The Average Body Surface Area of Adult Cancer Patients in the UK: A Multicentre Retrospective Study

The majority of chemotherapy drugs are dosed based on body surface area (BSA). No standard BSA values for patients being treated in the United Kingdom are available on which to base dose and cost calculations. We therefore retrospectively assessed the BSA of patients receiving chemotherapy treatment at three oncology centres in the UK between 1st January 2005 and 31st December 2005

Socioeconomic Status, Psychosocial Factors, Race and Nocturnal Blood Pressure Dipping in a Hispanic Cohort

BACKGROUND Little information is available about the relationship of socioeconomic status (SES) to blunted nocturnal ambulatory blood pressure (ABP) dipping among Hispanics and whether this relationship differs by race. We sought to characterize ABP nondipping and its determinants in a sample of Hispanics. METHODS We enrolled 180 Hispanic participants not on antihypertensive medications. SES was defined by years of educational attainment. All participants underwent 24-hour ABP monitoring. A decrease of <10% in the ratio between average awake and average asleep systolic BP was considered nondipping. RESULTS The mean age of the cohort was 67.1 ± 8.7, mean educational level was 9.4 ± 4.4 years, and 58.9% of the cohort was female. The cohort was comprised of 78.3% Caribbean Hispanics with the rest from Mexico and Central/South America; 41.4% self-identified as white Hispanic, 34.4% self-identified as black Hispanic, and 24.4% did not racially self- identify. The percentage of nondippers was 57.8%. Educational attainment (10.5 years vs. 8.6 years; P <0.01) was significantly higher among dippers than nondippers. In multivariable analyses, each 1-year increase in education was associated with a 9% reduction in the likelihood of being a nondipper (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.84–0.98; P = 0.01). There were significantly greater odds of being a nondipper for black Hispanics than for white Hispanics (OR, 2.83, 95% CI, 1.29–6.23; P = 0.005). Higher SES was significantly protective of nondipping in white Hispanics but not black Hispanics. CONCLUSIONS These results document a substantial prevalence of nondipping in a cohort of predominantly normotensive Hispanics. Dipping status varied significantly by race. Lower SES is significantly associated with nondipping status, and race potentially impacts on this relation

Positive Surgical Margins in the 10 Most Common Solid Cancers.

A positive surgical margin (PSM) following cancer resection oftentimes necessitates adjuvant treatments and carries significant financial and prognostic implications. We sought to compare PSM rates for the ten most common solid cancers in the United States, and to assess trends over time. Over 10 million patients were identified in the National Cancer Data Base from 1998-2012, and 6.5 million had surgical margin data. PSM rates were compared between two time periods, 1998-2002 and 2008-2012. PSM was positively correlated with tumor category and grade. Ovarian and prostate cancers had the highest PSM prevalence in women and men, respectively. The highest PSM rates for cancers affecting both genders were seen for oral cavity tumors. PSM rates for breast cancer and lung and bronchus cancer in both men and women declined over the study period. PSM increases were seen for bladder, colon and rectum, and kidney and renal pelvis cancers. This large-scale analysis appraises the magnitude of PSM in the United States in order to focus future efforts on improving oncologic surgical care with the goal of optimizing value and improving patient outcomes

Perceived Discrimination and Nocturnal Blood Pressure Dipping Among Hispanics: The Influence of Social Support and Race

OBJECTIVE: Little is known about the relationship of perceived racism to ambulatory blood pressure (ABP) in Hispanics. We explored possible associations between ABP nocturnal dipping and perceived racism in a Hispanic cohort. METHODS: Participants included 180 community-dwelling Hispanics from the Northern Manhattan Study. Measures included perceived racism, socioeconomic status, social support, and ABP monitoring. Nocturnal ABP nondipping was defined as a less than 10% decline in the average asleep systolic blood pressure relative to the awake systolic blood pressure. RESULTS: Overall, 77.8% of participants reported some form of perceived racism (Perceived Ethnic Discrimination Questionnaire scores >1.0). Greater social support was associated with less perceived discrimination (Spearman r = -0.54, p < .001). Those with higher perceived discrimination scores reported more depressive symptoms (r = 0.25, p < .001). Those with higher Perceived Ethnic Discrimination Questionnaire scores were less likely to show nocturnal ABP nondipping in multivariate models (odds ratio = 0.40, confidence interval = 0.17-0.98, p = .045). Among those with low perceived racism, black Hispanic participants were more likely to have nocturnal ABP nondipping (82.6%) compared with white Hispanics (53.9%; p = .02). Among those with high perceived racism, no associations between race and the prevalence of ABP nondipping was found (black Hispanic = 61.5% versus white Hispanic = 51.4%, p = .39; p interaction = .89). CONCLUSIONS: Perceived racism is relatively common among US Hispanics and is associated with ABP. Nondipping of ABP, a potential cardiovascular risk factor, was more common in black Hispanic participants with low perceived racism. This finding may reflect different coping mechanisms between black versus white Hispanics and related blood pressure levels during daytime exposures to discrimination

Results and lessons learnt from the WISTERIA phase I trial combining AZD1775 with cisplatin pre- or post-operatively in head and neck cancer

Background: Pre-clinical studies suggest AZD1775, a WEE1 kinase inhibitor, potentiates the activity of various chemotherapeutic agents. Methods: WISTERIA was a prospective, parallel two-group, open-label, dose-finding, phase I clinical trial. Eligible patients had histologically confirmed oral, laryngeal, or hypopharyngeal squamous cell carcinoma, ECOG performance status 0/1, and aged ≥18-to-≤70 years. Primary outcomes were adverse events and defining recommended dose and schedule of AZD1775 in combination with cisplatin in pre-operative (Group A), or with cisplatin/radiotherapy in post-operative (Group B) patients. Dose determination was guided by a modified time-to-event continual reassessment method (mTITE-CRM). Results: Between 30-Oct-2017 and 15-Jul-2019, nine patients were registered: Three into Group A and six into Group B. WISTERIA was closed early due to poor recruitment. Five dose-limiting toxicities (DLTs) were reported in four Group B patients. Seven serious adverse events were reported in four patients: One in Group A, and three in Group B. Three were related to treatment. No treatment-related deaths were reported. Conclusions: WISTERIA did not complete its primary objectives due to poor recruitment and toxicities reported in Group B. However, use of the novel mTITE-CRM improved flexibility in reducing accrual suspension periods and should be considered for future trials in complex patient populations. Clinical Trial Registration: ISRCTN7629195

Loss of BAP1 expression is associated with an immunosuppressive microenvironment in uveal melanoma, with implications for immunotherapy development.

Immunotherapy using immune checkpoint inhibitors (ICIs) induces durable responses in many metastatic cancers. Metastatic uveal melanoma (mUM), typically occurring in the liver, is one of the most refractory tumours to ICIs and has dismal outcomes. Monosomy 3 (M3), polysomy 8q and BAP1 loss in primary uveal melanoma (pUM) are associated with poor prognoses. The presence of tumour infiltrating lymphocytes (TILs) within pUM and surrounding mUM - and some evidence of clinical responses to adoptive TIL transfer - strongly suggest that UM are indeed immunogenic despite their low mutational burden. The mechanisms that suppress TILs in pUM and mUM are unknown. We show that BAP1 loss is correlated with upregulation of several genes associated with suppressive immune responses, some of which build an immune suppressive axis, including HLA-DR, CD38, and CD74. Further, single-cell analysis of pUM by mass cytometry confirmed the expression of these and other markers revealing important functions of infiltrating immune cells in UM, most being a regulatory CD8+ T lymphocytes and tumour associated macrophages (TAMs). Transcriptomic analysis of hepatic mUM revealed similar immune profiles to pUM with BAP1 loss, including the expression of IDO1. At the protein level, we observed TAMs and TILs entrapped within peritumoral fibrotic areas surrounding mUM, with increased expression of IDO1, PD-L1 and β-catenin (CTNNB1), suggesting tumour-driven immune exclusion and hence the immunotherapy resistance. These findings aid the understanding of how the immune response is organised in BAP1- mUM, which will further enable functional validation of detected biomarkers and the development of focused immunotherapeutic approaches. This article is protected by copyright. All rights reserved

The Chick Embryo Xenograft Model for Malignant Pleural Mesothelioma: A Cost and Time Efficient 3Rs Model for Drug Target Evaluation

Malignant pleural mesothelioma (MPM) has limited treatment options and poor prognosis. Frequent inactivation of the tumour suppressors BAP1, NF2 and P16 may differentially sensitise tumours to treatments. We have established chick chorioallantoic membrane (CAM) xenograft models of low-passage MPM cell lines and protocols for evaluating drug responses. Ten cell lines, representing the spectrum of histological subtypes and tumour suppressor status, were dual labelled for fluorescence/bioluminescence imaging and implanted on the CAM at E7. Bioluminescence was used to assess viability of primary tumours, which were excised at E14 for immunohistological staining or real-time PCR. All MPM cell lines engrafted efficiently forming vascularised nodules, however their size, morphology and interaction with chick cells varied. MPM phenotypes including local invasion, fibroblast recruitment, tumour angiogenesis and vascular remodelling were evident. Bioluminescence imaging could be used to reliably estimate tumour burden pre- and post-treatment, correlating with tumour weight and Ki-67 staining. In conclusion, MPM-CAM models recapitulate important features of the disease and are suitable to assess drug targets using a broad range of MPM cell lines that allow histological or genetic stratification. They are amenable to multi-modal imaging, potentially offering a time and cost-efficient, 3Rs-compliant alternative to rodent xenograft models to prioritise candidate compounds from in vitro studies

Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma

Background: Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100-positive cells. Methods: In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival. Results: A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intention-to-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P = 0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100-positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported. Conclusions: Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.). Copyright © 2021 Massachusetts Medical Society