Acceptability of the Distress Thermometer and Problem List to community-based telephone cancer helpline operators, and to cancer patients and carers

Background Cancer can be a distressing experience for cancer patients and carers, impacting on psychological, social, physical and spiritual functioning. However, health professionals often fail to detect distress in their patients due to time constraints and a lack of experience. Also, with the focus on the patient, carer needs are often overlooked. This study investigated the acceptability of brief distress screening with the Distress Thermometer (DT) and Problem List (PL) to operators of a community-based telephone helpline, as well as to cancer patients and carers calling the service. Methods Operators (n = 18) monitored usage of the DT and PL with callers (cancer patients/carers, >18 years, and English-speaking) from September-December 2006 (n = 666). The DT is a single item, 11-point scale to rate level of distress. The associated PL identifies the cause of distress. Results The DT and PL were used on 90% of eligible callers, most providing valid responses. Benefits included having an objective, structured and consistent means for distress screening and triage to supportive care services. Reported challenges included apparent inappropriateness of the tools due to the nature of the call or level of caller distress, the DT numeric scale, and the level of operator training. Conclusions We observed positive outcomes to using the DT and PL, although operators reported some challenges. Overcoming these challenges may improve distress screening particularly by less experienced clinicians, and further development of the PL items and DT scale may assist with administration. The DT and PL allow clinicians to direct/prioritise interventions or referrals, although ongoing training and support is critical in distress screening

Feasibility of brief psychological distress screening by a community-based telephone helpline for cancer patients and carers

Background Up to one-third of people affected by cancer experience ongoing psychological distress and would benefit from screening followed by an appropriate level of psychological intervention. This rarely occurs in routine clinical practice due to barriers such as lack of time and experience. This study investigated the feasibility of community-based telephone helpline operators screening callers affected by cancer for their level of distress using a brief screening tool (Distress Thermometer), and triaging to the appropriate level of care using a tiered model. Methods Consecutive cancer patients and carers who contacted the helpline from September-December 2006 (n = 341) were invited to participate. Routine screening and triage was conducted by helpline operators at this time. Additional socio-demographic and psychosocial adjustment data were collected by telephone interview by research staff following the initial call. Results The Distress Thermometer had good overall accuracy in detecting general psychosocial morbidity (Hospital Anxiety and Depression Scale cut-off score ≥ 15) for cancer patients (AUC = 0.73) and carers (AUC = 0.70). We found 73% of participants met the Distress Thermometer cut-off for distress caseness according to the Hospital Anxiety and Depression Scale (a score ≥ 4), and optimal sensitivity (83%, 77%) and specificity (51%, 48%) were obtained with cut-offs of ≥ 4 and ≥ 6 in the patient and carer groups respectively. Distress was significantly associated with the Hospital Anxiety and Depression Scale scores (total, as well as anxiety and depression subscales) and level of care in cancer patients, as well as with the Hospital Anxiety and Depression Scale anxiety subscale for carers. There was a trend for more highly distressed callers to be triaged to more intensive care, with patients with distress scores ≥ 4 more likely to receive extended or specialist care. Conclusions Our data suggest that it was feasible for community-based cancer helpline operators to screen callers for distress using a brief screening tool, the Distress Thermometer, and to triage callers to an appropriate level of care using a tiered model. The Distress Thermometer is a rapid and non-invasive alternative to longer psychometric instruments, and may provide part of the solution in ensuring distressed patients and carers affected by cancer are identified and supported appropriately

Improving quality of life through the routine use of the Patient Concerns Inventory for head and neck cancer patients: a cluster preference randomized controlled trial

This trial is funded by the RfPB on behalf of the NIHR (PB-PG-0215-36047).Background: The consequences of treatment for Head and Neck cancer (HNC) patients has profound detrimental impacts such as impaired QOL, emotional distress, delayed recovery and frequent use of healthcare. The aim of this trial is to determine if the routine use of the Patients Concerns Inventory (PCI) package in review clinics during the first year following treatment can improve overall quality of life, reduce the social-emotional impact of cancer and reduce levels of distress. Furthermore, we aim to describe the economic costs and benefits of using the PCI. Methods: This will be a cluster preference randomised control trial with consultants either ‘using’ or ‘not using’ the PCI package at clinic. It will involve two centres Leeds and Liverpool. 416 eligible patients from at least 10 consultant clusters are required to show a clinically meaningful difference in the primary outcome. The primary outcome is the percentage of participants with less than good overall quality of life at the final one-year clinic as measured by the University of Washington QOL questionnaire version 4 (UWQOLv4). Secondary outcomes at one-year are the mean social-emotional subscale (UWQOLv4) score, Distress Thermometer (DT) score ≥ 4, and key health economic measures (QALY-EQ-5D-5 L; CSRI). Discussion: This trial will provide knowledge on the effectiveness of a consultation intervention package based around the PCI used at routine follow-up clinics following treatment of head and neck cancer with curative intent. If this intervention is (cost) effective for patients, the next step will be to promote wider use of this approach as standard care in clinical practice. Trial registration: 32,382. Clinical Trials Identifier, NCT03086629. Protocol: Version 3.0, 1st July 2017.Publisher PDFPeer reviewe

B cell regulation of the anti-tumor response and role in carcinogenesis

The balance between immune effector cells such as T cells and natural killer cells, and immunosuppressive Treg cells, dendritic, myeloid and monocytic sub-populations in the tumor microenvironment acts to calibrate the immune response to malignant cells. Accumulating evidence is pointing to a role for B cells in modulating the immune response to both solid tumors and hematologic cancer. Evidence from murine autoimmune models has defined B regulatory cell (Breg) subsets that express cytokines such as IL-10, TGF-β, and/or express immune regulatory ligands such as PD-L1, which can suppress T cell and/or natural killer cell responses. Multiple murine tumor models exhibit decreased tumor growth in B cell deficient or B cell depleted mice. In several of these models, B cells inhibit T cell mediated tumor immunity and/or facilitate conversion of T cells to CD4(+)CD25(+)FoxP3(+) T regs, which act to attenuate the innate and/or adaptive antitumor immune response. Mechanisms of suppression include the acquisition of inhibitory ligand expression, and phosphorylation of Stat3, and induction of IL-10 and TGF-β, resulting in a Breg phenotype. Breg suppressive activity may affect diverse cell subtypes, including T effector cells, NK cells, myeloid derived suppressor cells (MDSC) and/or tumor associated macrophages. B cells may also directly promote tumorigenesis through recruitment of inflammatory cells, and upregulation of pro-angiogenic genes and pro-metastatic collagenases. Breg infiltration has now been identified in a variety of solid tumor malignancies including but not limited to ovarian, gastric, non-small cell lung cancer, pancreatic, esophageal, head and neck, and hepatocellular carcinomas. Increasing evidence suggests that recruitment of B cells and acquisition of suppressive activity within the tumor bed may be an important mechanism through which B cells may modulate innate and/or adaptive anti-tumor immunity. B cell depletion in the clinic using anti-CD20 antibodies and/or inhibitors of BTK and/or other signaling pathways, may be a useful strategy for augmenting the anti-tumor immune response

Pulmonary hypertension in interstitial lung disease: non-invasive techniques for screening and diagnosis

Background: Pulmonary hypertension (PH) complicating interstitial lung disease (ILD) may be associated with significant morbidity and mortality. Transthoracic echocardiography (TTE), the most widely used screening test for PH, may be inaccurate in up to 50% of ILD patients. We evaluate the utility of TTE, in isolation and in combination with several non-invasive screening tests, for predicting the presence and severity of ILD-PH. Novel techniques, including non-invasive assessment of pulmonary blood flow and dual energy CT pulmonary angiography (DE-CTPA), were also evaluated for identifying pulmonary vasospasm in systemic sclerosis (SSc).Methods: In 265 consecutive patients with ILD and suspected PH, the predictive utility of the updated European Society of Cardiology/European Respiratory Society (ESC/ERS) TTE PH screening recommendations was evaluated against RHC testing. In a subgroup of 114 patients, combined non-invasive investigations (including TTE, respiratory function tests, brain natriuretic peptide (BNP), vascular dimensions on CT, and 6 minute walk test) was assessed for predicting PH. Equations predicting the presence and severity of PH were then tested prospectively in a validation cohort. Results: In patients classified as ‘high probability’ of PH by ESC/ERS TTE criteria, PH was confirmed on RHC in 86%. However, 40% of patients were misclassified as ‘low probability’ of PH (tricuspid regurgitation velocity <2.8 m/s), when PH was confirmed on subsequent RHC. At regression analysis, TTE derived right ventricular systolic pressure (RVSP) (R2=0.37; p<0.01), BNP (R2=0.25; p<0.01), and main pulmonary artery diameter (mPA) on CT scan (R2=0.23; p<0.01) correlated most strongly with RHC measured mean pulmonary artery pressure (mPAP), and a ‘best fit’ equation for predicting mPAP (tested in the validation cohort) was more strongly predictive of PH (with a receiver operating characteristic AUC of 0.93) than any single non-invasive test in isolation.Conclusion: Current TTE screening recommendations are associated with a significant misclassification rate (40%) in excluding ILD-PH. Combining RVSP, mPA diameter and BNP more accurately predicted mPAP, the presence of PH and the presence of severe PH, compared to any single test in isolation. While pulmonary vasospasm was detectable in a subgroup of SSc patients, extensive post-processing of DE-CTPA data precluded this as a clinically useful test at this time

Initial testing (stage 1) of sunitinib by the pediatric preclinical testing program.

Sunitinib is an orally bioavailable, multi-targeted tyrosine kinase inhibitor with selectivity for PDGF receptors, VEGF receptors, FLT3, and KIT. Procedures. Sunitinib was tested at concentrations ranging from 0.1 nM to 1.0 mu M against 23 cell lines from the PPTP in vitro panel. We also compared sunitinib (53.5 mg/kg) or vehicle administered for 28 clays by oral gavage in 46 murine xenograft models representing 9 distinct pediatric cancer histologies. Results. The leukemia cell line, Kasumi-1 (gain-of-function KITAsn822Lys mutation) was the only line with an in vitro response to sunitinib (IC50 75.7 nM). Sunitinib significantly prolonged EFS in 19 of 35 (54%) of the solid tumor, and in 3 of 8 (38%) of the ALL xenografts analyzed. Using the PPTP time to event measure of efficacy, sunitinib had intermediate (13) and high (1) levels of activity against 14 of 34 evaluable solid tumor xenografts, including 4 of 6 rhabdomyosarcoma, 4 of 5 Ewing turner, and 2 of 3 rhabdoid tumor xenografts. Following cessation of treatment for the 14 solid tumor xenografts without tumor events by day 28, tumor growth rate increased in most. The only regression noted to sunitinib in the solid tumor panels was a complete response in a rhabdoid tumor xenograft. Conclusions. Sunitinib demonstrated significant tumor growth inhibition against most of the PPTP`s solid tumor panels, but little activity against the neuroblastoma and ALL panel. Antitumor activity was manifested primarily as tumor growth delay, consistent with an anti-angiogenic effect for sunitinib against many of the pediatric preclinical models evaluated

Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer

Recent epidemiologic studies report that regular exercise may be associated with substantial reductions in cancer-specific and all-cause mortality following a breast cancer diagnosis. The mechanisms underlying this relationship have not been identified. We investigated the effects of long-term voluntary wheel running on growth and progression using an animal model of human breast cancer. We also examined effects on the central features of tumor physiology, including markers of tumor blood perfusion/vascularization, hypoxia, angiogenesis, and metabolism. Athymic female mice fed a high-fat diet were orthotopically (direct into the mammary fat pad) implanted with human breast cancer cells (MDA-MB-231 at 1 &#xD7; 10&lt;jats:sup&gt;6&lt;/jats:sup&gt;) into the right dorsal mammary fat pad and randomly assigned (1:1) to voluntary wheel running ( n = 25) or a nonintervention (sedentary) control group ( n = 25). Tumor volume was measured every three days using digital calipers. All experimental animals were killed when tumor volume reached &#x2265;1,500 mm&lt;jats:sup&gt;3&lt;/jats:sup&gt;. Kaplan-Meier (KM) analysis indicated that tumor growth (survival) was comparable between the experimental groups (exercise 44 days vs. control 48 days; KM proportional hazard ratio = 1.41, 95% confidence interval, 0.77&#x2013;2.58, P = 0.14). However, tumors from exercising animals had significantly improved blood perfusion/vascularization relative to the sedentary control group ( P &amp;lt; 0.05). Histological analyses indicated that intratumoral hypoxia levels (as assessed by hypoxia-inducible factor 1) were significantly higher in the exercise group relative to sedentary control ( P &amp;lt; 0.05). Aerobic exercise can significantly increase intratumoral vascularization, leading to &#x201C;normalization&#x201D; of the tissue microenvironment in human breast tumors. Such findings may have important implications for inhibiting tumor metastasis and improving the efficacy of conventional cancer therapies

Initial testing (stage 1) of the polo-like kinase inhibitor volasertib (BI 6727), by the Pediatric Preclinical Testing Program

Volasertib (BI 6727) is a potent inhibitor of Polo-like kinase 1 (Plk1), that is overexpressed in several childhood cancers and cell lines. Because of its novel mechanism of action, volasertib was evaluated through the PPTP.PROCEDURES:Volasertib was tested against the PPTP in vitro cell line panel at concentrations from 0.1 nM to 1.0 μM and against the PPTP in vivo xenograft panels administered IV at a dose of 30 mg/kg (solid tumors) or 15 mg/kg (ALL models) using a q7dx3 schedule.RESULTS:In vitro volasertib demonstrated cytotoxic activity, with a median relative IC50 value of 14.1 nM, (range 6.0-135 nM). Volasertib induced significant differences in EFS in 19 of 32 (59%) of the evaluable solid tumor xenografts and in 2 of 4 (50%) of the evaluable ALL xenografts. Volasertib induced tumor growth inhibition meeting criteria for intermediate EFS T/C (>2) activity in 11 of 30 (37%) evaluable solid tumor xenografts, including neuroblastoma (4 of 6) and glioblastoma (2 of 3) panels, and 2 of 4 ALL models. Objective responses (CR's) were observed for 4 of 32 solid tumor (two neuroblastoma, one glioblastoma, and one rhabdomyosarcoma) and one of four ALL xenografts.CONCLUSIONS:Volasertib shows potent in vitro activity against the PPTP cell lines with no histotype selectivity. In vivo, volasertib induced regressions in several xenograft models. However, pharmacokinetic data suggest that mice tolerate higher systemic exposure to volasertib than humans, suggesting that the current results may over-estimate potential clinical efficacy against the childhood cancers studied