Hospital facility characteristics and socioeconomic factors on outcomes and treatment in patients with multiple myeloma: National Cancer Database analysis.

Previous studies have shown that socioeconomic factors play an important role in multiple myeloma (MM) health outcomes. We postulated that the type of treatment facilities and their volume of cases also affect overall survival, utilization of various therapies including palliative care services in newly diagnosed MM. Using the National Cancer Database (NCDB), we analyzed 174,551 newly diagnosed MM participants from across the country. We found that at high volume facility centers (over 90th percentile of new patient volume from 2004 to 2016), the median overall survival (OS) was 62.3 months versus 35.3 months at lower volume facilities (p <0.001). Similarly, high volume academic cancer centers had an improved median OS of 66.4 months (65.3-67.4 CI) versus 39.2 months (37.9-40.4 months CI) in lower volume academic centers (p <0.001). The odds of utilizing chemotherapy, immunotherapy, and autologous transplants were higher in academic cancer centers compared to community cancer centers, after adjusting for demographic and socioeconomic factors (OR 1.10, 1.23, and 2.06 respectively, all with p<0.001). There was significantly decreased odds of receiving palliative care (OR 0.89, 95% CI 0.85-0.93) in high volume facilities compared to low volume. Palliative care services were more frequently utilized at integrated network cancers and comprehensive community cancer centers compared to community cancer centers, with similar odds of receiving palliative care between community and academic facility types. Our results likely reflect increased provider experience and resources in higher volume and academic facilities. This highlights the need to integrate resources and improve access to community programs.

Limited Effectiveness of Carbonaceous Sorbents in Sequestering Aged Organic Contaminants in Sediments.

Carbonaceous materials are often proposed for use in restoring soils or sediments contaminated with hydrophobic organic contaminants (HOCs). However, the contamination of most sites is a result of historical events, where HOCs have resided in the solid compartment for many years or decades. The prolonged contact time, or aging, leads to reduced contaminant availability and likely diminished effectiveness of using sorbents. In this study, three different carbonaceous sorbents, i.e., biochars, powdered activated carbon, and granular activated carbon, were amended to a Superfund site marine sediment contaminated with DDT residues from decades ago. The amended sediments were incubated in seawater for up to 1 year, and the freely dissolved concentration (Cfree) and the biota-sediment accumulation factors (BSAFs) for a native polychaete (Neanthes arenaceodentata) were measured. Even though the bulk sediment concentrations were very high (6.4-154.9 µg/g OC), both Cfree and BSAFs were very small, ranging from nd to 1.34 ng/L and from nd to 0.024, respectively. The addition of carbonaceous sorbents, even at 2% (w/w), did not consistently lead to reduced DDT bioaccumulation. The limited effectiveness of carbonaceous sorbents was attributed to the low DDT availability due to prolonged aging, highlighting the need for considering contaminant aging when using sorbents for remediation.

Hypoalbuminemia as a prognostic biomarker for higher mortality and treatment complications in acute myeloid leukemia.

Older age and poor performance status lead to worse outcomes in acute myeloid leukemia (AML) patients. Hypoalbuminemia is a negative predictor of morbidity and mortality in several malignancies. We evaluated the relationship between baseline serum albumin levels on treatment-related complications, as well as short-term mortality and overall survival (OS) in 756 newly diagnosed AML patients. We conducted a retrospective multicenter study to examine treatment-related complications and OS according to pretreatment serum albumin levels: normal albumin ≥3.5 g/dl, marked hypoalbuminemia <2.5 g/dl, and hypoalbuminemia 2.5-3.4 g/dl. In an adjusted multivariate analysis, a lower baseline albumin was independently associated with a higher number of grade ≥3 complications when adjusting for age, secondary AML, sex and intensive treatment. When comparing normal to markedly low albumin levels, the estimated mean number of complications increases by a factor of 1.35. Patients who had a normal baseline albumin had a 30 day-mortality rate of 4.8%, which was significantly lower compared with patients with hypoalbuminemia (16.5%) and marked hypoalbuminemia (33.9%; p < 0.01). Similarly, 60-day mortality rate was significantly higher in the hypoalbuminemia group (24.0%) and marked hypoalbuminemia group (45%) compared with normal albumin group (8.3%; p < 0.01). Patients with lower baseline albumin levels have increased treatment-related morbidity and mortality, suggesting that pre-treatment serum albumin is an important independent prognostic marker.

Why femme stories matter: Constructing femme theory through historical femme life writing.

We argue that historical femme life writing forms a rich resource for femme theory that contributes to, challenges, and extends contemporary academic femme literature. We focus on the experiences of femmes during the second-wave feminist movement, specifically within the context of 1970s and 1980s U.S. lesbian feminism. The texts we examine include My Dangerous Desires by Amber Hollibaugh (2000), A Restricted Country by Joan Nestle (1987), Minnie Bruce Pratt's (1995) S/he, and selections from The Persistent Desire: A Femme-Butch Reader, edited by Nestle (1992). Informed by Clare Hemmings' (2011) and Victoria Hesford's (2013) critiques that past feminisms are often retold using reductive narratives, we (re)read this femme life writing to foreground the ways in which femmes have historically troubled and resisted monolithic accounts of lesbian feminism, lesbian identities, femininity, and sexuality. By centering queer feminine voices from this period to highlight major themes of this life writing, and drawing on Andi Schwartz's (2018) positioning of femme cultural production as a basis for theory, we argue that earlier iterations of queer femininities are relevant to and important for contemporary femme theory. Ultimately, we analyze what historical femme life writing reveals about the place of femininity within the lesbian and feminist communities of their time, how these dynamics inform current perceptions of queer and femme politics, and how femmes resist their cultural and critical marginalization.

"Femme ain't frail": (re)considering femininity, aging, and gender theory.

We analyze the intersection of femme, aging, and later-in-life disability by using the popular, contemporary slogan "femme ain't frail" to explore who is erased, excluded, and overlooked when fem(me)ininity is conceptualized as strong, fierce, and chosen. Building from Lisa Walker's position that dominant femme discourse marginalizes the experiences of aging femmes, we analyze the narratives of Amber Hollibaugh, Joan Nestle, Mary Frances Platt and Sharon Wachsler to explore femme experiences of later-in-life disability and aging, and to further trouble existing, popular constructions of femme identity that are predicated upon youth and able-bodiedness. We elaborate on discourses of femme and frailty, bringing them together to explore the ways femme is or, can be, frail. Insofar as femme is located in vulnerability, and vulnerability is associated with frailty, we see how femme might, indeed, be frail, and why this relationship is important to explore, not disavow. We contend that considerations of the frailty of fem(me)ininity can challenge the ageist and ableist orientation of contemporary femme politics and the broader cultural devaluation of fem(me)ininity.

Occurrence and Probable Sources of Urban-Use Insecticides in Marine Sediments off the Coast of Los Angeles.

Insecticides such as pyrethroids and fipronil are used in large amounts in both agricultural and urban settings and have the potential to elicit toxicity to nontarget aquatic organisms. In California, like in many other regions of the world, urban centers are located along the coast, and it is documented that urban-use insecticides enter the marine environment, where little is known about their occurrence and consequences. In this study, we measured the spatial distribution of pyrethroids and fipronil (and its metabolites) on the Palos Verdes Shelf off the coast of Los Angeles. Total pyrethroid levels ranged from nd to 170 µg/kg (dry weight), and fipronil sulfide levels ranged from 1.8 to 5.6 µg/kg. Two pyrethroids were traced to wastewater effluent discharge, while two others and fipronil sulfide were traced to to surface runoff. Toxicity units (TUs) were estimated for benthic invertebrates, which ranged from no toxicity (nt) to 146 for total pyrethroids, and 0.09 to 1.6 and 4.2 to 75 for fipronil sulfide, depending on the indicator species. Therefore, near-shore deposition of urban-use insecticides due to wastewater discharge and surface runoff poses a significant risk to marine benthic invertebrates and highlights the importance of monitoring near-shore ocean environments and developing mitigation strategies to reduce seaward movement.

Inference of Organophosphate Ester Emission History from Marine Sediment Cores Impacted by Wastewater Effluents.

Organophosphate esters (OPEs) have been in use as flame retardants for many decades, with their actual usage varying over time. Knowledge of the emission history of OPEs is valuable for improving our prediction of their environmental loadings and associated risks. In this study, concentrations and compositions of 10 OPEs were measured in three dated sediment cores from the Palos Verdes Shelf (PVS) off the coast of Los Angeles, which has been impacted by wastewater treatment plant (WWTP) effluents for over a century. The total OPE concentrations varied from 0.68 to 1064 ng/g along the sediment profile, with two apparent peaks. The first peak occurred in the 1970s, coinciding with peak emissions from WWTPs. The second peak appeared in the 2000s and was possibly attributed to increased consumption of OPEs as replacement flame retardants. Since downward movement of OPEs in the PVS sediment bed was retarded by their slow desorption, the reconstructed history likely provided an accurate picture of OPE emissions in Southern California and North America. These findings suggest that the near-shore marine sediments affected by WWTP effluents could serve as an environmental proxy documenting history in OPE use and emissions.

Palliative Radiation Therapy for Recurrent Ovarian Cancer: Efficacy and Predictors of Clinical Response.

OBJECTIVE: This study aimed to report response rates and predictors of response to palliative radiotherapy (RT) for recurrent ovarian cancer. METHODS/MATERIALS: Database review identified 64 patients with symptomatic ovarian cancer recurrence who received a total of 76 courses of RT for 103 indications from March 2003 to August 2014. Radiotherapy indications were pain (44%), bleeding (32%), obstruction (15%), and other (9%). Responses were categorized as complete, partial, or none; all response (AR) was the sum of complete and partial responses. Response rates were compared using a χ test. Multivariate analysis was performed using logistic regression. Patients were followed up for symptom recurrence and death. RESULTS: Response rates were significantly higher for pain (AR, 87%) and bleeding (93%) than for obstruction (62%) and other (60%; P < 0.01). Patients treated for pain at nonbony sites had higher response rates (AR 96%) compared with those treated at bony sites (75%; P = 0.04). Patients with clear cell histology had the lowest response rates (AR, 60%) compared with those with serous (82%), endometrioid (95%), or other Müllerian histology (85%; P = 0.01). Platinum status at diagnosis or the time of RT was not associated with response, nor was tumor size or number of prior chemotherapy regimens. On multivariate analysis, histology, RT indication, and RT dose were independent predictors of response (all P < 0.01). CONCLUSIONS: Palliative RT provides relief of pain and bleeding in most patients with ovarian cancer recurrence. Patients with symptomatic obstruction, bony involvement, and clear cell histology may experience lower clinical response rates.

"Flabulously" femme: Queer fat femme women's identities and experiences.

This article explores how queer fat femme women experience, negotiate, and resist heteronormativity, misogyny, and fatphobia, alongside other intersecting oppressions. By analyzing fat femmes' narratives presented in blogs and personal essays, this article examines themes including: the role of femme in fat queers (re)claiming femininities, the masculinizing and/or feminizing effects of "fatness" for queer femmes, the mutual constitution of fatphobia and femmephobia, femme fa(t)shion, fat femme (in)visibility, and the importance of intersectional conceptions of queer fat femininities. In doing so, this article argues that "queer fat femme" subjectivities offer fat and femme queers unique and significant opportunities for articulating resistant subjectivities, creating communities, and challenging oppressions.

Influence of Income, Education, and Medicaid Expansion on Palliative Care in Acute Myeloid Leukemia Using the National Cancer Database.

Palliative care is integral to symptom management, and we examined its relationship with income, education, and Medicaid expansion in acute myeloid leukemia. This was a retrospective cross-sectional study using the National Cancer Database that included patients with acute myeloid and monocytic leukemias > 18 years of age treated at Commission on Cancer facilities from 2004 to 2016. Univariate and multivariate models were adjusted for demographic variables and facility characteristics. There were 124,988 patients, but only 106,495 had palliative care data, and of this 4111 (3%) received palliative care. The most educated had the highest odds of receiving palliative care (odds ratio, OR 1.23, 95% CI 1.08-1.41; P = 0.002), but the highest income bracket (≥ $63,333) had the lowest odds (OR 0.82, 95% CI 0.72-0.93; P = 0.003). Residence in states with Medicaid expansion (January 2014 onward) had greater palliative care utilization. Palliative care use was associated with higher education but underutilized with higher incomes. Increased access with Medicaid expansion suggests the importance of public insurance.

Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: a prospective cohort study.

BACKGROUND: The prevalence of extensively drug-resistant (XDR) tuberculosis is increasing due to the expanded use of second-line drugs in people with multidrug-resistant (MDR) disease. We prospectively assessed resistance to second-line antituberculosis drugs in eight countries. METHODS: From Jan 1, 2005, to Dec 31, 2008, we enrolled consecutive adults with locally confirmed pulmonary MDR tuberculosis at the start of second-line treatment in Estonia, Latvia, Peru, Philippines, Russia, South Africa, South Korea, and Thailand. Drug-susceptibility testing for study purposes was done centrally at the Centers for Disease Control and Prevention for 11 first-line and second-line drugs. We compared the results with clinical and epidemiological data to identify risk factors for resistance to second-line drugs and XDR tuberculosis. FINDINGS: Among 1278 patients, 43·7% showed resistance to at least one second-line drug, 20·0% to at least one second-line injectable drug, and 12·9% to at least one fluoroquinolone. 6·7% of patients had XDR tuberculosis (range across study sites 0·8-15·2%). Previous treatment with second-line drugs was consistently the strongest risk factor for resistance to these drugs, which increased the risk of XDR tuberculosis by more than four times. Fluoroquinolone resistance and XDR tuberculosis were more frequent in women than in men. Unemployment, alcohol abuse, and smoking were associated with resistance to second-line injectable drugs across countries. Other risk factors differed between drugs and countries. INTERPRETATION: Previous treatment with second-line drugs is a strong, consistent risk factor for resistance to these drugs, including XDR tuberculosis. Representative drug-susceptibility results could guide in-country policies for laboratory capacity and diagnostic strategies. FUNDING: US Agency for International Development, Centers for Disease Control and Prevention, National Institutes of Health/National Institute of Allergy and Infectious Diseases, and Korean Ministry of Health and Welfare.

EVALI Vaping Liquids Part 1: GC-MS Cannabinoids Profiles and Identification of Unnatural THC Isomers.

Tetrahydrocannabinol (THC)-containing products played a major role in the 2019 US nationwide outbreak of pulmonary lung illness associated with e-cigarettes or vaping liquids (EVALI). Due to the severity of the illness which resulted in 68 deaths, a comprehensive identification of the components in the vaping liquids was required. Our laboratory received over 1000 vaping liquid products for analysis including hundreds of vaping products from EVALI patients. In this work, we present the results for the GC-MS identification of the cannabinoids from a large subset of ca. 300 Cannabis-based vaping liquids, with emphasis on the identification of a series of unnatural THC isomers. GC-MS analysis was conducted using a validated, published method in which the cannabinoids were identified as the trimethylsilyl derivatives after separation on a commercial 35% silphenylene phase. Δ9- Tetrahydrocannabinol is the naturally occurring THC isomer found in the Cannabis plant, and was found in the majority of the vaping liquids. However, we also identified the presence of one or more additional THC isomers in many of the vaping liquids including Δ8-tetrahydrocannabinol, Δ6a,10a-tetrahydrocannabinol, Δ10-tetrahydrocannabinol, and exo-tetrahydrocannabinol. Significant or major amounts of unnatural THC isomers were found in over 10% of the THC vaping liquids, with lesser amounts found in another 60% of the vaping liquids. Exposure of the Cannabis source materials (such as marijuana concentrates or converted hemp materials) to chemical and thermal treatments during manufacturing, is proposed as the primary cause for the THC isomerizations.

EVALI Vaping Liquids Part 2: Mass Spectrometric Identification of Diluents and Additives.

The vaping liquid additive vitamin E acetate (VEA) was strongly linked to the 2019 United States nationwide outbreak of pulmonary lung illness (EVALI) associated with e-cigarettes or vaping liquids. Our laboratory received over 1,000 vaping liquid products for identification of the vaping liquid additives, including hundreds of vaping products from EVALI patients. In this work, we present results obtained for the GC-MS identification of numerous vaping liquid additives in a large subset of ca. 300 Cannabis vaping liquids, including vitamin E acetate, medium chain triglycerides oil (MCT oil), polyethylene glycols, squalane, triethyl citrate, dipropylene glycol dibenzoate (DPG dibenzoate), pine rosin acids, pine rosin methyl esters, and sucrose acetate isobutyrate (SAIB). Confirmation of DPG dibenzoate and SAIB using LC-HRMS is also presented. GC-MS analysis for additives identified as the parent compounds was conducted after separation on a commercial 5% phenyl phase. GC-MS analysis for additives identified as the trimethylsilyl derivatives was conducted after separation on a commercial 35% silphenylene phase. LC-HRMS analysis was conducted using gradient elution with either C18 or phenyl-hexyl phases and determination of exact masses for the target compounds. In addition to providing rapid methods for the identification of vaping liquid additives, this work highlights the variety of Cannabis vaping liquid additives in current use.

"It's Not Just About a Paycheck": Perspectives on Employment Preparation of Students With Intellectual Disability in Federally Funded Higher Education Programs.

Students with intellectual disability (ID) are increasingly attending postsecondary education institutions and acquiring work experiences while completing their studies. One of the main motivations for students with ID to seek higher education is to broaden and increase their chance for finding fulfilling, paid employment in their communities. Findings from a qualitative study on staff perspectives regarding career development and employment supports and services provided to students attending Transition and Postsecondary Education Programs for Students With Intellectual Disability (TPSID) model demonstration programs in the United States are presented. Results reflect consensus across program staff regarding the goals and expectations for employment of TPSID students. Programs vary considerably in their institutional context, their partnership with other entities, and the structure of employment services, as well as the emphasis placed on paid versus unpaid employment. Some of the key strategies shared by staff regarding successful student employment practices involved outreach and engagement, visibility on campus, improving access to career services, and cultivating partnerships. As higher education continues to expand its offerings to students with ID, postsecondary education programs need to continue to emphasize and honor the importance of paid employment, and continue to seek the best methods to achieve this outcome for students with ID.

Characteristics of Patients and Treatment Recommendations from a Multidisciplinary Spinal Tumor Program.

Objective: We describe characteristics of patient and treatment recommendations from a spinal tumor board at one institution, including representation from palliative care. Background: The impact of prospective multidisciplinary input for patients with spinal tumors is poorly understood despite their increasing complexity. Methods: We retrospectively reviewed 622 cases sequentially discussed at a weekly spinal tumor board, and abstracted patient and treatment information from the medical record and meeting minutes. Results: From April 2017 to February 2019, 622 cases representing 438 unique patients were discussed. The median age was 62 years (range 21-92). Most patients had spinal tumors originating from metastases (91.78%), including breast (14.3%), nonsmall cell lung cancer (13.4%), prostate (10.9%), and renal cell cancer (8.8%), and the remainder had primary central nervous system (4.3%) or benign tumors (3.9%). Sixty-five percent of patients were alive at last follow-up. Conventional external beam radiotherapy was the most common treatment recommendation (33.8%) followed by surgery (26.2%), stereotactic body radiation therapy (17.8%), imaging follow-up (16.6%), and vertebroplasty (15.9%). Palliative care was the primary treatment recommended for 4.5%, and no therapy recommended for 4.0%. Treatment recommendation involved two modalities for 29% of cases, and three in 1.3% of cases. In four cases, biopsy to confirm pathology changed management due to unexpected findings of osteomyelitis, hematopoiesis, or new diagnosis of plasmacytoma. Conclusions: Multidisciplinary input is integral to the optimal care of spinal tumor patients. The high risk of death highlights the need to prioritize modalities that optimize quality of life in the context of a patient's individual prognosis.

Effect of aging on bioaccessibility of DDTs and PCBs in marine sediment.

Hydrophobic legacy contaminants like dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs) were banned almost half a century ago. While their residues still remain in many environmental compartments, they have undergone extensive aging and likely have lower bioaccessibility (the available fraction) compared to fresh residues. However, risk assessment relies heavily on the use of total chemical concentration, rather than accounting for age-diminished bioaccessibility, likely leading to overestimated risks. In this study, we used 24 h Tenax desorption to measure the potential bioaccessibility of DDTs and PCBs in two sediment cores taken from the Palos Verdes Shelf Superfund site in the Pacific Ocean. The total concentrations of DDTs and PCBs from the core located at the sewage outfall (8C) were as high as 41,000-15,700 µg/kg (dry weight, dw) and 530-2600 µg/kg dw, respectively, while those from a location 7 km northeast of the outfall (3C) were 2-3 orders of magnitude lower. Bioaccessibility estimated by 24-h Tenax-aided desorption (F24h) decreased in the order of DDD > DDE > DDT for DDT derivatives, and PCB 52 > PCB 70 > PCB 153 for PCB congeners, showing a negative correlation with their log Kow. Due to the extensive aging, F24h values were <20% of the total chemical concentration for most contaminants and <5% for DDT, DDE and PCB 153, suggesting that aging greatly diminished their bioavailability. However, a quantitative relationship between F24h and sediment age along the vertical profile was not found, likely because the contaminant residues had undergone aging before their offsite transport and deposition onto the ocean floor. As the use of man-made chemicals such as DDT and PCBs was discontinued in the U.S. many decades ago, the reduction in their bioavailability due to aging may be universal and should be taken into consideration to avoid overly conservative risk predictions or unnecessary mitigation interventions.

Palliative Radiation Therapy for Vertebral Metastases and Metastatic Cord Compression in Patients Treated With Anti-PD-1 Therapy.

Background: There is increasing use of immune checkpoint blockade (ICB) across multiple cancer types, including in patients at risk for vertebral metastases and cord compression. These patients are often treated with palliative radiotherapy (PRT); however, data evaluating the combination of PRT and ICB in patients with vertebral metastases is limited. Furthermore, patients with cord compression are generally excluded from prospective clinical trials. Therefore, we retrospectively evaluated outcomes following PRT and PD-1 inhibition in patients with vertebral metastases. Methods: We performed a retrospective chart review of 37 consecutive patients (total 57 lesions) treated with radiation for vertebral metastases who also received PD-1 inhibition. Patient, treatment and outcomes data were abstracted from the medical records. Results: Histologies included non-small cell lung cancer (n = 21), renal cell carcinoma (n = 9) and melanoma (n = 7). Out of 57 lesions,18 involved >1 segments of the vertebral column. There were isolated lesions in thoracic (16), lumbar (9), cervical (6), and sacral (8) vertebrae. Presenting symptoms included pain (19), numbness (10), and weakness (3). Eleven patients were asymptomatic. Radiologic cord compression was present in 12, epidural extension in 28 and compression fracture in 14. Eleven patients underwent surgical decompression prior to the onset of RT. Median radiation dose was 24 Gy (range 8-30 Gy). Stereotactic radiation was delivered in 4 patients; 33 patients received conformal RT. 21 patients received PD-1 inhibition after RT, 9 before RT and 7 with RT. Seven patients received concurrent CTLA-4 inhibitors with anti-PD-1 therapy. Treatment was in general well-tolerated. Toxicities included fatigue (6), transient pain flare (1), nausea/vomiting (1) and G1 skin changes (1). All patients reported some degree of pain relief. Numbness/weakness was improved in 6 of 13 patients with baseline symptoms (46%) and this was more likely in patients that received vertebral radiation after starting PD-1 inhibitors (71 vs. 17%, p = 0.04). Most patients (22 of 33 evaluable patients, 67%) had stability of irradiated lesions on subsequent follow up imaging performed at median of 30 days from RT, whereas 3 had a complete local response and 4 had a partial local response. Conclusions: We demonstrate that PRT administered to vertebral metastases was well-tolerated and effective in patients treated with PD-1 inhibitors. There was an encouraging rate of pain reduction and neurological improvement.

The Impact of Radiation Therapy on Lymphocyte Count and Survival in Metastatic Cancer Patients Receiving PD-1 Immune Checkpoint Inhibitors.

PURPOSE: Therapeutic radiation has conflicting immune effects: radiation therapy (RT)-induced immunogenic cell death can contribute to immune response, but lymphocytes are also sensitive to RT. It is unknown whether palliative RT leads to lymphopenia in patients treated with immune checkpoint inhibitors (ICIs) and whether this affects outcomes. As such, we sought to assess the impact of palliative RT on circulating lymphocyte count and neutrophil-to-lymphocyte ratio in patients being treated with PD-1-directed ICI and associations with survival. METHODS AND MATERIALS: We identified patients from 5 radiation oncology centers, treated with palliative RT and either pembrolizumab or nivolumab with non-small cell lung cancer, metastatic melanoma, and renal cell carcinoma. Patients who received intervening cytotoxic chemotherapy were excluded. We recorded absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio before and after palliative RT and at the start of ICI. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazard models. RESULTS: One hundred ten patients received 225 courses of palliative RT. Median change in ALC after RT was -161 cells/mL. Decreases in ALC were greater with RT to the spine, lung/mediastinum, and chest wall compared with the brain, extremity, or abdomen/pelvis (P = .002) and after courses >5 fractions (P = .003). Extracranial and >5-fraction RT was associated with increased odds of severe lymphopenia (ALC <500) at the end of RT (odds ratio [OR], 3.7; P = .001; and OR, 3.9; P = .001, respectively). Patients who developed RT-induced severe lymphopenia were more likely to have severe lymphopenia when ICI was initiated (OR, 6.4; P = .0001), particularly when RT was administered in the previous 3 months (OR, 189; P < .0001). Severe lymphopenia at onset of ICI therapy was associated with increased mortality on multivariable analysis (hazard ratio, 2.1; P = .03). CONCLUSIONS: Extracranial or prolonged courses of RT increase the risk of severe lymphopenia, which is associated with poorer survival in patients treated with ICI.

Rational design of a trimeric APRIL-based CAR-binding domain enables efficient targeting of multiple myeloma.

Chimeric antigen receptor (CAR) T cells (CARTs) have shown tremendous potential for the treatment of certain B-cell malignancies, including patients with relapsed/refractory multiple myeloma (MM). Targeting the B-cell maturation antigen (BCMA) has produced the most promising results for CART therapy of MM to date, but not all remissions are sustained. Emergence of BCMA escape variants has been reported under the selective pressure of monospecific anti-BCMA CART treatment. Thus, there is a clinical need for continuous improvement of CART therapies for MM. Here, we show that a novel trimeric APRIL (a proliferation-inducing ligand)-based CAR efficiently targets both BCMA+ and BCMA- MM. Modeled after the natural ligand-receptor pair, APRIL-based CARs allow for bispecific targeting of the MM-associated antigens BCMA and transmembrane activator and CAML interactor (TACI). However, natural ligands as CAR antigen-binding domains may require further engineering to promote optimal binding and multimerization to adequately trigger T-cell activation. We found that using a trimeric rather than a monomeric APRIL format as the antigen-binding domain enhanced binding to BCMA and TACI and CART activity against MM in vitro and in vivo. Dual-specific, trimeric APRIL-based CAR are a promising therapeutic approach for MM with potential for preventing and treating BCMA escape.