PEDIATRIC CANCERS

Fine Particulate Matter Air Pollution and Mortality among Pediatric, Adolescent, and Young Adult Cancer Patients

An analysis of nearly 16,000 young patients with cancer in Utah revealed that exposure to fine particulate matter was associated with increased mortality at five and 10 years after diagnosis of certain cancers (Cancer Epidemiol Biomarkers Prev 2020; doi: 10.1158/1055-9965.EPI-19-1363). Using information from the Utah Population Database and Utah Cancer Registry, researchers followed 2,444 pediatric (ages 0 to 14) and 13,459 young adult and adolescent (AYA; ages 15 to 39) patients diagnosed with cancer while living in Utah from 1986 to 2015. These patients were followed from diagnosis to the clinically relevant time points of five and 10 years after diagnosis. To estimate cumulative exposure to fine particulate matter, the researchers used data from stationary monitors provided by the Environmental Protection Agency (EPA). Using this information, the researchers could model the association between cumulative exposure and mortality from cancer and all-causes. The exposure to fine particulate matter was measured continuously (in increments of 5 micrograms per cubic meter of air; [mu]g/m3) and categorically (if exposure was equal to/exceeded the EPA annual standard of 12 [mu]g/m3, based on the three-year average of annual mean concentration of fine particulate matter) for these models. Models were adjusted for sex, race/ethnicity, and socioeconomic status, among other factors. Overall, among AYA patients, exposure to fine particulate matter was associated with an increased risk of cancer mortality and all-cause mortality at both time points when exposure was measured categorically. Exposure to fine particulate matter was associated with an increased risk of all-cause mortality at five years post diagnosis when exposure was measured continuously.

PROSTATE CANCER

Head-to-Head Comparison of 68Ga-PSMA-11 with 18F-PSMA-1007 PET/CT in Staging Prostate Cancer Using Histopathology and Immunohistochemical Analysis as a Reference Standard

The novel radiopharmaceutical 18F-PSMA-1007 is both effective and readily available for detecting malignant prostate cancer lesions, according to research published in The Journal of Nuclear Medicine (2019, doi: 10.2967/jnumed.119.234187). With this new option and 68Ga-PSMA-11, which is already widely used, nuclear medicine departments will have two effective options for staging of prostate cancer, potentially increasing availability for patients worldwide. 68Ga-PSMA is the most commonly used PSMA-labeled tracer in clinical practice for evaluating extent of disease in prostate cancer patients. However, it is produced by a specific generator and has a short half-life of 68 minutes. The prospective study aimed to compare the diagnostic accuracy of 18F-PSMA-1007 with 68Ga-PSMA-11 positron emission tomography (PET)/computed tomography (CT) in the same patients presenting with newly diagnosed intermediate- or high-risk prostate cancer. 18F-PSMA-1007 and 68Ga-PSMA-11 PET/CT were performed within 15 days of each other in sixteen patients with intermediate- or high-risk prostate cancer who were scheduled to undergo a radical prostatectomy. Findings from the two PET tracers were compared with histopathologic findings obtained from radical prostatectomy specimens, considered the gold standard. Labeled PSMA-avid lesions in the prostate were identified in all 16 patients with almost perfect agreement between the two tracers regarding tumor location. Additionally, in four patients, a second positive focus, though less intense, was detected only by 18F-PSMA-1007. Three of these secondary foci were confirmed as areas of prostate cancer, while the fourth was shown on pathological examination to represent chronic prostatitis.

MELANOMA

Phase II Trial of IL-12 Plasmid Transfection and PD-1 Blockade in Immunologically Quiescent Melanoma

Combining intratumoral electroporation of interleukin-12 (IL-12) DNA with the immune checkpoint inhibitor pembrolizumab led to clinical responses in patients with immunologically quiescent advanced melanoma, according to results from a single-arm phase II trial (Clinical Cancer Research 2020; doi: 10.1158/1078-0432.CCR-19-2217). Researchers treated patients with "cold" melanomas with a combination of the immune checkpoint inhibitor pembrolizumab and a DNA plasmid encoding IL-12 (TAVO). To help reduce toxicities, researchers used electroporation to deliver TAVO directly into melanoma lesions. The trial enrolled 23 adult patients with unresectable or metastatic melanoma who had accessible lesions and who were predicted to respond poorly to pembrolizumab, based on the proportion of checkpoint-positive immune cells in their tumors. Patients underwent TAVO electroporation on days 1, 5, and 8 of every six-week cycle, and they received pembrolizumab every three weeks. Patients remained on treatment until confirmed disease progression, up to two years. Responses were observed in nine of 22 evaluable patients, for an ORR of 41 percent. Thirty-six percent of patients experienced a complete response. The median PFS was 5.6 months, and the median overall survival was not reached after a median follow-up of 19.6 months. In addition to regression of electroporated lesions, regression was also observed in 29.2 percent of untreated lesions. Grade 3 or higher adverse effects were limited and included pain, chills, sweats, and cellulitis, in addition to the toxicities typically observed with pembrolizumab alone. By examining pre- and post-treatment tissue samples, researchers found that the combination treatment increased the number of immune cells in the tumor microenvironment, compared with baseline levels for both responders and nonresponders; however, nonresponders had greater numbers of immunosuppressive cells.

GLIOBLASTOMA

The Dopamine Receptor Antagonist Trifluoperazine Prevents Phenotype Conversion and Improves Survival in Mouse Models of Glioblastoma

Researchers found that adding a drug once commonly used to treat schizophrenia to traditional radiation therapy helped improve overall survival in mice with glioblastoma, one of the deadliest and most difficult-to-treat brain tumors. The findings show that a combination of radiation and the drug trifluoperazine not only targets glioblastoma cells but also helps overcome the resistance to treatment so common to this aggressive form of cancer (PNAS 2020; doi.org/10.1073/pnas.1920154117). The results could prove promising for patients with the disease, for whom the median survival time is only 12 to 18 months following diagnosis. In glioblastoma, tumor cells often become resistant to radiation treatment because the radiation itself can induce "phenotype conversion". Researchers have been exploring new ways to prevent glioblastoma tumor cells from becoming resistant to radiation by adding drugs to the treatment regimen that have traditionally been used for other purposes. To find out if there were any existing drugs that could interfere with the radiation-induced phenotype conversion, the team screened more than 83,000 compounds through the shared resources at UCLA. They were able to identify nearly 300 compounds, including the dopamine receptor antagonist trifluoperazine, that had the potential to block phenotype conversion and improve the efficacy of radiation therapy. Once trifluoperazine was identified, it was tested on mice with patient-derived orthotopic tumors. The team found that, when used in combination with radiation, trifluoperazine successfully delayed the growth of the tumors and significantly prolonged the overall survival of the animals. Combining radiation treatment with trifluoperazine extended survival in 100 percent of the mice to more than 200 days, compared to 67.7 days in the control group receiving only radiation.