introduce targeted therapy to improve therapeutic efficacy in these high-risk patients.

The pre-B-cell receptor checkpoint in acute lymphoblastic leukaemia.

The B-cell receptor (BCR) and its immature form, the precursor-BCR (pre-BCR), have a central role in the control of B-cell development, which is dependent on a sequence of cell-fate decisions at specific antigen-independent checkpoints. Pre-BCR expression provides the first checkpoint, which controls differentiation of pre-B to immature B-cells in normal haemopoiesis. Pre-BCR signalling regulates and co-ordinates diverse processes within the pre-B cell, including clonal selection, proliferation and subsequent maturation. In B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), B-cell development is arrested at this checkpoint. Moreover, malignant blasts avoid clonal extinction by hijacking pre-BCR signalling in favour of the development of BCP-ALL. Here, we discuss three mechanisms that occur in different subtypes of BCP-ALL: (i) blocking pre-BCR expression; (ii) activating pre-BCR-mediated pro-survival and pro-proliferative signalling, while inhibiting cell cycle arrest and maturation; and (iii) bypassing the pre-BCR checkpoint and activating pro-survival signalling through pre-BCR independent alternative mechanisms. A complete understanding of the BCP-ALL-specific signalling networks will highlight their application in BCP-ALL therapy.

c-MYC is a radiosensitive locus in human breast cells.

Ionising radiation is a potent human carcinogen. Epidemiological studies have shown that adolescent and young women are at increased risk of developing breast cancer following exposure to ionising radiation compared with older women, and that risk is dose-dependent. Although it is well understood which individuals are at risk of radiation-induced breast carcinogenesis, the molecular genetic mechanisms that underlie cell transformation are less clear. To identify genetic alterations potentially responsible for driving radiogenic breast transformation, we exposed the human breast epithelial cell line MCF-10A to fractionated doses of X-rays and examined the copy number and cytogenetic alterations. We identified numerous alterations of c-MYC that included high-level focal amplification associated with increased protein expression. c-MYC amplification was also observed in primary human mammary epithelial cells following exposure to radiation. We also demonstrate that the frequency and magnitude of c-MYC amplification and c-MYC protein expression is significantly higher in breast cancer with antecedent radiation exposure compared with breast cancer without a radiation aetiology. Our data also demonstrate extensive intratumor heterogeneity with respect to c-MYC copy number in radiogenic breast cancer, suggesting continuous evolution at this locus during disease development and progression. Taken together, these data identify c-MYC as a radiosensitive locus, implicating this oncogenic transcription factor in the aetiology of radiogenic breast cancer.

An international study of intrachromosomal amplification of chromosome 21 (iAMP21): cytogenetic characterization and outcome.

Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of childhood B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). To date, fluorescence in situ hybridisation (FISH), with probes specific for the RUNX1 gene, provides the only reliable detection method (five or more RUNX1 signals per cell). Patients with iAMP21 are older (median age 9 years) with a low white cell count. Previously, we demonstrated a high relapse risk when these patients were treated as standard risk. Recent studies have shown improved outcome on intensive therapy. In view of these treatment implications, accurate identification is essential. Here we have studied the cytogenetics and outcome of 530 iAMP21 patients that highlighted the association of specific secondary chromosomal and genetic changes with iAMP21 to assist in diagnosis, including the gain of chromosome X, loss or deletion of chromosome 7, ETV6 and RB1 deletions. These iAMP21 patients when treated as high risk showed the same improved outcome as those in trial-based studies regardless of the backbone chemotherapy regimen given. This study reinforces the importance of intensified treatment to reduce the risk of relapse in iAMP21 patients. This now well-defined patient subgroup should be recognised by World Health Organisation (WHO) as a distinct entity of BCP-ALL.

Hyperdiploidy with 49-65 chromosomes represents a heterogeneous cytogenetic subgroup of acute myeloid leukemia with differential outcome.

Chromosome gain is frequent in acute myeloid leukemia (AML) and is counted alongside structural abnormalities when determining karyotype complexity. However, there are few studies investigating the cytogenetic profile and outcome of patients with a hyperdiploid karyotype (49-65 chromosomes, HK). We identified 221 (14%) patients with HK out of 1563 patients with three or more chromosomal abnormalities. HK was not associated with sex, white cell count and secondary disease status, but was more prevalent among children (22% vs 13%). The pattern of chromosomal gain and loss was non-random and chromosomes 8, 13 and 21 were the most frequently gained. Three distinct subgroups (numerical, structural and adverse) were identified with differential outcome: 5-year cumulative incidence of relapse of 52%, 68% and 76%, respectively (P=0.008). Patients in the adverse subgroup had poorer survival compared with patients with only numerical abnormalities (adjusted hazard ratio: 2.01 (95% confidence interval: 1.43-2.83), P=0.0002). This outcome heterogeneity was similar among children and adults. In conclusion, AML patients with a HK should not automatically be assigned to the adverse cytogenetic risk group on the basis of complexity. Instead they should be assessed for the presence of specific chromosomal abnormalities, which are known to harbour an adverse effect.