Total scalp irradiation: A study comparing multiple types of bolus and VMAT optimization techniques.

PURPOSE: To investigate bolus design and VMAT optimization settings for total scalp irradiation. METHODS: Three silicone bolus designs (flat, hat, and custom) from .decimal were evaluated for adherence to five anthropomorphic head phantoms. Flat bolus was cut from a silicone sheet. Generic hat bolus resembles an elongated swim cap while custom bolus is manufactured by injecting silicone into a 3D printed mold. Bolus placement time was recorded. Air gaps between bolus and scalp were quantified on CT images. The dosimetric effect of air gaps on target coverage was evaluated in a treatment planning study where the scalp was planned to 60 Gy in 30 fractions. A noncoplanar VMAT technique based on gEUD penalties was investigated that explored the full range of gEUD alpha values to determine which settings achieve sufficient target coverage while minimizing brain dose. ANOVA and the t-test were used to evaluate statistically significant differences (threshold = 0.05). RESULTS: The flat bolus took 32 ± 5.9 min to construct and place, which was significantly longer (p < 0.001) compared with 0.67 ± 0.2 min for the generic hat bolus or 0.53 ± 0.10 min for the custom bolus. The air gap volumes were 38 ± 9.3 cc, 32 ± 14 cc, and 17 ± 7.0 cc for the flat, hat, and custom boluses, respectively. While the air gap differences between the flat and custom boluses were significant (p = 0.011), there were no significant dosimetric differences in PTV coverage at V57Gy or V60Gy. In the VMAT optimization study, a gEUD alpha of 2 was found to minimize the mean brain dose. CONCLUSIONS: Two challenging aspects of total scalp irradiation were investigated: bolus design and plan optimization. Results from this study show opportunities to shorten bolus fabrication time during simulation and create high quality treatment plans using a straightforward VMAT template with simple optimization settings.

Perceived changes in lifestyle behaviours and in mental health and wellbeing of elementary school children during the first COVID-19 lockdown in Canada.

OBJECTIVES: The closure of schools to prevent the spread of COVID-19 prompted concerns of deteriorating lifestyle behaviours, mental health, and wellbeing of children, particularly those in socioeconomically disadvantaged settings. We assessed changes in lifestyle behaviours (physical activity, screen time, eating habits and bed/wake-up times), mental health and wellbeing during the first lockdown in Spring 2020 as perceived by school children from disadvantaged settings, and examined determinants of these changes. STUDY DESIGN: Cross-sectional study. METHODS: We surveyed 1095 grade 4 to 6 students (age 9-12 years) from 20 schools in socioeconomically disadvantaged communities in northern Canada. Students reported on changes in lifestyle behaviours, mental health and wellbeing during the lockdown. Determinants of these perceived changes were examined in multivariable regression models. RESULTS: A majority of students reported declines in physical activity, having late bed/wake-up times, and modest improvements in mental health and wellbeing. Many students reported increases rather than decreases in screen time and snacking. Positive attitudes toward being active, eating healthy, going to sleep on time and being healthy were strongly associated with maintaining healthy lifestyle behaviours during the lockdown. Positive attitudes toward active and healthy living and healthy lifestyle behaviours were associated with maintaining positive mental health and wellbeing during the lockdown. CONCLUSIONS: The considerable changes in lifestyle behaviors, superimposed on the pre-existing burden of unhealthy lifestyle behaviours, put this generation of children at increased risk for future chronic disease. Findings call for effective health promotion of active and healthy lifestyles to benefit both physical and mental health.

Effect of immunotherapy time-of-day infusion on overall survival among patients with advanced melanoma in the USA (MEMOIR): a propensity score-matched analysis of a single-centre, longitudinal study.

BACKGROUND: The dependence of the adaptive immune system on circadian rhythm is an emerging field of study with potential therapeutic implications. We aimed to determine whether specific time-of-day patterns of immune checkpoint inhibitor infusions might alter melanoma treatment efficacy. METHODS: Melanoma Outcomes Following Immunotherapy (MEMOIR) is a longitudinal study of all patients with melanoma who received ipilimumab, nivolumab, or pembrolizumab, or a combination of these at a single tertiary cancer centre (Winship Cancer Institute of Emory University, Atlanta, GA, USA). For this analysis, we collected deidentified participant-level data from the MEMOIR database for adults (age ≥18 years) diagnosed with stage IV melanoma between 2012 and 2020. Those who received fewer than four infusions were excluded. Standard of care doses were used, with modifications at the treating physicians' discretion. The primary outcome was overall survival, defined as death from any cause and indexed from date of first infusion of immune checkpoint inhibitor. We calculated the association between overall survival and proportion of infusions of immune checkpoint inhibitors received after 1630 h (a composite time cutoff derived from seminal studies of the immune-circadian rhythm to represent onset of evening) using Cox regression and propensity score-matching on age, Eastern Cooperative Oncology Group performance status, serum lactate dehydrogenase concentration, and receipt of corticosteroids and radiotherapy. Treatment-related adverse events that led to change or discontinuation of immune checkpoint inhibitors were also assessed. FINDINGS: Between Jan 1, 2012, and Dec 31, 2020, 481 patients with melanoma received treatment with immune checkpoint inhibitors at the study centre, of whom 299 had stage IV disease and were included in this study; median follow-up was 27 months (IQR 14 to 47). In the complete unmatched sample, 102 (34%) patients were female and 197 (66%) were male, with a median age of 61 years (IQR 51 to 72). Every additional 20% of infusions of immune checkpoint inhibitors received after 1630 h (among all infusions received by a patient) conferred an overall survival hazard ratio (HR) of 1·31 (95% CI 1·00 to 1·71; p=0·046). A propensity score-matched analysis of patients who did (n=73) and did not (n=73) receive at least 20% of their infusions of immune checkpoint inhibitors after 1630 h (54 [37%] of 146 patients were women and 92 [63%] were men, with a median age of 58 years [IQR 48 to 68]) showed that having at least 20% of infusions in the evening was associated with shorter overall survival (median 4·8 years [95% CI 3·9 to not estimable] vs not reached; HR 2·04 [1·04 to 4·00; p=0·038]). This result remained robust to multivariable proportional hazards adjustment with (HR 1·80 [1·08 to 2·98; p=0·023]) and without (2·16 [1·10 to 4·25; p=0·025]) inclusion of the complete unmatched study sample. The most common adverse events were colitis (54 [18%] of 299 patients), hepatitis (27 [9%]), and hypophysitis (15 [5%]), and there were no treatment-related deaths. INTERPRETATION: Our findings are in line with an increasing body of evidence that adaptive immune responses are less robust when initially stimulated in the evening than if stimulated in the daytime. Although prospective studies of the timing of immune checkpoint inhibitor infusions are warranted, efforts towards scheduling infusions before mid-afternoon could be considered in the multidisciplinary management of advanced melanoma. FUNDING: National Institutes of Health, American Society for Radiation Oncology and Melanoma Research Alliance, and Winship Cancer Institute.

Clustering of cutaneous T-cell lymphoma is associated with increased levels of the environmental toxins benzene and trichloroethylene in the state of Georgia.

BACKGROUND: Cutaneous T-cell lymphoma (CTCL) is a rare form of non-Hodgkin lymphoma arising in the skin. Geographic clustering of CTCL has recently been reported, but its association with environmental factors is unknown. Benzene and trichloroethylene (TCE) are environmental toxins with carcinogenic properties. The authors investigated associations between geographic clustering of CTCL incidence in the state of Georgia with benzene and TCE exposure. METHODS: The statewide county-level incidence of CTCL within Georgia was obtained from the Georgia Cancer Registry for the years 1999 to 2015. Standardized incidence ratios (SIRs) were calculated by dividing observed cases by expected cases using national incidence rates by age, sex, and race. Clustering of CTCL was analyzed using spatial analyses. County-level concentrations of benzene and TCE between 1996 and 2014 were collected from the Environmental Protection Agency's National Air Toxics Assessment database. Linear regression analyses on CTCL incidence were performed comparing SIRs with levels of benzene and TCE by county. RESULTS: There was significant geographic clustering of CTCL in Georgia, particularly around Atlanta, which was correlated with an increased concentration of benzene and TCE exposure. Among the 4 most populous counties in Georgia, CTCL incidence was between 1.2 and 1.9 times higher than the state average, and benzene and TCE levels were between 2.9 and 8.8 times higher. CONCLUSIONS: The current results demonstrate nonrandom geographic clustering of CTCL incidence in Georgia. To the authors' knowledge, this is the first analysis to identify a correlation between geographic clustering of CTCL and environmental toxic exposures.

Low-dose whole-lung radiation for COVID-19 pneumonia: Planned day 7 interim analysis of a registered clinical trial.

BACKGROUND: Individuals of advanced age with comorbidities face a higher risk of death from coronavirus disease 2019 (COVID-19), especially once they are ventilator-dependent. Respiratory decline in patients with COVID-19 is precipitated by a lung-mediated aberrant immune cytokine storm. Low-dose lung radiation was used to treat pneumonia in the pre-antibiotic era. Radiation immunomodulatory effects may improve outcomes for select patients with COVID-19. METHODS: A single-institution trial evaluating the safety and efficacy of single-fraction, low-dose whole-lung radiation for patients with COVID-19 pneumonia is being performed for the first time. This report describes outcomes of a planned day 7 interim analysis. Eligible patients were hospitalized, had radiographic consolidation, required supplemental oxygen, and were clinically deteriorating. RESULTS: Of 9 patients screened, 5 were treated with whole-lung radiation on April 24 until April 28 2020, and they were followed for a minimum of 7 days. The median age was 90 years (range, 64-94 years), and 4 were nursing home residents with multiple comorbidities. Within 24 hours of radiation, 3 patients (60%) were weaned from supplemental oxygen to ambient air, 4 (80%) exhibited radiographic improvement, and the median Glasgow Coma Scale score improved from 10 to 14. A fourth patient (80% overall recovery) was weaned from oxygen at hour 96. The mean time to clinical recovery was 35 hours. There were no acute toxicities. CONCLUSIONS: In a pilot trial of 5 oxygen-dependent elderly patients with COVID-19 pneumonia, low-dose whole-lung radiation led to rapid improvements in clinical status, encephalopathy, and radiographic consolidation without acute toxicity. Low-dose whole-lung radiation appears to be safe, shows early promise of efficacy, and warrants further study. LAY SUMMARY: Researchers at Emory University report preliminary safety outcomes for patients treated with low-dose lung irradiation for coronavirus disease 2019 (COVID-19) pneumonia. Five residents of nursing or group homes were hospitalized after testing positive for COVID-19. Each had pneumonia visible on a chest x-ray, required supplemental oxygen, and experienced a clinical decline in mental status or in work of breathing or a prolonged or escalating supplemental oxygen requirement. A single treatment of low-dose (1.5-Gy) radiation to both lungs was delivered over the course of 10 to 15 minutes. There was no acute toxicity attributable to radiation therapy. Within 24 hours, 4 patients had rapidly improved breathing, and they recovered to room air at an average of 1.5 days (range, 3-96 hours). Three were discharged at a mean time of 12 days, and 1 was preparing for discharge. Blood tests and repeat imaging confirm that low-dose whole-lung radiation treatment appears safe for COVID-19 pneumonia. Further trials are warranted.

The future of radiation-induced abscopal response: beyond conventional radiotherapy approaches.

Advances in the immunological pharmaceuticals, such as checkpoint inhibitors and agonists, have positive implications for the future of the radiotherapy abscopal response. A once rare phenomenon, whereby distant nonirradiated tumor sites regressed after radiotherapy alone, may become more common when combined with the immune modulating agents. Radiotherapy can increase neoantigen expression, increased tumor PD-L1 expression, increase MHC class I expression, reverse exhausted CD8 T cells and increase tumor-infiltrating tumors within the tumor microenvironment. These changes in the tumor and the tumor microenvironment after radiotherapy could potentiate responses to anti-CTL-4, anti-PD-L1/PD-1 and other immunotherapy agents. Thus, advances in checkpoint inhibitors have increased interest in re-evaluation of the role of conventional radiotherapy approaches on the immune system. We reviewed newer nonconventional approaches such as SBRT-PATHY, GRID, FLASH, carbon ion and proton therapy and their role in eliciting immune responses. We believe that combining these novel radiation methods may enhance the outcome with the newly US FDA approved immune modulating agents.

Is it nutrients, food items, diet quality or eating behaviours that are responsible for the association of children's diet with sleep?

Both diet quality and sleep duration of children have declined in the past decades. Several studies have suggested that diet and sleep are associated; however, it is not established which aspects of the diet are responsible for this association. Is it nutrients, food items, diet quality or eating behaviours? We surveyed 2261 grade 5 children on their dietary intake and eating behaviours, and their parents on their sleep duration and sleep quality. We performed factor analysis to identify and quantify the essential factors among 57 nutrients, 132 food items and 19 eating behaviours. We considered these essential factors along with a diet quality score in multivariate regression analyses to assess their independent associations with sleep. Nutrients, food items and diet quality did not exhibit independent associations with sleep, whereas two groupings of eating behaviours did. 'Unhealthy eating habits and environments' was independently associated with sleep. For each standard deviation increase in their factor score, children had 6 min less sleep and were 12% less likely to have sleep of good quality. 'Snacking between meals and after supper' was independently associated with sleep quality. For each standard deviation increase in its factor score, children were 7% less likely to have good quality sleep. This study demonstrates that eating behaviours are responsible for the associations of diet with sleep among children. Health promotion programmes aiming to improve sleep should therefore focus on discouraging eating behaviours such as eating alone or in front of the TV, and snacking between meals and after supper.

The Independent Importance of Pre-pregnancy Weight and Gestational Weight Gain for the Prevention of Large-for Gestational Age Brazilian Newborns.

Objectives To study the independent effect of pre-pregnancy weight, gestational weight gain (GWG), and other important risk factors on newborn birth weight. Methods Baseline data of 435 adult women and their singletons born between January and February 2012 at a public hospital in Brazil were used. Logistic regression was applied to determine the independent importance of pre-pregnancy weight and GWG for large for gestational age (LGA) newborns. Results Among all mothers, 37.9 % were overweight and obese before pregnancy and 45.3 % experienced excessive GWG. Among the newborns, 24.4 % were classified as LGA. Univariate analysis showed an association of family income, GWG, pre-pregnancy BMI and excessive GWG with LGA newborns. Smoking before and during pregnancy was associated with a decreased likelihood of giving birth to an LGA newborn compared to mothers who did not smoke. After adjustment for confounding variables, age at birth of first child, GWG, HbA1c and pre-pregnancy weight-GWG were significant and independent determinants of giving birth to an LGA newborn. Mothers with pre-pregnancy overweight and excessive GWG were more likely to deliver an LGA newborn (OR 2.54, P < 0.05) compared to mothers who were normal weight and experienced adequate GWG. Conclusions for Practice Age at first birth of child, GWG, HbA1c and pre-pregnancy overweight combined with excessive GWG are independent determinants of LGA newborns. The results of this study suggest that both primary prevention of overweight in women of childbearing age and management of GWG may be important strategies to reduce the number of LGA newborns and, consequently, the long-term public health burden of obesity.

Breast, Formula and Combination Feeding in Relation to Childhood Obesity in Nova Scotia, Canada.

Breastfeeding has been rigorously studied in relation to childhood obesity prevention. Few studies have examined whether combination feeding­breast milk and formula­may also be protective against obesity. This study aimed to investigate the relationship between breastfeeding duration, combination feeding and overweight and obesity among Canadian school children. We analyzed data from a 2011 cross-sectional, population based survey (n = 5,560), which included self-reported infant feeding behaviours, a food frequency questionnaire and measured height and weight. Multilevel regression methods were used to examine the association between breastfeeding duration and overweight and obesity adjusting for socioeconomic status, diet quality and physical activity. Thirty-four percent of children were breastfed for <1 week or never while 32% were breastfed for at least 6 months. In the fully adjusted model, children who were only formula fed or who were combination fed for <6 months were more likely to be overweight or obese relative to children who were only breastfed (OR 1.29, 95% CI 1.04-1.60 and OR 1.35, 95% CI 1.09-1.69, respectively). When examining overweight and obese children separately, those who were only formula fed were more likely obese (OR 1.57, 95% CI 1.10-2.25) relative to their peers who were only breastfed. And those who were combination fed for <6 months relative to those only breastfed were more likely to be overweight (OR 1.29, 95% CI 1.01-1.66). Breastfeeding, in the absence of formula feeding, appears to have a protective effect on childhood obesity. While combination feeding confers less benefit than only breastfeeding, it is more desirable than formula feeding alone. Strategies and social policies are needed to promote exclusive and longer breastfeeding duration and should be integrated with comprehensive efforts to prevent childhood obesity and to reduce the burden of chronic diseases in the long term.

Intracranial control and radiographic changes with adjuvant radiation therapy for resected brain metastases: whole brain radiotherapy versus stereotactic radiosurgery alone.

The aim of this study was to compare outcomes of postoperative whole brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) alone in patients with resected brain metastases (BM). We reviewed records of patients who underwent surgical resection of BM followed by WBRT or SRS alone between 2003 and 2013. Local control (LC) of the treated resected cavity, distant brain control (DBC), leptomeningeal disease (LMD), overall survival (OS), and radiographic leukoencephalopathy rates were estimated by the Kaplan-Meier method. One-hundred thirty-two patients underwent surgical resection for 141 intracranial metastases: 36 (27 %) patients received adjuvant WBRT and 96 (73 %) received SRS alone to the resection cavity. One-year OS (56 vs. 55 %, p = 0.64) and LC (83 vs. 74 %, p = 0.31) were similar between patients receiving WBRT and SRS. After controlling for number of BM, WBRT was associated with higher 1-year DBC compared with SRS (70 vs. 48 %, p = 0.03); single metastasis and WBRT were the only significant predictors for reduced distant brain recurrence in multi-variate analysis. Freedom from LMD was higher with WBRT at 18 months (87 vs. 69 %, p = 0.045), while incidence of radiographic leukoencephalopathy was higher with WBRT at 12 months (47 vs. 7 %, p = 0.001). One-year freedom from WBRT in the SRS alone group was 86 %. Compared with WBRT for patients with resected BM, SRS alone demonstrated similar LC, higher rates of LMD and inferior DBC, after controlling for the number of BM. However, OS was similar between groups. The results of ongoing clinical trials are needed to confirm these findings.

Evaluation of radiation dose to cardiac and pulmonary tissue among patients with stage IV Wilms tumor and pulmonary metastases.

BACKGROUND: Most patients with stage IV Wilms tumor (WT) and pulmonary metastases are treated with surgery, local radiotherapy (RT), and whole-lung irradiation (WLI). The Children's Oncology Group is studying whether WLI should only be given if metastatic lung lesions persist following induction chemotherapy. We hypothesized that radiation dose to cardiac and pulmonary organs are increased when WLI and abdominal RT fields are administered sequentially. PROCEDURE: We retrospectively identified 16 patients with stage IV WT and pulmonary metastases to model dosimetry plans for concurrent and sequential flank or whole abdomen and whole-lung fields. RESULTS: Treatment plans were evaluated for dosimetric endpoints to the heart and the lungs. The mean dose (Gy) was significantly higher to the heart (15.8 vs. 12.1, P < 0.0001) and lungs (14.1 vs. 12.2, P < 0.0002) when patients with stage IV WT and pulmonary metastases were treated with sequential RT. The percent tissue organ volumes (V) receiving high RT doses of 15 and 20 Gy (V(15) and V(20)) were negligible in concurrent treatment plans. Comparatively, mean V(15) and V(20) values for sequential treatment plans were 35% and 27%, respectively, for the heart, and 15% and 12%, for the lungs. CONCLUSIONS: The dose to the heart and lung tissue is significantly increased when WLI and abdominal RT fields are administered sequentially. While omission of WLI may be beneficial for patients achieving good response to induction chemotherapy, the less favorable response group may be subjected to increased risk of cardiac and pulmonary toxicities from sequential WLI.

Anatomic surgical management of chronic low back pain.

OBJECTIVE: To review spine surgery management strategies for patients with chronic low back pain (CLBP) that has failed to respond to all nonsurgical treatment options. MATERIALS AND METHODS: Literature review was conducted for spine surgery in the treatment of CLBP without compressive anatomical disease. The main diagnosis identified was degenerated disc disease, and surgical options targeted for the treatment of CLBP were reviewed. RESULTS: The history of current spine intervention for CLBP was reviewed, including various surgical options. Surgical treatment options for patients with CLBP include lumbar fusion, lumbar disc arthroplasty, and dynamic stabilization. Lumbar fusion remains the most frequent spine surgery performed for CLBP, but questions still exist regarding its efficacy in comparison with conservative care or interventional pain management. Lumbar disc arthroplasty and dynamic stabilization can both be considered only for select patients with CLBP, and their uses are currently limited. CONCLUSION: Despite the number of spine surgeries that have been performed for CLBP, the surgical outcome still remains questionable. Until a precise identification of the cause of CLBP in any given patient can be precisely determined, surgical solutions will continue to be less than optimal.

Chitosan/functionalized fruit stones as a highly efficient adsorbent biomaterial for adsorption of brilliant green dye: Comprehensive characterization and statistical optimization.

In this research, a highly efficient adsorbent biomaterial (hereinafter, CTS/PPS-HS) of chitosan/functionalized fruit stones (peach and plum) with H2SO4 was produced for the adsorption of brilliant green (BG) dye from aquatic systems. The developed biomaterial was characterized by several techniques like SEM-EDX, FTIR, XRD, BET, and pHpzc. To systematically optimize the adsorption performance of CTS/PPS-HS, the Box-Behnken design (BBD) based on response surface methodology (RSM) was attained. The factors considered for optimization included A: CTS/PPS-HS dosage (0.02-0.08 g), B: pH (4-10), and C: removal time (10-60 min). The pseudo-first-order and Langmuir isotherm models exhibited excellent agreement with the experimental results of BG adsorption by CTS/PPS-HS. The outstanding adsorption capacity (409.63 mg/g) of CTS/PPS-HS was obtained. The remarkable adsorption of BG onto CTS/PPS-HS can be primarily attributed to electrostatic forces between the acidic sites of CTS/PPS-HS and the BG cations, accompanied by interactions such as π-π, Yoshida H-bonding, n-π, and H-bond interactions. The current data underscores the significant potential inherent in combining biomass with CTS polymer to create an exceptionally effective adsorbent biomaterial tailored for the elimination of cationic dyes.

Development of chitosan biopolymer by chemically modified orange peel for safranin O dye removal: A sustainable adsorbent and adsorption modeling using RSM-BBD.

This study aimed to develop a biocomposite (hereinafter, CHI/OP-H2SO4) via the functionalization of chitosan (CHI) biopolymer by chemically modified orange peel (OP-H2SO4). The physicochemical characteristics of CHI/OP-H2SO4 were studied using methods such as pHpzc, XRD, FTIR, BET, and FESEM-EDX. The efficacy of the CHI/OP-H2SO4 biocomposite in removing cationic dye (safranin O, SAF-O) from aqueous solutions was assessed. The Box-Behnken Design (BBD) based on response surface methodology (RSM) was employed to optimize the adsorption performance of CHI/OP-H2SO4, considering factors such as A: CHI/OP-H2SO4 dose (0.02-0.08 g), B: pH (4-10), and C: time (10-60 min). The pseudo-first-order and Freundlich isotherm models align well with the experimental data of SAF-O adsorption by CHI/OP-H2SO4. The excellent adsorption capacity for CHI/OP-H2SO4 was recorded (321.2 mg/g). The notable adsorption of SAF-O onto CHI/OP-H2SO4 is attributed primarily to electrostatic forces between the acidic groups of CHI/OP-H2SO4 and the SAF-O cation, along with H-bonding, and n-π interactions. By transforming waste materials into valuable resources, this approach not only mitigates environmental impact but also produces a promising and sustainable adsorbent for the removal of cationic dyes, exemplified here by the effective removal of SAF-O dye.

Pembrolizumab and low-dose, single-fraction radiotherapy for patients with relapsed or refractory multiple myeloma: a prospective, single-centre, single-group, open-label, phase 2 pilot trial in the USA.

BACKGROUND: Currently, the use of radiotherapy alone for people with multiple myeloma is limited to palliation of pain, pending fracture, and control of spinal-cord compression. Single immune-checkpoint inhibitors, such as anti-programmed death-1 (anti-PD1), have not been successful. We aimed to evaluate the activity and safety of the combination of pembrolizumab and low-dose, single-fraction, hypofractionated radiotherapy to treat patients with relapsed or refractory multiple myeloma. METHODS: For this prospective, single-centre, single-group, open-label, phase 2 trial, we recruited patients with relapsed or refractory multiple myeloma from the Winship Cancer Institute (Emory University, Atlanta, GA, USA). Key inclusion criteria were aged 18 years or older, Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1, relapsed or refractory multiple myeloma as indicated by progression under International Myeloma Working Group (IMWG) criteria, and adequate candidacy for both pembrolizumab and radiotherapy. Baseline and post-treatment assessments were serial bone-marrow biopsy, peripheral blood collections, staging, serial serum and urine paraprotein analysis, serial PET-CT imaging, and a physical examination. On day 1, patients received hypofractionated 8 gray in 1 fraction (8 Gy/1 fx) radiotherapy to either symptomatic or progressing extra-osseous or osseous myeloma sites. Patients also received pembrolizumab (200 mg/kg intravenously) on day 2 or 3, then once every 3 weeks (±7 days) for 2 years or until progressive disease, unacceptable toxicity, withdrawal of consent, loss to follow-up, or death. Dose reduction and interruptions were not allowed. The primary outcome was acute toxicity defined as grade 3 or worse toxicity at 3 months within the radiated site when used in combination with pembrolizumab. All patients were analysed per protocol and included in safety analyses. This trial is registered on ClinicalTrials.gov (NCT03267888); it is completed and closed to accrual. FINDINGS: 32 patients were screened between June 1, 2018, and Sept 2, 2022, and 25 were enrolled in the trial and treated on protocol. Of the 25 treated patients, 11 (44%) were female and 14 (56%) were male. 19 (76%) patients were White and six (24%) were Black or African American. Toxicity, as the primary outcome, was deemed to be acceptable as no grade 4 or 5 adverse events were observed. At 3-month follow-up, eight (32%) of 25 patients had treatment benefit (one had stable disease, three had partial response, two had very good partial response, and two had complete response). There was no grade 3 or worse radiation-related toxicity within irradiated volumes. One (4%) patient of the 25 who received combination treatment had a grade 3 pembrolizumab-related adverse event. There were no treatment-related deaths. INTERPRETATION: Combination treatment of low-dose, single-fraction radiotherapy with pembrolizumab was safe, with early promise of response activity. Our approach could be an option for patients with relapsed or refractory multiple myeloma who have not responded to previous treatment. Larger trials to substantiate our findings are needed. FUNDING: Merck Sharp & Dohme.

Impact of immunotherapy time-of-day infusion on survival and immunologic correlates in patients with metastatic renal cell carcinoma: a multicenter cohort analysis.

BACKGROUND: Recent studies have demonstrated that earlier time-of-day infusion of immune checkpoint inhibitors (ICIs) is associated with longer progression-free survival (PFS) and overall survival (OS) among patients with metastatic melanoma and non-small cell lung cancer. These data are in line with growing preclinical evidence that the adaptive immune response may be more effectively stimulated earlier in the day. We sought to determine the impact of time-of-day ICI infusions on outcomes among patients with metastatic renal cell carcinoma (mRCC). METHODS: The treatment records of all patients with stage IV RCC who began ICI therapy within a multicenter academic hospital system between 2015 and 2020 were reviewed. The associations between the proportion of ICI infusions administered prior to noon (denoting morning infusions) and PFS and OS were evaluated using univariate and multivariable Cox proportional hazards regression. RESULTS: In this study, 201 patients with mRCC (28% women) received ICIs and were followed over a median of 18 months (IQR 5-30). The median age at the time of ICI initiation was 63 years (IQR 56-70). 101 patients (50%) received ≥20% of their ICI infusions prior to noon (Group A) and 100 patients (50%) received <20% of infusions prior to noon (Group B). Across the two comparison groups, initial ICI agents consisted of nivolumab (58%), nivolumab plus ipilimumab (34%), and pembrolizumab (8%). On univariate analysis, patients in Group A had longer PFS and OS compared with those in Group B (PFS HR 0.67, 95% CI 0.48 to 0.94, Punivar=0.020; OS HR 0.57, 95% CI 0.34 to 0.95, Punivar=0.033). These significant findings persisted following multivariable adjustment for age, sex, performance status, International Metastatic RCC Database Consortium risk score, pretreatment lactate dehydrogenase, histology, and presence of bone, brain, and liver metastases (PFS HR 0.70, 95% CI 0.50 to 0.98, Pmultivar=0.040; OS HR 0.57, 95% CI 0.33 to 0.98, Pmultivar=0.043). CONCLUSIONS: Patients with mRCC may benefit from earlier time-of-day receipt of ICIs. Our findings are consistent with established mechanisms of chrono-immunology, as well as with preceding analogous studies in melanoma and lung cancer. Additional prospective randomized trials are warranted.

SAMHD1 expression contributes to doxorubicin resistance and predicts survival outcomes in diffuse large B-cell lymphoma patients.

Diffuse large B-cell lymphoma (DLBCL) is a commonly diagnosed, aggressive non-Hodgkin's lymphoma. While R-CHOP chemoimmunotherapy is potentially curative, about 40% of DLBCL patients will fail, highlighting the need to identify biomarkers to optimize management. SAMHD1 has a dNTPase-independent role in promoting resection to facilitate DNA double-strand break (DSB) repair by homologous recombination. We evaluated the relationship of SAMHD1 levels with sensitivity to DSB-sensitizing agents in DLBCL cells and the association of SAMHD1 expression with clinical outcomes in 79 DLBCL patients treated with definitive therapy and an independent cohort dataset of 234 DLBCL patients. Low SAMHD1 expression, Vpx-mediated, or siRNA-mediated degradation/depletion in DLBCL cells was associated with greater sensitivity to doxorubicin and PARP inhibitors. On Kaplan-Meier log-rank survival analysis, low SAMHD1 expression was associated with improved overall survival (OS), which on subset analysis remained significant only in patients with advanced stage (III-IV) and moderate to high risk (2-5 International Prognostic Index (IPI)). The association of low SAMHD1 expression with improved OS remained significant on multivariate analysis independent of other adverse factors, including IPI, and was validated in an independent cohort. Our findings suggest that SAMHD1 expression mediates doxorubicin resistance and may be an important prognostic biomarker in advanced, higher-risk DLBCL patients.

Radiation and anti-PD-L1 synergize by stimulating a stem-like T cell population in the tumor-draining lymph node.

Radiotherapy (RT) and anti-PD-L1 synergize to enhance local and distant (abscopal) tumor control. However, clinical results in humans have been variable. With the goal of improving clinical outcomes, we investigated the underlying synergistic mechanism focusing on a CD8+ PD-1+ Tcf-1+ stem-like T cell subset in the tumor-draining lymph node (TdLN). Using murine melanoma models, we found that RT + anti-PD-L1 induces a novel differentiation program in the TdLN stem-like population which leads to their expansion and differentiation into effector cells within the tumor. Our data indicate that optimal synergy between RT + anti-PD-L1 is dependent on the TdLN stem-like T cell population as either blockade of TdLN egress or specific stem-like T cell depletion reduced tumor control. Together, these data demonstrate a multistep stimulation of stem-like T cells following combination therapy which is initiated in the TdLN and completed in the tumor.

Pre-operative stereotactic radiosurgery and peri-operative dexamethasone for resectable brain metastases: a two-arm pilot study evaluating clinical outcomes and immunological correlates.

Enhancing the efficacy of immunotherapy in brain metastases (BrM) requires an improved understanding of the immune composition of BrM and how this is affected by radiation and dexamethasone. Our two-arm pilot study (NCT04895592) allocated 26 patients with BrM to either low (Arm A) or high (Arm B) dose peri-operative dexamethasone followed by pre-operative stereotactic radiosurgery (pSRS) and resection (n= 13 per arm). The primary endpoint, a safety analysis at 4 months, was met. The secondary clinical endpoints of overall survival, distant brain failure, leptomeningeal disease and local recurrence at 12-months were 66%, 37.3%, 6%, and 0% respectively and were not significantly different between arms (p= 0.7739, p= 0.3884, p= 0.3469). Immunological data from two large retrospective BrM datasets and confirmed by correlates from both arms of this pSRS prospective trial revealed that BrM CD8 T cells were composed of predominantly PD1+ TCF1+ stem-like and PD1+ TCF1-TIM3+ effector-like cells. Clustering of TCF1+ CD8 T cells with antigen presenting cells in immune niches was prognostic for local control, even without pSRS. Following pSRS, CD8 T cell and immune niche density were transiently reduced compared to untreated BrM, followed by a rebound 6+ days post pSRS with an increased frequency of TCF1- effector-like cells. In sum, pSRS is safe and therapeutically beneficial, and these data provide a framework for how pSRS may be leveraged to maximize intracranial CD8 T cell responses.