Early switch to oral antibiotic therapy in patients with low-risk neutropenic sepsis (EASI-SWITCH): a randomized non-inferiority trial.

OBJECTIVES: To determine whether early switch to oral antibiotic treatment in adults with neutropenic sepsis at low risk of complications is non-inferior to switching later. METHODS: This non-inferiority, parallel-group, randomized, open-label clinical trial enrolled UK adults hospitalized with neutropenic sepsis. Participants were randomly assigned to either switch to oral ciprofloxacin plus co-amoxiclav within 12-24 hours or to continue intravenous treatment for at least 48 hours. The primary outcome was a composite measure of treatment failure, 14 days after randomization. The non-inferiority margin was 15%. RESULTS: There were 129 participants from 16 centres and 125 were assessed for the primary outcome. Of these, 113 patients completed protocolized treatment and comprised the per-protocol population. In total, 9 (14.1%) of 64 patients in the standard care arm met the primary end point, compared with 15 (24.6%) of 61 in the early switch arm, giving a risk difference of 10.5% (1-sided 95% CI, -∞% to 22%; p 0.14). In the per-protocol population, 8 (13.3%) of the 60 patients in the standard care arm met the primary end point, compared with 9 (17%) of 53 in the intervention arm giving a risk difference of 3.7% (one-sided 95% CI, -∞% to 14.8%; p 0.59). Duration of hospital stay was shorter in the intervention arm (median 2 [inter-quartile range (IQR) 2-3] vs. 3 days [IQR 2-4]; p 0.002). DISCUSSION: Although non-inferiority of early oral switch was found in the per-protocol population, the intervention was not non-inferior in the intent-to-treat population.

Trusting relationships between patients with non-curative cancer and healthcare professionals create ethical obstacles for informed consent in clinical trials: a grounded theory study.

BACKGROUND: Clinical trial participation for patients with non-curative cancer is unlikely to present personal clinical benefit, which raises the bar for informed consent. Previous work demonstrates that decisions by patients in this setting are made within a 'trusting relationship' with healthcare professionals. The current study aimed to further illuminate the nuances of this relationship from both the patients' and healthcare professionals' perspectives. METHODS: Face-to-face interviews using a grounded theory approach were conducted at a regional Cancer Centre in the United Kingdom. Interviews were performed with 34 participants (patients with non-curative cancer, number (n) = 16; healthcare professionals involved in the consent process, n = 18). Data analysis was performed after each interview using open, selective, and theoretical coding. RESULTS: The 'Trusting relationship' with healthcare professionals underpinned patient motivation to participate, with many patients 'feeling lucky' and articulating an unrealistic hope that a clinical trial could provide a cure. Patients adopted the attitude of 'What the doctor thinks is best' and placed significant trust in healthcare professionals, focusing on mainly positive aspects of the information provided. Healthcare professionals recognised that trial information was not received neutrally by patients, with some expressing concerns that patients would consent to 'please' them. This raises the question: Within the trusting relationship between patients and healthcare professionals, 'Is it possible to provide balanced information?'. The theoretical model identified in this study is central to understanding how the trusting professional-patient relationship influences the decision-making process. CONCLUSION: The significant trust placed on healthcare professionals by patients presented an obstacle to delivering balanced trial information, with patients sometimes participating to please the 'experts'. In this high-stakes scenario, it may be pertinent to consider strategies, such as separation of the clinician-researcher roles and enabling patients to articulate their care priorities and preferences within the informed consent process. Further research is needed to expand on these ethical conundrums and ensure patient choice and autonomy in trial participation are prioritised, particularly when the patient's life is limited.

Thromboxane biosynthesis in cancer patients and its inhibition by aspirin: a sub-study of the Add-Aspirin trial.

BACKGROUND: Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases. METHODS: Urinary 11-dehydro-thromboxane B2 (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values. RESULTS: In total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77-82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg. CONCLUSIONS: Persistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin.

Clinical Interpretation of Word-Recognition Scores for Listeners with Sensorineural Hearing Loss: Confidence Intervals, Limits, and Levels.

OBJECTIVES: Confidence levels were established to determine if a word-recognition score is within the expected range for a hearing loss group (based on 3-frequency pure-tone average) or significantly below or above the expected range. DESIGN: Two large clinical databases were mined to produce data-sets composed of word-recognition scores obtained with Q/MASS NU-6 materials and VA NU-6 materials for patients with average hearing losses ranging from 0 to 70 dB HL. Percentiles representing scores that are below (2.5%, 5%, and 10%) and above (90%, 95%, and 97.5%) the expected range (defined as the 80% confidence interval) were established. To estimate the distribution of scores and percentiles for the Auditec NU-6 materials (for which a large database is not available) Q/MASS scores were transformed to Auditec scores based on published psychometric functions. RESULTS: The resulting confidence levels and expected ranges of word-recognition scores should be useful for interpreting the relationship between a score and the distribution of scores for the patient's hearing loss severity. Confidence levels are described as low, moderate, and high corresponding to the statistical level of assurance that a score is lower or higher than the expected score. CONCLUSIONS: The confidence levels and expected ranges may be helpful for interpreting word-recognition scores obtained with three widely used sets of NU-6 test materials.

Non-linguistic auditory speech processing.

OBJECTIVES: A method for testing auditory processing of non-linguistic speech-like stimuli was developed and evaluated. DESIGN: Monosyllabic words were temporally reversed and distorted. Stimuli were matched for spectrum and level. Listeners discriminated between distorted and undistorted stimuli. STUDY SAMPLE: Three groups were tested. The Normal group was comprised of 12 normal-hearing participants. The Senior group was comprised of 12 seniors. The Hearing Loss group was comprised of 12 participants with thresholds of at least 35 dB HL at one or more frequencies. RESULTS: The Senior group scored lower than the Normal group, and the Hearing Loss group scored lower than the Senior group. Scores for forward compressed speech were slightly higher than backward compressed speech but the difference was not statistically significant. Retest scores were slightly higher than scores on the first test, but the difference was not statistically significant. CONCLUSIONS: Large differences in discrimination of distorted speech were observed among the three groups. Age and hearing loss separately affected performance. The depressed performance of the Senior group may be a result of "hidden hearing loss" that is attributed to cochlear synaptopathy. The backward-distorted speech task may be a useful non-linguistic test of speech processing that is language independent.

Evaluation of binomial distribution estimates of confidence intervals of speech-recognition test scores.

Speech-recognition tests are a routine component of the clinical hearing evaluation. The most common type of test uses recorded monosyllabic words presented in quiet. The interpretation of test scores relies on an understanding of the variance of repeated tests. Confidence intervals are useful for determining if two scores are significantly different or if the difference is due to the variability of test scores. Because the response to each test item is binary, either correct or incorrect, the binomial distribution has been used to estimate confidence intervals. This method requires that test scores be independent. If the scores are not independent, the binomial distribution will not accurately estimate the variance of repeated scores. A previously published dataset with repeated scores from normal-hearing and hearing-impaired listeners was used to derive confidence intervals from actual test scores in contrast to the predicted confidence intervals in earlier reports. This analysis indicates that confidence intervals predicted by the binomial distribution substantially overestimate the variance of repeated scores resulting in erroneously broad confidence intervals. High correlations were found for repeated scores, indicating that scores are not independent. The interdependence of repeated scores invalidates confidence intervals predicted by the binomial distribution. Confidence intervals and confidence levels for repeated measures were determined empirically from measured test scores to assist in interpreting differences between repeat scores.

Ambient Noise Monitoring during Pure-Tone Audiometry.

BACKGROUND: There is an increasing need to administer hearing tests outside of sound-attenuating rooms. Maximum permissible ambient noise levels (MPANLs) from published in standards (Occupational Health and Safety Administration [OSHA] 1983; American National Standards Institute [ANSI] S3.1-1999 (R2018)) can be modified to account for the additional attenuation provided by circumaural earphones (relative to supra-aural earphones) that are used for pure-tone audiometry. Ambient noise can influence the results of pure-tone audiometry by elevating thresholds by direct masking and by producing distractions that affect the accuracy of the test. The effects of these distractions have not been studied in relation to pure-tone audiometry in adult listeners. PURPOSE: In Part I MPANLs provided by ANSI and OSHA standards are extended to account for the greater attenuation provided by circumaural earphones. Rules ("alerts") were developed taking into account the listeners' thresholds. In Part II effects of distracting noise on pure-tone thresholds are reported. METHODS AND RESULTS: In Part I MPANLs two standards were modified for circumaural earphones by adding the additional attenuation provided by three circumaural earphones (relative to supra-aural earphones). A set of rules ("alerts") is provided for identifying masking effects from ambient noise in a variety of conditions (earphone type, threshold elevation, uncovered ear). In Part II the distracting effects of an industrial noise sample on thresholds obtained from five listeners with normal hearing are described. Pure-tone thresholds were measured in quiet and in distracting noise presented at various levels. The effects of the distracting noise on the following variables were measured: time per trial, number of trials required to measure threshold, threshold shift, and perceived distractibility of the noise. Time per trial was unaffected by distracting noise. Number of trials required for threshold, threshold shift, and perceived distractibility increased with distracting noise level. CONCLUSION: Part I: The modified MPANLs provide more relevant determinations of the potential effects of ambient noise on pure-tone thresholds than the values in the standards. Part II: Distracting noise affects pure-tone threshold measurements in a manner that is different from direct masking. The potential contaminating effect of distracting noise can be measured and reported.

A first-in-human Phase I dose-escalation trial of the novel therapeutic peptide, ALM201, demonstrates a favourable safety profile in unselected patients with ovarian cancer and other advanced solid tumours.

BACKGROUND: We aimed to assess the safety, tolerability and pharmacokinetics of a novel anti-angiogenic peptide. METHODS: We used an open-label, multicentre, dose-escalation Phase I trial design in patients with solid tumours. ALM201 was administered subcutaneously once daily for 5 days every week in unselected patients with solid tumours. RESULTS: Twenty (8 male, 12 female) patients with various solid tumours were treated (18 evaluable for toxicity) over eight planned dose levels (10-300 mg). ALM201 was well-tolerated at all dose levels without CTCAE grade 4 toxicities. Adverse events were predominantly grades 1-2, most commonly, localised injection-site reactions (44.4%), vomiting (11%), fatigue (16.7%), arthralgia (5.6%) and headache (11%). Thrombosis occurred in two patients at the 100 mg and 10 mg dose levels. The MTD was not reached, and a recommended Phase II dose (RP2D) based on feasibility was declared. Plasma exposure increased with dose (less than dose-proportional at the two highest dose levels). No peptide accumulation was evident. The median treatment duration was 11.1 (range 3-18) weeks. Four of 18 evaluable patients (22%) had stable disease. CONCLUSIONS: Doses up to 300 mg of ALM201 subcutaneously are feasible and well-tolerated. Further investigation of this agent in selected tumour types/settings would benefit from patient-selection biomarkers.

Experiences of running a stratified medicine adaptive platform trial: Challenges and lessons learned from 10 years of the FOCUS4 trial in metastatic colorectal cancer.

BACKGROUND: Complex innovative design trials are becoming increasingly common and offer potential for improving patient outcomes in a faster time frame. FOCUS4 was the first molecularly stratified trial in metastatic colorectal cancer and it remains one of the first umbrella trial designs to be launched globally. Here, we aim to describe lessons learned from delivery of the trial over the last 10 years. METHODS: FOCUS4 was a Phase II/III molecularly stratified umbrella trial testing the safety and efficacy of targeted therapies in metastatic colorectal cancer. It used adaptive statistical methodology to decide which sub-trial should close early, and new therapies were added as protocol amendments. Patients with newly diagnosed metastatic colorectal cancer were registered, and central laboratory testing was used to stratify their tumour into molecular subtypes. Following 16 weeks of first-line therapy, patients with stable or responding disease were eligible for randomisation into either a molecularly stratified sub-trial (FOCUS4-B, C or D) or non-stratified FOCUS4-N. The primary outcome for all studies was progression-free survival comparing the intervention with active monitoring/placebo. At the close of the trial, feedback was elicited from all investigators through surveys and interviews and consolidated into a series of recommendations and lessons learned for the delivery of similar future trials. RESULTS: Between January 2014 and October 2020, 1434 patients were registered from 88 UK hospitals. Of the 20 drug combinations that were explored for inclusion in the platform trial, three molecularly targeted sub-trials were activated: FOCUS4-D (February 2014-March 2016) evaluated AZD8931 in the BRAF-PIK3CA-RAS wildtype subgroup; FOCUS4-B (February 2016-July 2018) evaluated aspirin in the PIK3CA mutant subgroup and FOCUS4-C (June 2017-October 2020) evaluated adavosertib in the RAS+TP53 double mutant subgroup. FOCUS4-N was active throughout and evaluated capecitabine monotherapy versus a treatment break. A total of 361 (25%) registered patients were randomised into a sub-trial. Feedback on the experiences of delivery of FOCUS4 could be grouped into three main areas of challenge: funding/infrastructure, biomarker testing procedures and trial design efficiencies within which 20 recommendations are summarised. CONCLUSION: Adaptive stratified medicine platform studies are feasible in common cancers but present challenges. Our stakeholder feedback has helped to inform how these trial designs can succeed and answer multiple questions efficiently, providing resource is adequate.

Dataset for Pathology Reporting of Colorectal Cancer: Recommendations From the International Collaboration on Cancer Reporting (ICCR).

OBJECTIVE: The aim of this study to describe a new international dataset for pathology reporting of colorectal cancer surgical specimens, produced under the auspices of the International Collaboration on Cancer Reporting (ICCR). BACKGROUND: Quality of pathology reporting and mutual understanding between colorectal surgeon, pathologist and oncologist are vital to patient management. Some pathology parameters are prone to variable interpretation, resulting in differing positions adopted by existing national datasets. METHODS: The ICCR, a global alliance of major pathology institutions with links to international cancer organizations, has developed and ratified a rigorous and efficient process for the development of evidence-based, structured datasets for pathology reporting of common cancers. Here we describe the production of a dataset for colorectal cancer resection specimens by a multidisciplinary panel of internationally recognized experts. RESULTS: The agreed dataset comprises eighteen core (essential) and seven non-core (recommended) elements identified from a review of current evidence. Areas of contention are addressed, some highly relevant to surgical practice, with the aim of standardizing multidisciplinary discussion. The summation of all core elements is considered to be the minimum reporting standard for individual cases. Commentary is provided, explaining each element's clinical relevance, definitions to be applied where appropriate for the agreed list of value options and the rationale for considering the element as core or non-core. CONCLUSIONS: This first internationally agreed dataset for colorectal cancer pathology reporting promotes standardization of pathology reporting and enhanced clinicopathological communication. Widespread adoption will facilitate international comparisons, multinational clinical trials and help to improve the management of colorectal cancer globally.

Waveform Amplitude and Temporal Symmetric/Asymmetric Characteristics of Phoneme and Syllable Segments in the W-1 Spondaic Words Recorded by Four Speakers.

BACKGROUND: The amplitude and temporal asymmetry of the speech waveform are mostly associated with voiced speech utterances and are obvious in recent graphic depictions in the literature. The asymmetries are attributed to the presence and interactions of the major formants characteristic of voicing with possible contributions from the unidirectional air flow that accompanies speaking. PURPOSE: This study investigated the amplitude symmetry/asymmetry characteristics (polarity) of speech waveforms that to our knowledge have not been quantified. STUDY SAMPLE: Thirty-six spondaic words spoken by two male speakers and two female speakers were selected because they were multisyllabic words providing a reasonable sampling of speech sounds and four recordings were available that were not related to the topic under study. RESEARCH DESIGN: Collectively, the words were segmented into phonemes (vowels [130], diphthongs [77], voiced consonants [258], voiceless consonants [219]), syllables (82), and blends (6). For each segment the following were analyzed separately for the positive and negative datum points: peak amplitude, the percent of the total segment datum points, the root-mean-square (rms) amplitude, and the crest factor. DATA COLLECTION AND ANALYSES: The digitized words (44,100 samples/s; 16-bit) were parsed into 144 files (36 words × 4 speakers), edited, transcribed to numeric values (±1), and stored in a spread sheet in which all analyses were performed with in-house routines. Overall approximately 85% of each waveform was analyzed, which excluded portions of silent intervals, transitions, and diminished waveform endings. RESULTS: The vowel, diphthong, and syllable segments had durations (180-220 ms) that were about twice as long as the consonant durations (∼90 ms) and peak and rms amplitudes that were 6 to 12 dB higher than the consonant peak and rms amplitudes. Vowel, diphthong, and syllable segments had 10% more positive datum points (55%) than negative points (45%), which suggested temporal asymmetries within the segments. With voiced consonants, the distribution of positive and negative datum points dropped to 52 and 48% and essentially was equal with the voiceless consonants (50.3 and 49.6%). The mean rms amplitudes of the negative datum points were higher than the rms amplitudes for the positive points by 2 dB (vowels, diphthongs, and syllables), 1 dB (voiced consonants), and 0.1 dB (voiceless consonants). The 144 waveforms and segmentations are illustrated in the Supplementary Material along with the tabularized positive and negative segment characteristics. CONCLUSIONS: The temporal and amplitude waveform asymmetries were by far most notable in segments that had a voicing component, which included the voiced consonants. These asymmetries were characterized by larger envelopes and more energy in the negative side of the waveform segment than in the positive side. Interestingly, these segments had more positive datum points than negative points, which indicated temporal asymmetry. All aspects of the voiceless consonants were equally divided between the positive and negative domains. There were female/male differences but with these limited samples such differences should not be generalized beyond the speakers in this study. The influence of the temporal and amplitude asymmetries on monaural word-recognition performance is thought to be negligible.

Inhibition of WEE1 Is Effective in TP53- and RAS-Mutant Metastatic Colorectal Cancer: A Randomized Trial (FOCUS4-C) Comparing Adavosertib (AZD1775) With Active Monitoring.

PURPOSE: Outcomes in RAS-mutant metastatic colorectal cancer (mCRC) remain poor and patients have limited therapeutic options. Adavosertib is the first small-molecule inhibitor of WEE1 kinase. We hypothesized that aberrations in DNA replication seen in mCRC with both RAS and TP53 mutations would sensitize tumors to WEE1 inhibition. METHODS: Patients with newly diagnosed mCRC were registered into FOCUS4 and tested for TP53 and RAS mutations. Those with both mutations who were stable or responding after 16 weeks of chemotherapy were randomly assigned 2:1 between adavosertib and active monitoring (AM). Adavosertib (250 mg or 300 mg) was taken orally once on days 1-5 and days 8-12 of a 3-week cycle. The primary outcome was progression-free survival (PFS), with a target hazard ratio (HR) of 0.5 and 80% power with a one-sided 0.025 significance level. RESULTS: FOCUS4-C was conducted between April 2017 and Mar 2020 during which time 718 patients were registered; 247 (34%) were RAS/TP53-mutant. Sixty-nine patients were randomly assigned from 25 UK hospitals (adavosertib = 44; AM = 25). Adavosertib was associated with a PFS improvement over AM (median 3.61 v 1.87 months; HR = 0.35; 95% CI, 0.18 to 0.68; P = .0022). Overall survival (OS) was not improved with adavosertib versus AM (median 14.0 v 12.8 months; HR = 0.92; 95% CI, 0.44 to 1.94; P = .93). In prespecified subgroup analysis, adavosertib activity was greater in left-sided tumors (HR = 0.24; 95% CI, 0.11 to 0.51), versus right-sided (HR = 1.02; 95% CI, 0.41 to 2.56; interaction P = .043). Adavosertib was well-tolerated; grade 3 toxicities were diarrhea (9%), nausea (5%), and neutropenia (7%). CONCLUSION: In this phase II randomized trial, adavosertib improved PFS compared with AM and demonstrates potential as a well-tolerated therapy for RAS/TP53-mutant mCRC. Further testing is required in this sizable population of unmet need.

Capecitabine Versus Active Monitoring in Stable or Responding Metastatic Colorectal Cancer After 16 Weeks of First-Line Therapy: Results of the Randomized FOCUS4-N Trial.

PURPOSE: Despite extensive randomized evidence supporting the use of treatment breaks in metastatic colorectal cancer (mCRC), they are not universally offered to patients despite improvements in quality of life without detriment to overall survival (OS). FOCUS4-N was set up to explore the impact of oral maintenance therapy in patients who are responding to first-line therapy. METHODS: FOCUS4 was a molecularly stratified trial program that registered patients with newly diagnosed mCRC. The FOCUS4-N trial was offered to patients in whom a targeted subtrial was unavailable or biomarker tests failed. Patients were randomly assigned using a 1:1 ratio between maintenance capecitabine and active monitoring (AM). The primary outcome was progression-free survival (PFS) with secondary outcomes including OS toxicity and tolerability. RESULTS: Between March 2014 and March 2020, 254 patients were randomly assigned (127 to capecitabine and 127 to AM) across 88 UK sites. Baseline characteristics were balanced. There was strong evidence of efficacy for PFS (hazard ratio = 0.40; 95% CI, 0.21 to 0.75; P < .0001), but no significant improvement in OS (hazard ratio, 0.93; 95% CI, 0.69 to 1.27; P = .66) was observed. Compliance with treatment was good, and toxicity from capecitabine versus AM was as expected with grade ≥ 2 fatigue (25% v 12%), diarrhea (23% v 13%), and hand-foot syndrome (26% v 3%). Quality of life showed little difference between the groups. CONCLUSION: Despite strong evidence of disease control with maintenance therapy, OS remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as safe management alternatives for patients who are stable or responding to first-line treatment for mCRC. Capecitabine without bevacizumab may be used to extend PFS in the interval after 16 weeks of first-line therapy.

Orthogonal MET analysis in a population-representative stage II-III colon cancer cohort: prognostic and potential therapeutic implications.

Clinical trials for MET inhibitors have demonstrated limited success for their use in colon cancer (CC). However, clinical efficacy may be obscured by a lack of standardisation in MET assessment for patient stratification. In this study, we aimed to determine the molecular context in which MET is deregulated in CC using a series of genomic and proteomic tests to define MET expression and identify patient subgroups that should be considered in future studies with MET-targeted agents. To this aim, orthogonal expression analysis of MET was conducted in a population-representative cohort of stage II/III CC patients (n = 240) diagnosed in Northern Ireland from 2004 to 2008. Targeted sequencing was used to determine the relative incidence of MET R970C and MET T992I mutations within the cohort. MET amplification was assessed using dual-colour dual-hapten brightfield in situ hybridisation (DDISH). Expression of transcribed MET and c-MET protein within the cohort was assessed using digital image analysis on MET RNA in situ hybridisation (ISH) and c-MET immunohistochemistry (IHC) stained slides. We found that less than 2% of the stage II/III CC patient population assessed demonstrated a genetic MET aberration. Determination of a high MET RNA-ISH/low c-MET IHC protein subgroup was found to be associated with poor 5-year cancer-specific outcomes compared to patients with concordant MET RNA-ISH and c-MET IHC protein expression (HR 2.12 [95%CI: 1.27-3.68]). The MET RNA-ISH/c-MET IHC protein biomarker paradigm identified in this study demonstrates that subtyping of MET expression may be required to identify MET-addicted malignancies in CC patients who will truly benefit from MET inhibition.

ZEBRA: A Multicenter Phase II Study of Pembrolizumab in Patients with Advanced Small-Bowel Adenocarcinoma.

PURPOSE: Small-bowel adenocarcinoma (SBA) is rare, and no standard of care exists for metastatic disease beyond first-line FOLFOX/CAPOX. SBA has higher rates of microsatellite instability (MSI-H) and T-lymphocyte infiltration than other gastrointestinal cancers. We hypothesize that pembrolizumab, a PD-1 inhibitor, will induce antitumor response. PATIENTS AND METHODS: Patients with previously treated advanced SBA received pembrolizumab 200 mg i.v. every 3 weeks until disease progression (PD), toxicity, or 35 doses maximum. Primary endpoint was confirmed overall response rate (ORR) with secondary progression-free survival (PFS), overall survival (OS), and toxicity assessment endpoints. Outcomes were stratified by tumor location, microsatellite stability (MSS) or instability (MSI-H), and PD-L1 level. RESULTS: Forty patients were treated for a median duration of four cycles (range, 1-35). All patients are off study treatment due to PD (75%), death (10%), 35 cycles completed (8%), refusal (3%), and adverse effects (AEs, 5%). Three confirmed partial responses [PRs; 8%; 95% confidence interval (CI), 2-20] did not meet predefined success criteria of ORR 30%. Median OS (7.1 months; 95% CI, 5.1-17.1) and median PFS (2.8 months; 95% CI, 2.7-4.2) were similar across primary tumor sites. One confirmed PR (3%) was seen in patients with low MSS/MSI tumors and correlated with high tumor mutation burden (TMB). Fifty percent of patients with MSI-H tumors achieved PR and remain alive without progression. Twenty-five patients (63%) had grade ≥3 AEs and 11 patients (28%) had grade 4/5 AEs. CONCLUSIONS: In the largest study of SBA to date, pembrolizumab did not induce the hypothesized response rate; however, we did identify responses in key biomarker-selected cohorts.

Targeting nucleotide metabolism enhances the efficacy of anthracyclines and anti-metabolites in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) remains the most lethal breast cancer subtype with poor response rates to the current chemotherapies and a lack of additional effective treatment options. We have identified deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase) as a critical gatekeeper that protects tumour DNA from the genotoxic misincorporation of uracil during treatment with standard chemotherapeutic agents commonly used in the FEC regimen. dUTPase catalyses the hydrolytic dephosphorylation of deoxyuridine triphosphate (dUTP) to deoxyuridine monophosphate (dUMP), providing dUMP for thymidylate synthase as part of the thymidylate biosynthesis pathway and maintaining low intracellular dUTP concentrations. This is crucial as DNA polymerase cannot distinguish between dUTP and deoxythymidylate triphosphate (dTTP), leading to dUTP misincorporation into DNA. Targeting dUTPase and inducing uracil misincorporation during the repair of DNA damage induced by fluoropyrimidines or anthracyclines represents an effective strategy to induce cell lethality. dUTPase inhibition significantly sensitised TNBC cell lines to fluoropyrimidines and anthracyclines through imbalanced nucleotide pools and increased DNA damage leading to decreased proliferation and increased cell death. These results suggest that repair of treatment-mediated DNA damage requires dUTPase to prevent uracil misincorporation and that inhibition of dUTPase is a promising strategy to enhance the efficacy of TNBC chemotherapy.

Automated Forced-Choice Tests of Speech Recognition.

PURPOSE: This project was undertaken to develop automated tests of speech recognition, including speech-recognition threshold (SRT) and word-recognition test, using forced-choice responses and computerized scoring of responses. Specific aims were (1) to develop an automated method for measuring SRT for spondaic words that produces scores that are in close agreement with average pure-tone thresholds and (2) to develop an automated test of word recognition that distinguishes listeners with normal hearing from those with sensorineural hearing loss and which informs the hearing aid evaluation process. METHOD: An automated SRT protocol was designed to converge on the lowest level at which the listener responds correctly to two out of two spondees presented monaurally. A word-recognition test was conducted with monosyllabic words (female speaker) presented monaurally at a fixed level. For each word, there were three rhyming foils, displayed on a touchscreen with the test word. The listeners touched the word they thought they heard. Participants were young listeners with normal hearing and listeners with sensorineural hearing loss. Words were also presented with nonrhyming foils and in an open-set paradigm. The open-set responses were scored by a graduate student research assistant. RESULTS: The SRT results agreed closely with the pure-tone average (PTA) obtained by automated audiometry. The agreement was similar to results obtained with the conventional SRT scoring method. Word-recognition scores were highest for the closed-set, nonrhyming lists and lowest for open-set responses. For the hearing loss participants, the scores varied widely. There was a moderate correlation between word-recognition scores and pure-tone thresholds which increased as more high frequencies were brought into the PTA. Based on the findings of this study, a clinical protocol was designed that determines if a listener's performance was in the normal range and if the listener benefited from increasing the level of the stimuli. CONCLUSION: SRTs obtained using the automated procedure are comparable to the results obtained by the conventional clinical method that is in common use. The automated closed-set word-recognition test results show clear differentiation between scores for the normal and hearing loss groups. These procedures provide clinical test results that are not dependent on the availability of an audiologist to perform the tests.

Nothing to lose: a grounded theory study of patients' and healthcare professionals' perspectives of being involved in the consent process for oncology trials with non-curative intent.

BACKGROUND: Clinical cancer research trials may offer little or no direct clinical benefit to participants where a cure is no longer possible. As such, the decision-making and consent process for patient participation is often challenging. AIM: To gain understanding of how patients make decisions regarding clinical trial participation, from the perspective of both the patient and healthcare professionals involved. METHODS: In-depth, face to face interviews using a grounded theory approach. This study was conducted in a regional Cancer Centre in the United Kingdom. Of the 36 interviews, 16 were conducted with patients with cancer that had non-curative intent and 18 with healthcare professionals involved in the consent process. RESULTS: 'Nothing to lose' was identified as the core category that underpinned all other data within the study. This highlighted the desperation articulated by participants, who asserted trial participation was the 'only hope in the room'. The decision regarding participation was taken within a 'trusting relationship' that was important to both patients and professionals. Both were united in their 'fight against cancer'. These two categories are critical in understanding the decision-making/consent process and are supported by other themes presented in the theoretical model. CONCLUSION: This study presents an important insight into the complex and ethically contentious situation of consent in clinical trials that have non-curative intent. It confirms that patients with limited options trust their doctor and frequently hold unrealistic hopes for personal benefit. It highlights a need for further research to develop a more robust and context appropriate consent process.

Psychometric Characteristics of Spanish Monosyllabic, Bisyllabic, and Trisyllabic Words for Use in Word-Recognition Protocols.

BACKGROUND: English materials for speech audiometry are well established. In Spanish, speech-recognition materials are not standardized with monosyllables, bisyllables, and trisyllables used in word-recognition protocols. PURPOSE: This study aimed to establish the psychometric characteristics of common Spanish monosyllabic, bisyllabic, and trisyllabic words for potential use in word-recognition procedures. RESEARCH DESIGN: Prospective descriptive study. STUDY SAMPLE: Eighteen adult Puerto Ricans (M = 25.6 years) with normal hearing [M = 7.8-dB hearing level (HL) pure-tone average] were recruited for two experiments. DATA COLLECTION AND ANALYSES: A digital recording of 575 Spanish words was created (139 monosyllables, 359 bisyllables, and 77 trisyllables), incorporating materials from a variety of Spanish word-recognition lists. Experiment 1 (n = 6) used 25 randomly selected words from each of the three syllabic categories to estimate the presentation level ranges needed to obtain recognition performances over the 10 to 90% range. In Experiment 2 (n = 12) the 575 words were presented over five 1-hour sessions using presentation levels from 0- to 30-dB HL in 5-dB steps (monosyllables), 0- to 25-dB HL in 5-dB steps (bisyllables), and -3- to 17-dB HL in 4-dB steps (trisyllables). The presentation order of both the words and the presentation levels were randomized for each listener. The functions for each listener and each word were fit with polynomial equations from which the 50% points and slopes at the 50% point were calculated. RESULTS: The mean 50% points and slopes at 50% were 8.9-dB HL, 4.0%/dB (monosyllables), 6.9-dB HL, 5.1%/dB (bisyllables), and 1.4-dB HL, 6.3%/dB (trisyllables). The Kruskal-Wallis test with Mann-Whitney U post-hoc analysis indicated that the mean 50% points and slopes at the 50% points of the individual word functions were significantly different among the syllabic categories. Although significant differences were observed among the syllabic categories, substantial overlap was noted in the individual word functions, indicating that the psychometric characteristics of the words were not dictated exclusively by the syllabic number. Influences associated with word difficulty, word familiarity, singular and plural form words, phonetic stress patterns, and gender word patterns also were evaluated. CONCLUSION: The main finding was the direct relation between the number of syllables in a word and word-recognition performance. In general, words with more syllables were more easily recognized; there were, however, exceptions. The current data from young adults with normal hearing established the psychometric characteristics of the 575 Spanish words on which the formulation of word lists for both threshold and suprathreshold measures of word-recognition abilities in quiet and in noise and other word-recognition protocols can be based.

Early switch from intravenous to oral antibiotic therapy in patients with cancer who have low-risk neutropenic sepsis (the EASI-SWITCH trial): study protocol for a randomised controlled trial.

BACKGROUND: Neutropenic sepsis remains a common treatment complication for patients receiving systemic anti-cancer treatment. The UK National Institute for Health and Care Excellence have not recommended switching from empirical intravenous antibiotics to oral antibiotics within 48 h for patients assessed as low risk for septic complications because of uncertainty about whether this would achieve comparable outcomes to using intravenous antibiotics for longer. The UK National Institute for Health Research funded the EASI-SWITCH trial to tackle this uncertainty. METHODS: The trial is a pragmatic, randomised, non-inferiority trial that aims to establish the clinical and cost-effectiveness of early switching from intravenous to oral antibiotics in cancer patients with low-risk neutropenic sepsis. Patients ≥ 16 years, receiving systemic anti-cancer treatment (acute leukaemics/stem cell transplants excluded), with a temperature of > 38 °C, neutrophil count ≤ 1.0 × 109/L, MASCC (Multinational Association of Supportive Care in Cancer) score ≥ 21 and receiving IV piperacillin/tazobactam or meropenem for less than 24 h are eligible to participate. Patients are randomised 1:1 either (i) to switch to oral ciprofloxacin and co-amoxiclav within 12-24 h of commencing intravenous antibiotics, completing at least 5 days total antibiotics (intervention), or (ii) to continue intravenous antibiotics for at least 48 h, with ongoing antibiotics being continued at the physician's discretion (control). Patients are discharged home when their physician deems it appropriate. The primary outcome measure is a composite of treatment failures as assessed at day 14. The criteria for treatment failure include fever persistence or recurrence 72 h after starting intravenous antibiotics, escalation from protocolised antibiotics, hospital readmission related to infection/antibiotics, critical care support or death. Based on a 15% treatment failure rate in the control group and a 15% non-inferiority margin, the recruitment target is 230 patients. DISCUSSION: If the trial demonstrates non-inferiority of early switching to oral antibiotics, with potential benefits for patient quality of life and resource savings, this finding will have significant implications for the routine clinical management of those with low-risk neutropenic sepsis. TRIAL REGISTRATION: ISRCTN: 84288963. Registered on the 1 July 2015. https://doi.org/10.1186/ISRCTN84288963. EudraCT: 2015-002830-35.