Urinary biomarkers in metastatic bone pain: Results from a multicentre randomized trial of ibandronate compared to single dose radiotherapy for localized metastatic bone pain in prostate cancer (RIB).

Background: The Radiotherapy IBandronate (RIB) trial compared single dose radiotherapy and a single infusion of ibandronate in 470 bisphosphonate naïve patients with metastatic bone pain from prostate cancer randomised into a non-inferiority two arm study. Results for the primary endpoint of pain score response at 4 weeks showed that the ibandronate arm was non-inferior to single dose radiotherapy. Patients and method: In addition to pain assessments including analgesic use made at baseline, 4, 8, 12, 26 and 52 weeks, urine was collected at baseline, 4 and 12 weeks. It was subsequently analysed for urinary N-telopeptide (NTx) and cystatin C. Linear regression models were used to compare the continuous outcome measures for urinary markers within treatment arms and baseline measurements were included as covariates. Interaction terms were fitted to allow for cross-treatment group comparisons. Results: The primary endpoint of the RIB trial was worst pain response at 4 weeks and there was no treatment difference seen. Urine samples and paired pain scores at 4 weeks were available for 273 patients (radiotherapy 168; ibandronate 159)The baseline samples measured for the RIB trial had an average concentration of 193 nM BCE/mM creatinine (range of 7.3-1871) compared to the quoted normal range of 33 nM BCE/mM creatinine (3 to 63). In contrast the average value of Cystatin C was 66 ng/ml (ranges ND - 1120 ng/ml) compared to the quoted normal range of 62.9 ng/ml (ranges 12.6-188 ng/ml). A statistically significant reduction in NTx concentrations between baseline and 4 weeks was seen in the ibandronate arm but not in the radiotherapy arm. No correlation between pain response and urinary marker concentration was seen in either the ibandronate or radiotherapy cohort at any time point. Conclusion: NTx was significantly raised compared to the normal range consistent with a role as a biomarker for bone metastases from prostate cancer. A significant reduction in NTx 4 weeks after ibandronate is consistent with its action in osteoclast inhibition which was not seen after radiotherapy implying a different mode of action for radiation. There was no correlation between bone biomarker levels and pain response.

Faecal immunochemical testing for haemoglobin in detecting bowel polyps in symptomatic patients: multicentre prospective cohort study.

BACKGROUND: Measurement of faecal haemoglobin using faecal immunochemistry testing is recommended in patients presenting with symptoms suspicious for colorectal cancer, to aid in triage and prioritization of definitive investigations. While its role in colorectal cancer has been extensively investigated, the ability of faecal immunochemistry testing to detect adenomas in symptomatic patients is unclear. METHODS: A multicentre prospective observational study was conducted between April 2017 and March 2019, recruiting adults from 24 hospitals across England and 59 general practices in London who had been urgently referred with suspected colorectal cancer symptoms. Each patient provided a stool sample for faecal immunochemistry testing, in parallel with definitive investigation. A final diagnosis for each patient was recorded, including the presence, size, histology, and risk type of colonic polyps. The outcome of interest was the sensitivity of faecal immunochemistry testing in detecting the presence of adenomas. RESULTS: Of 3496 patients included in the analysis, 553 (15.8 per cent) had polyps diagnosed. Sensitivity of faecal immunochemistry testing for polyp detection was low across all ranges; with a cut-off for faecal haemoglobin of 4 µg/g or lower, sensitivity was 34.9 per cent and 46.8 per cent for all polyp types and high-risk polyps respectively. The area under the receiver operating characteristic curve in detection probability was relatively low for both intermediate-risk (0.63) and high-risk polyps (0.63). CONCLUSION: While faecal immunochemistry testing may be useful in prioritizing investigations to diagnose colorectal cancer, if used as a sole test, the majority of polyps would be missed and the opportunity to prevent progression to colorectal cancer may be lost.

A novel predictive algorithm to personalize autologous T-cell harvest for chimeric antigen receptor T-cell manufacture.

BACKGROUND AIMS: The most widely accepted starting materials for chimeric antigen receptor T-cell manufacture are autologous CD3+ T cells obtained via the process of leukapheresis, also known as T-cell harvest. As this treatment modality gains momentum and apheresis units struggle to meet demand for harvest slots, strategies to streamline this critical step are warranted. METHODS: This retrospective review of 262 T-cell harvests, with a control cohort of healthy donors, analyzed the parameters impacting CD3+ T-cell yield in adults with B-cell malignancies. The overall aim was to design a novel predictive algorithm to guide the required processed blood volume (PBV) (L) on the apheresis machine to achieve a specific CD3+ target yield. RESULTS: Factors associated with CD3+ T-cell yield on multivariate analysis included peripheral blood CD3+ count (natural log, ×109/L), hematocrit (HCT) and PBV with coefficients of 0.86 (95% confidence interval [CI], 0.80-0.92, P < 0.001), 1.30 (95% CI, 0.51-2.08, P = 0.001) and 0.09 (95% CI, 0.07-0.11, P < 0.001), respectively. The authors' model, incorporating CD3+ cell count, HCT and PBV (L), with an adjusted R2 of 0.87 and root-mean-square error of 0.26 in the training dataset, was highly predictive of CD3+ cell yield in the testing dataset. An online application to estimate PBV using this algorithm can be accessed at https://cd3yield.shinyapps.io/cd3yield/. CONCLUSIONS: The authors propose a transferrable model that incorporates clinical and laboratory variables accessible pre-harvest for use across the field of T-cell therapy. Pending further validation, such a model may be used to generate an individual leukapheresis plan and streamline the process of cell harvest, a well-recognized bottleneck in the industry.

Faecal immunochemical test for patients with 'high-risk' bowel symptoms: a large prospective cohort study and updated literature review.

BACKGROUND: We evaluated whether faecal immunochemical testing (FIT) can rule out colorectal cancer (CRC) among patients presenting with 'high-risk' symptoms requiring definitive investigation. METHODS: Three thousand five hundred and ninety-six symptomatic patients referred to the standard urgent CRC pathway were recruited in a multi-centre observational study. They completed FIT in addition to standard investigations. CRC miss rate (percentage of CRC cases with low quantitative faecal haemoglobin [f-Hb] measurement) and specificity (percentage of patients without cancer with low f-Hb) were calculated. We also provided an updated literature review. RESULTS: Ninety patients had CRC. At f-Hb < 10 µg/g, the miss rate was 16.7% (specificity 80.1%). At f-Hb < 4 µg/g, the miss rate was 12.2% (specificity 73%), which became 3.3% if low FIT plus the absence of anaemia and abdominal pain were considered (specificity 51%). Within meta-analyses of 9 UK studies, the pooled miss rate was 7.2% (specificity 74%) for f-Hb < 4 µg/g. DISCUSSION: FIT alone as a triage tool would miss an estimated 1 in 8 cases in our study (1 in 14 from meta-analysis), while many people without CRC could avoid investigations. FIT can focus secondary care diagnostic capacity on patients most at risk of CRC, but more work on safety netting is required before incorporating FIT triage into the urgent diagnostic pathway.