Effects of low-dose naltrexone on quality of life in high-grade glioma patients: a placebo-controlled, double-blind randomized trial.

PURPOSE: At diagnosis and throughout the disease course, patients with high-grade glioma (HGG) experience a diminished quality of life (QOL) and increased fatigue. Naltrexone, an orally semisynthetic opiate antagonist, is FDA-approved for the treatment of heroin/alcohol addiction, and low-dose naltrexone (LDN) has been observed to improve QOL and lower fatigue in other neurological illnesses, such as multiple sclerosis. LDN is believed to function as a partial agonist and can lead to shifts in neurochemicals that reduce fatigue. Based on this, we sought to study whether LDN has an impact on QOL and fatigue in patients with HGG. METHODS: In a placebo-controlled, double-blind study, we randomized 110 HGG patients to receive placebo (N = 56) or LDN 4.5 mg orally at night (N = 54). Subjects received LDN or placebo at day 1 of concurrent radiation and temozolomide therapy and continued for 16 weeks. Change from baseline in patient-reported outcomes of QOL (Functional Assessment of Cancer Therapy-Brain) and fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue) was assessed. RESULTS: Demographics were WHO grade IV (85%), male (56%), KPS 90-100 (51%), grossly resected (55%), and mean age of 56 years. QOL and fatigue changes between baseline and post concurrent chemotherapy and radiation therapy were not significantly different between patients receiving LDN or placebo. The adverse event profiles for LDN and placebo were similar and attributed to concomitant use of temozolomide. CONCLUSIONS: LDN has no effect on QOL and fatigue in HGG patients during concurrent chemotherapy and radiation therapy. TRIAL REGISTRATION: United States National Library of Medicine Clinical Trials.gov NCT01303835, Date 2/25/2011.

A prospective trial of abiraterone acetate plus prednisone in Black and White men with metastatic castrate-resistant prostate cancer.

BACKGROUND: Retrospective analyses of randomized trials suggest that Black men with metastatic castration-resistant prostate cancer (mCRPC) have longer survival than White men. The authors conducted a prospective study of abiraterone acetate plus prednisone to explore outcomes by race. METHODS: This race-stratified, multicenter study estimated radiographic progression-free survival (rPFS) in Black and White men with mCRPC. Secondary end points included prostate-specific antigen (PSA) kinetics, overall survival (OS), and safety. Exploratory analysis included genome-wide genotyping to identify single nucleotide polymorphisms associated with progression in a model incorporating genetic ancestry. One hundred patients self-identified as White (n = 50) or Black (n = 50) were enrolled. Eligibility criteria were modified to facilitate the enrollment of individual Black patients. RESULTS: The median rPFS for Black and White patients was 16.6 and 16.8 months, respectively; their times to PSA progression (TTP) were 16.6 and 11.5 months, respectively; and their OS was 35.9 and 35.7 months, respectively. Estimated rates of PSA decline by ≥50% in Black and White patients were 74% and 66%, respectively; and PSA declines to <0.2 ng/mL were 26% and 10%, respectively. Rates of grade 3 and 4 hypertension, hypokalemia, and hyperglycemia were higher in Black men. CONCLUSIONS: Multicenter prospective studies by race are feasible in men with mCRPC but require less restrictive eligibility. Despite higher comorbidity rates, Black patients demonstrated rPFS and OS similar to those of White patients and trended toward greater TTP and PSA declines, consistent with retrospective reports. Importantly, Black men may have higher side-effect rates than White men. This exploratory genome-wide analysis of TTP identified a possible candidate marker of ancestry-dependent treatment outcomes.

Patterns of relapse after successful completion of initial therapy in primary central nervous system lymphoma: a case series.

PURPOSE: Primary central nervous system lymphoma (PCNSL) is a subtype of non-Hodgkin's lymphoma that involves the brain, spinal cord, or leptomeninges, without evidence of systemic disease. This rare disease accounts for ~ 3% of all primary central nervous system (CNS) tumors. Methotrexate-based regimens are the standard of care for this disease with overall survival rates ranging from 14 to 55 months. Relapse after apparent complete remission can occur. We sought to understand the outcomes of patients who relapsed. METHODS: This is an IRB-approved investigation of patients treated at our institution between 12/31/2004 and 10/12/2016. We retrospectively identified all cases of PCNSL as part of a database registry and evaluated these cases for demographic information, absence or presence of relapse, location of relapse, treatment regimens, and median relapse-free survival. RESULTS: This analysis identified 44 patients with a pathologically confirmed diagnosis of PCNSL. Mean age at diagnosis was 63.1 years (range 20-86, SD = 13.2 years). Of the 44 patients, 28 patients successfully completed an initial treatment regimen without recurrence or toxicity that required a change in therapy. Relapse occurred in 11 patients with the location of relapse being in the CNS only (n = 5), vitreous fluid only (n = 1), outside CNS only (n = 3), or a combination of CNS and outside of the CNS (n = 2). Sites of relapse outside of the CNS included testes (n = 1), lung (n = 1), adrenal gland (n = 1), kidney/adrenal gland (n = 1), and retroperitoneum (n = 1). Median relapse-free survival after successful completion of therapy was 6.7 years (95% CI 1.1, 12.6). CONCLUSION: After successful initial treatment, PCNSL has a propensity to relapse, and this relapse can occur both inside and outside of the CNS. Vigilant monitoring of off-treatment patients with a history of PCNSL is necessary to guide early diagnosis of relapse and to initiate aggressive treatment.

Randomized open-label phase II trial of 5-day aprepitant plus ondansetron compared to ondansetron alone in the prevention of chemotherapy-induced nausea-vomiting (CINV) in glioma patients receiving adjuvant temozolomide.

PURPOSE: CINV remains a distressing side effect experienced by glioma patients receiving multi-day temozolomide therapy, in spite of guideline-based antiemetic therapy with selective serotonin-receptor-antagonists. Antiemetic research with aprepitant has routinely excluded glioma patients. In this randomized open-label phase II study, use of a nonstandard 5-day regimen of aprepitant for glioma patients was investigated. METHODS: One hundred thirty-six glioma patients receiving their first cycle of adjuvant temozolomide (150-200 mg/m2/day × 5 days every 28 days) were randomized to Arm-A (ondansetron 8 mg days 1-5 with aprepitant day 1: 125 mg, days 2-5: 80 mg) or Arm-B (ondansetron). Randomization was stratified by tumor grade and number of prior chemotherapy regimens. The primary endpoint was the percentage of patients achieving complete control (CC), defined as no emetic episode or antiemetic rescue medication over the 7-day study period. Secondary endpoints included CINV efficacy in the acute phase (≤ 24 h) and delayed phase (days 2-7), as well as safety and quality of life (QoL). RESULTS: Patients were 61% male, 97% white, 48% with KPS > 90%, 60% non-smokers, mean age 54, 92% with low alcohol use, and 46% with a CINV history. The CC was 58.6% (Arm-A) and 54.5% (Arm-B). Acute-complete response (CR) rates, defined as CC on day 1 in Arm-A and -B, were 97.1% and 87.9%, respectively (p = 0.056). Treatment-related toxicities were mild or moderate in severity. CONCLUSIONS: Aprepitant plus ondansetron may increase acute-CR, may have benefit regarding CINV's effect on QoL, and is safe for 5-day temozolomide compared to ondansetron. This study provides no evidence that aprepitant increases CC rate over ondansetron alone.

Phase 1b trial of docetaxel, prednisone, and pazopanib in men with metastatic castration-resistant prostate cancer.

BACKGROUND: Docetaxel prednisone is a standard of care for men with metastatic castration-resistant prostate cancer (mCRPC), and plasma vascular endothelial growth factor (VEGF) levels are a poor prognostic factor in this population; therefore, we evaluated the combination of docetaxel prednisone with pazopanib, an oral VEGF receptor inhibitor, for safety and preliminary efficacy. METHODS: This is a two-site phase 1b Department of Defense Prostate Cancer Clinical Trials Consortium trial of docetaxel, prednisone, and pazopanib once daily and ongoing androgen deprivation therapy and prophylactic pegfilgrastim in men with mCRPC. The primary endpoint was safety and the determination of a maximum tolerated dose (MTD) through a dose-escalation and expansion design; secondary endpoints included progression-free and overall survival (OS), prostate specific antigen (PSA) declines, radiographic responses, and pharmacokinetic and plasma angiokine biomarker analyses. RESULTS: Twenty-five men were treated over six dose levels. Pegfilgrastim was added to the regimen after myelosuppression limited dose escalation. With pegfilgrastim, our target MTD of docetaxel 75 mg/m2 q3 weeks; prednisone 10 mg daily; and pazopanib 800 mg daily was reached. Eleven additional patients were accrued at this dose level for a total of 36 patients. Dose-limiting toxicities included neutropenia, syncope, and hypertension. Three deaths attributed to study treatment occurred. The objective response rate was 31%; median PFS was 14.1 months (95% confidence interval [CI]: 7.1 and 22.2); and OS was 18.6 months (95% CI: 11.8 and 22.2). CONCLUSIONS: The combination of docetaxel, prednisone, and pazopanib (with pegfilgrastim) was tolerable at full doses and demonstrated promising efficacy in a relatively poor risk patients with mCRPC. Further development of predictive biomarkers may enrich for patients who receive clinical benefit from this regimen.

Phase Ib Trial of Cabazitaxel and Tasquinimod in Men With Heavily Pretreated Metastatic Castration Resistant Prostate Cancer (mCRPC): The CATCH Trial.

BACKGROUND: Tasquinimod is an immunomodulating and anti-antiangiogenic oral agent with anti-prostate cancer activity in preclinical studies and in clinical trials of men with metastatic castration resistant prostate cancer (mCRPC), including single agent activity and in combination with taxanes. We sought to identify the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of tasquinimod in combination with cabazitaxel and prednisone in men with chemorefractory mCRPC. METHODS: Men with mCRPC who had failed prior docetaxel chemotherapy received cabazitaxel 25 mg/m2 every 3 weeks with oral tasquinimod at 1 of 3 escalating dose levels (0.25, 0.5, and 1.0 mg once daily) with prednisone and PEG-filgastrim support, using a 3 + 3 dose escalation design. Treatment continued until progressive disease or unacceptable toxicity. RESULTS: We enrolled 25 men with chemorefractory mCRPC. The RP2D was 0.5 mg tasquinimod based on excess DLTs (two of three men) observed at dose level 3 (1.0 mg) including grade 3 sensory neuropathy and grade 3 atrial fibrillation. Dose level 2 was expanded to 14 men, where 3 DLTs were observed: grade 3 fatigue, grade 4 febrile neutropenia, and grade 3 liver function abnormalities. The proportion of men with a ≥30% PSA decline was 63% and the median composite progression-free survival (PFS) was 8.5 months (95% CI 4.2-16.4 months) based on 12 PFS events. The median number of cycles of cabazitaxel was 6 (range 1-13), with six men receiving >10 cycles. Best overall RECIST responses (CR + PR) were observed in three men (12%), with stable disease in 12 (48%). No pharmacokinetic interactions were observed. CONCLUSIONS: We determined the RP2D of tasquinimod combined with cabazitaxel to be 0.5 mg daily following a 3 week lead-in of tasquinimod 0.25 mg with growth factor support. No unexpected toxicities occurred. Prostate 77: 385-395, 2017. © 2016 Wiley Periodicals, Inc.

A cross sectional analysis from a single institution's experience of psychosocial distress and health-related quality of life in the primary brain tumor population.

Primary brain tumor patients experience high levels of distress. The purpose of this cross-sectional, retrospective study is to evaluate the level and different sources of psychosocial distress and how these pertain to health-related quality of life (HRQoL). The Primary and Recurrent Glioma registry at Duke's The Preston Robert Tisch Brain Tumor Center was queried retrospectively for demographic and clinical information on patients seen between December 2013 and February 2014. Data also included the National Comprehensive Cancer Network's Distress Thermometer (NCCN-DT), Functional Assessment of Cancer Therapy-Brain Cancer (FACT-Br), and Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-F). 829 subjects completed questionnaires. 54% were male; 96% completed the NCCN-DT; 33.3% had a DT score ≥4 (moderate/severe distress). Women reported DT ≥ 4 more often than men (38.6 vs 29.0%; p = 0.005). Patients within 1 year of diagnosis reported DT ≥ 4 more often than those 1+ years after diagnosis (38.8 vs 30.9%; p = 0.034). 73.0% reported physical problems; the most frequent being fatigue (43.2%) and memory/concentration (40.9%). 42.0% complained of emotional problems with worry (29.4%) and nervousness (22.4%) being the most common. Patients who reported at least one practical, family, emotional or physical problem had significantly lower HRQoL scores (p < 0.001). Primary brain tumor patients experience memory dysfunction, fatigue, nervousness, worry, and financial concerns, which have a negative effect on the patient's HRQoL. By identifying and addressing these stressors, it may be possible to improve patient HRQoL.

Serum elevation of B lymphocyte stimulator does not increase regulatory B cells in glioblastoma patients undergoing immunotherapy.

Regulatory B cells that secrete IL-10 (IL-10(+) Bregs) represent a suppressive subset of the B cell compartment with prominent anti-inflammatory capacity, capable of suppressing cellular and humoral responses to cancer and vaccines. B lymphocyte stimulator (BLyS) is a key regulatory molecule in IL-10(+) Breg biology with tightly controlled serum levels. However, BLyS levels can be drastically altered upon chemotherapeutic intervention. We have previously shown that serum BLyS levels are elevated, and directly associated, with increased antigen-specific antibody titers in patients with glioblastoma (GBM) undergoing lymphodepletive temozolomide chemotherapy and vaccination. In this study, we examined corresponding IL-10(+) Breg responses within this patient population and demonstrate that the IL-10(+) Breg compartment remains constant before and after administration of the vaccine, despite elevated BLyS levels in circulation. IL-10(+) Breg frequencies were not associated with serum BLyS levels, and ex vivo stimulation with a physiologically relevant concentration of BLyS did not increase IL-10(+) Breg frequency. However, BLyS stimulation did increase the frequency of the overall B cell compartment and promoted B cell proliferation upon B cell receptor engagement. Therefore, using BLyS as an adjuvant with therapeutic peptide vaccination could promote humoral immunity with no increase in immunosuppressive IL-10(+) Bregs. These results have implications for modulating humoral responses in human peptide vaccine trials in patients with GBM.

Phase II study to evaluate the safety and efficacy of intravenous palonosetron (PAL) in primary malignant glioma (MG) patients receiving standard radiotherapy (RT) and concomitant temozolomide (TMZ).

BACKGROUND: In malignant glioma (MG) patients undergoing radiation therapy (RT) with concomitant temozolomide, chemoradiation-induced nausea and vomiting (cRINV) degrades quality of life (QoL) and reduces treatment adherence, which thereby potentially compromises cancer control. METHODS: We conducted a 6-week phase II single-arm trial of PAL, a second-generation 5-HT3RA antiemetic, for cRINV prevention in MG patients receiving radiation therapy (RT; 54-60 Gy) and concomitant daily temozolomide (TMZ; 75 mg/m(2)/dX42d). Each week before radiation, patients received single-dose palonosetron (PAL) 0.25 mg IV (total = 6 doses). With safety/tolerability as the primary endpoint, the study was designed to differentiate between toxicity rates of 25 % (unacceptable) and 10 % (acceptable) toxicity rates. Secondary endpoints included the percentage of patients achieving cRINV complete response (CR: no emesis or rescue antiemetic) and QoL. Patients reported adverse effects in Common Toxicity Criteria for Adverse Events diaries; recorded vomiting, nausea, and rescue medication use in diaries (which were used to assess cRINV-CR); and reported QoL 4 days/week using the Modified Functional Living Index-Emesis (M-FLIE) and Osoba nausea and vomiting/retching modules. RESULTS: We enrolled 38 patients (mean age 59 years, 55 % female, 95 % white, 68 % used oral corticosteroids, 76 % reported low alcohol use). Four patients (10.5 %) experienced unacceptable treatment-related toxicity, defined as any grade 3, 4, or 5 non-hematologic toxicity. M-FLIE and Osoba scores showed no evidence of treatment impact on QoL. Overall, cRINV-CR rates for 6 weeks ranged from 67-79 %. CONCLUSION: Single-dose weekly PAL is a safe and tolerable antiemetic for cRINV prevention in MG patients receiving standard RT and concomitant TMZ.

Prognostic marker analysis in pediatric intracranial ependymomas.

Histologic grading methods dependent upon H&E staining review have not been shown to reliably predict survival in children with intracranial ependymomas due to the subjectivity of the analytical methods. We hypothesized that the immunohistochemical detection of MIB-1, Tenascin C, CD34, VEGF, and CA IX may represent objective markers of post-operative survival (Progression Free and Overall Survival; PFS, OS) in these patients. Intracranial ependymomas from patients aged 22 years or less were studied. The original histologic grade was recorded, H&E sections were reviewed for vascular proliferation status, and immunohistochemistry was used to determine MIB-1, Tenascin C, CD34, VEGF, and CA IX status. Based upon the World Health Organization (WHO) grading system, 3 Grade I, 18 Grade II and 9 Grade III ependymomas were studied. Median follow-up time was 9.0 years; median PFS was, 6.1 years. Original WHO grade did not correlate with PFS or OS. Peri-necrotic CA IX localization correlated with PFS (Log rank = 0.0181) and OS (Log rank p = 0.0015). All patients with a CA IX ≤ 5 % total area localization were alive at last follow-up. Perinecrotic CA IX staining was also associated with vascular proliferation (p = 0.006), though not with VEGF expression score. MIB-1 labeling index (LI) correlated with OS (HR 1.06, 95 % CI 1.01, 1.12) and PFS (HR 1.08, 95 % CI 1.02, 1.14). MIB-1 LI and perinecrotic CA IX individually correlated with PFS. The effect of perinecrotic CA IX remained when grade was added to a Cox model predicting PFS. Immunodetection of CA IX and MIB-1 expression are predictive biomarkers for survival in children with posterior fossa ependymomas. These markers represent objective indicators of survival that supplement H&E grading alone.

Invasive ductal carcinoma with lobular features: a comparison study to invasive ductal and invasive lobular carcinomas of the breast.

Invasive ductal carcinoma with lobular features (IDC-L) is not recognized as a distinct subtype of breast cancer, and its clinicopathologic features and outcomes are unknown. In this retrospective study, we focused on characterization of clinicopathologic features and outcomes of IDC-L and compared them to invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC). 183 cases of IDC-L from 1996 to 2011 were compared with 1,499 cases of IDC and 375 cases of ILC. Available slides of IDC-L (n = 150) were reviewed to quantify the lobular component (≤ 20, 21-50, 51-80, >80 %), defined as small cells individually dispersed, arranged in linear cords, or in loose aggregates without the formation of tubules or cohesive nests. E-cadherin immunostain was performed to confirm ductal origin. Compared to IDC, IDC-L was more likely to have lower histologic grade (p < 0.001), be positive for estrogen receptor (96 vs. 70 %; p < 0.0001) and progesterone receptor (84 vs. 57 %; p < 0.0001), and less likely to overexpress HER-2/neu (12 vs. 23 %; p = 0.001). Despite these favorable prognostic features, IDC-L had a higher frequency of nodal metastases (51 vs. 34 %; p < 0.0001) and a worse 5-year disease-free survival than IDC (hazard ratio = 0.454; p = 0.0004). ILC and IDC-L had similar clinicopathologic features and outcomes. The proportion of the lobular component in IDC-L had no impact on the size, nodal status, stage, or outcome. Our data suggest that although IDC-L may be a variant of IDC, with >90 % of cases being E-cadherin positive, the clinical and biological characteristics are more similar to that of ILC.

Cigarette smoking and gemcitabine-induced neutropenia in advanced solid tumors.

BACKGROUND: Chemotherapy-associated neutropenia has been reported to be a pharmacodynamic marker of response in some advanced solid tumors. Factors that accelerate drug clearance lead to lower plasma concentrations and toxicity, including neutropenia. Smoking accelerates the metabolism of several drugs, including chemotherapy. We sought to study the effects of smoking on gemcitabine-induced neutropenia in this retrospective study. METHODS: Smoking status and neutropenia along with other clinical parameters were recorded in 151 patients receiving first-line gemcitabine-based chemotherapy for advanced solid tumors. RESULTS: Tumor types included breast (9.3%), lung (4.6%), pancreatobiliary (70.9%), or other/unknown primary cancer (15.2%). Logistic regression showed that never smokers had increased neutropenia versus current smokers (odds ratio: 3.5; 95% confidence interval, CI: 1.1-11.4). A 5-unit increase in pack-years reduced the odds of having higher neutropenia toxicity by 6.3% (95% CI 12 to 1%; p = 0.036). CONCLUSION: Smokers had less neutropenia than nonsmokers, a finding that was more pronounced with increasing pack-years. This pharmacodynamic marker of gemcitabine-induced neutropenia may result in less efficacy of gemcitabine. Future prospective trials should correlate smoking, metabolizing phenotype, neutropenia, and response to gemcitabine therapy.

IL-4 induces proliferation in prostate cancer PC3 cells under nutrient-depletion stress through the activation of the JNK-pathway and survivin up-regulation.

Interleukin (IL)-4 plays a critical role in the regulation of immune responses and has been detected at high levels in the tumor microenvironment of cancer patients where it correlates with the grade of malignancy. The direct effect of IL-4 on cancer cells has been associated with increased cell survival; however, its role in cancer cell proliferation and related mechanisms is still unclear. Here it was shown that in a nutrient-depleted environment, IL-4 induces proliferation in prostate cancer PC3 cells. In these cells, under nutrient-depletion stress, IL-4 activates mitogen-activated protein kinases (MAPKs), including Erk, p38, and JNK. Using MAP-signaling-specific inhibitors, it was shown that IL-4-induced proliferation is mediated by JNK activation. In fact, JNK-inhibitor-V (JNKi-V) stunted IL-4-mediated cell proliferation. Furthermore, it was found that IL-4 induces survivin up-regulation in nutrient-depleted cancer cells. Using survivin-short-hairpin-RNAs (shRNAs), it was demonstrated that in this milieu survivin expression above a threshold limit is critical to the mechanism of IL-4-mediated proliferation. In addition, the significance of survivin up-regulation in a stressed environment was assessed in prostate cancer mouse xenografts. It was found that survivin knockdown decreases tumor progression in correlation with cancer cell proliferation. Furthermore, under nutrient depletion stress, IL -4 could induce proliferation in cancer cells from multiple origins: MDA-MB-231 (breast), A253 (head and neck), and SKOV-3 (ovarian). Overall, these findings suggest that in a tumor microenvironment under stress conditions, IL-4 triggers a simultaneous activation of the JNK-pathway and the up-regulation of survivin turning on a cancer proliferation mechanism.

Availability and role of clinical pharmacists in ambulatory neuro-oncology.

BACKGROUND: Outpatient clinics treating neuro-oncology patients are becoming more multidisciplinary. Utilization of all team members is critical for the holistic care of these complex patients. Specifically, the role of clinical pharmacist (CP) in the ambulatory clinic remains undefined and will likely evolve as more therapeutics are developed for CNS malignancies. We queried the Society for Neuro-Oncology (SNO) membership about the availability of a CP in their ambulatory setting and, if present, the role of that CP. METHODS: In an IRB-exempt study, we surveyed the SNO community and analyzed responses to queries about CPs in the ambulatory setting. RESULTS: Of the 65 SNO members who responded, 52 were clinical members. Of these 52 clinicians, the majority were physicians (88.5%, n = 46). Of these physicians, most were in academic practices (93.5%, n = 43). Over half of the 52 clinical respondents (51.9%, n = 27) reported that they saw ≥30 primary brain tumor patients per month, thus typifying busy clinics. Despite having busy clinics, only 12 (28.6%) of 42 providers with access to a CP reported that their CP was solely dedicated to neuro-oncology patients. For the respondents who had access to a CP, only ~two-thirds of those CPs had direct patient interaction. The top 3 roles of the CP included medication review, chemotherapy dosing/modifications, and practice guideline development; none of which involve direct patient interaction. CONCLUSIONS: We found that while our surveyed population of SNO clinical members have demanding outpatient practices, most do not have the support or expertise of dedicated neuro-oncology CPs.

Innovating in a crisis: a qualitative evaluation of a hospital and Google partnership to implement a COVID-19 inpatient video monitoring program.

OBJECTIVE: To describe adaptations necessary for effective use of direct-to-consumer (DTC) cameras in an inpatient setting, from the perspective of health care workers. METHODS: Our qualitative study included semi-structured interviews and focus groups with clinicians, information technology (IT) personnel, and health system leaders affiliated with the Mount Sinai Health System. All participants either worked in a coronavirus disease 2019 (COVID-19) unit with DTC cameras or participated in the camera implementation. Three researchers coded the transcripts independently and met weekly to discuss and resolve discrepancies. Abiding by inductive thematic analysis, coders revised the codebook until they reached saturation. All transcripts were coded in Dedoose using the final codebook. RESULTS: Frontline clinical staff, IT personnel, and health system leaders (N = 39) participated in individual interviews and focus groups in November 2020-April 2021. Our analysis identified 5 areas for effective DTC camera use: technology, patient monitoring, workflows, interpersonal relationships, and infrastructure. Participants described adaptations created to optimize camera use and opportunities for improvement necessary for sustained use. Non-COVID-19 patients tended to decline participation. DISCUSSION: Deploying DTC cameras on inpatient units required adaptations in many routine processes. Addressing consent, 2-way communication issues, patient privacy, and messaging about video monitoring could help facilitate a nimble rollout. Implementation and dissemination of inpatient video monitoring using DTC cameras requires input from patients and frontline staff. CONCLUSIONS: Given the resources and time it takes to implement a usable camera solution, other health systems might benefit from creating task forces to investigate their use before the next crisis.

Effectiveness of the internet-based Unified Protocol transdiagnostic intervention for the treatment of depression, anxiety and related disorders in a primary care setting: a randomized controlled trial.

BACKGROUND: Research has shown that internet-based cognitive behavioural therapy (iCBT) can be a very promising solution to increase access to and the dissemination of evidence-based treatments to all of the population in need. However, iCBT is still underutilized in clinical contexts, such as primary care. In order to achieve the effective implementation of these protocols, more studies in ecological settings are needed. The Unified Protocol (UP) is a transdiagnostic CBT protocol for the treatment of emotional disorders, which includes depression, anxiety and related disorders, that has shown its efficacy across different contexts and populations. An internet-based UP (iUP) programme has recently been developed as an emerging internet-based treatment for emotional disorders. However, the internet-delivered version of the UP (iUP) has not yet been examined empirically. The current project seeks to analyse the effectiveness of the iUP as a treatment for depression, anxiety and related emotional disorders in a primary care public health setting. METHODS: The current study will employ a parallel-group, randomized controlled trial design. Participants will be randomly assigned to (a) the internet-based Unified Protocol (iUP), or (b) enhanced waiting list control (eWLC). Randomization will follow a 2:1 allocation ratio, with sample size calculations suggesting a required sample of 120 (iUP=80; eWLC=40). The Mini-International Neuropsychiatric Interview (M.I.N.I.) will be used for assessing potential participants. The Overall Anxiety Severity and Impairment Scale (OASIS) and the Overall Depression Severity and Impairment Scale (ODSIS) as well as other standardized questionnaires will be used for assessments at baseline, 4 weeks, 8 weeks and 12 weeks from baseline and for the iUP condition during the follow-up. DISCUSSION: Combining the advantages of a transdiagnostic treatment with an online delivery format may have the potential to significantly lower the burden of emotional disorders in public health primary care setting. Anxiety and depression, often comorbid, are the most prevalent psychological disorders in primary care. Because the iUP allows for the treatment of different disorders and comorbidity, this treatment could represent an adequate choice for patients that demand mental health care in a primary care setting. TRIAL REGISTRATION: ISRCTN18056450 https://doi.org/10.1186/ISRCTN18056450 .

The SERK1 receptor-like kinase regulates organ separation in Arabidopsis flowers.

Through a sensitized screen for novel components of pathways regulating organ separation in Arabidopsis flowers, we have found that the leucine-rich repeat receptor-like kinase SOMATIC EMBRYOGENESIS RECEPTOR-LIKE KINASE1 (SERK1) acts as a negative regulator of abscission. Mutations in SERK1 dominantly rescue abscission in flowers without functional NEVERSHED (NEV), an ADP-ribosylation factor GTPase-activating protein required for floral organ shedding. We previously reported that the organization of the Golgi apparatus and location of the trans-Golgi network (TGN) are altered in nev mutant flowers. Disruption of SERK1 restores Golgi structure and the close association of the TGN in nev flowers, suggesting that defects in these organelles may be responsible for the block in abscission. We have also found that the abscission zones of nev serk1 flowers are enlarged compared to wild-type. A similar phenotype was previously observed in plants constitutively expressing a putative ligand required for organ separation, INFLORESCENCE DEFICIENT IN ABSCISSION (IDA), suggesting that signalling through IDA and its proposed receptors, HAESA and HAESA-LIKE2, may be deregulated in nev serk1 abscission zone cells. Our studies indicate that in addition to its previously characterized roles in stamen development and brassinosteroid perception, SERK1 plays a unique role in modulating the loss of cell adhesion that occurs during organ abscission.

Combination of Radiation Therapy and Short-Term Androgen Blockade With Abiraterone Acetate Plus Prednisone for Men With High- and Intermediate-Risk Localized Prostate Cancer.

PURPOSE: Long-term androgen-deprivation therapy (ADT) is the standard of care in combination with radiation therapy (RT) in high-risk prostate cancer (PC), despite substantial toxicity from the resulting hypogonadism. We hypothesized that a combination of more potent but shorter-term androgen inhibition in men with intermediate- or high-risk localized PC would synergize with definitive RT to provide short-term testosterone recovery and improve disease control. METHODS AND MATERIALS: This prospective phase 2 single-arm trial enrolled men with low-volume unfavorable intermediate or high-risk localized PC. Treatment included 6 months of ADT concurrent with abiraterone acetate plus prednisone (AAP) once daily and RT to prostate and seminal vesicles. The primary endpoint was the proportion of men with an undetectable prostate-specific antigen (PSA) at 12-months; secondary objectives included biochemical progression-free survival (PFS), testosterone recovery, toxicity, and sexual and hormonal quality of life. RESULTS: We enrolled 37 men between January 2014 and August 2016, 45% of whom were high risk. All patients had T1-2 disease and PSA < 20 ng/mL. Median follow-up is 37 months (95% confidence interval [CI], 35.7-39.1). Treatment noted 32% grade 3 toxicities related to AAP, predominantly hypertension, with no toxicities ≥G4. The rate of undetectable PSA at 12 months was 55% (95% CI, 36%-72%). With 46 months of median follow-up, 2 of 37 patients developed PSA progression (36-month PFS = 96%; 95% CI, 76%-99%), and 81% of patients recovered testosterone with a median time to recovery of 9.2 months. Hormonal or sexual function declined at 6 months with subsequent improvement by 24 months. CONCLUSIONS: The combination of RT and 6 months of ADT and AAP demonstrated acceptable toxicity and a high rate of testosterone recovery with restoration of quality of life and excellent disease control in men with low-volume, intermediate- or high-risk localized prostate cancer. Prospective comparative studies are justified.

Expression of immune checkpoints on circulating tumor cells in men with metastatic prostate cancer.

BACKGROUND: A subset of men with metastatic prostate cancer (mPC) responds to immune checkpoint inhibitors, and there is an unmet need to predict those most likely to benefit. We characterized circulating tumor cells (CTCs) for expression of immune checkpoint ligands in men with mPC as a non-invasive biomarker of immune evasion and immunotherapy benefit. METHODS: Three cohorts of patients were enrolled: 1) men with mCRPC starting abiraterone acetate/prednisone or enzalutamide (pre-ARSI), 2) men with mCRPC who were progressing on enzalutamide or abiraterone acetate/prednisone (post-ARSI), and 3) men with newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) starting androgen deprivation therapy. CTCs were captured using the CellSearch® system and stained for PD-L1, PD-L2, B7-H3, and CTLA-4 at baseline, on treatment, and disease progression. Summary statistics on mean CTCs per cohort, as well as rates of ligand positivity were used to analyze CTCs by cohort and by timepoint. RESULTS: Men in all cohorts and timepoints had prevalent CTC B7-H3 expression (> 80%). We found evidence for CTC PD-L1 expression across disease states, in which > 1 positive CTC or > 50% of CTCs were positive for PD-L1 in 40 and 30% of men with mHSPC, respectively, 60 and 20% of men with mCRPC pre-ARSI, and 70 and 30% of men with mCRPC post-ARSI. CTC PD-L2 expression was present in 20-40% of men in each disease state, while CTC CTLA-4 expression was rare, present in 20% of men with mCRPC pre-ARSI and 10% of men with mCRPC post-ARSI or with mHSPC. CTC immune checkpoint expression was heterogeneous within/between men and across disease states. CONCLUSIONS: We have identified that CTCs from men with mPC heterogeneously express immune checkpoints B7-H3, PD-L1, PD-L2, and CTLA-4, and the detection of these immune checkpoints may enable monitoring on immunotherapy.

Phase II Trial of Enzalutamide and Androgen Deprivation Therapy with Salvage Radiation in Men with High-risk Prostate-specific Antigen Recurrent Prostate Cancer: The STREAM Trial.

BACKGROUND: Salvage external beam radiotherapy (RT) with androgen deprivation therapy (ADT) improves survival over RT in men with prostate cancer (PC) and rising prostate-specific antigen (PSA) levels after radical prostatectomy (RP). OBJECTIVE: To investigate the safety and efficacy of enzalutamide concurrent with salvage RT and ADT. DESIGN, SETTING, AND PARTICIPANTS: This was a three-center prospective phase 2 single-arm trial (NCT02057939) of men with Gleason 7-10 PC and PSA recurrence within 4 yr of RP ranging from 0.2 to 4.0 ng/dl, no prior hormonal therapy, and no radiographic evidence of metastases. We enrolled 38 men; 37 completed therapy and were evaluable with testosterone recovery at 2 yr. INTERVENTION: Six months of ADT with 160 mg/d enzalutamide and 66 Gy RT to the prostate bed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was improved 2-yr progression-free survival (PFS) over historical controls. Secondary objectives included 3-yr PFS, safety, and patient-reported quality of life (QOL). RESULTS AND LIMITATIONS: The primary endpoint of 2-yr PFS was 65% (95% confidence interval [CI]: 47, 78) versus 51% (95% CI: 33, 67) in a trial of men with similar eligibility treated with salvage RT and adjuvant docetaxel. The 3-yr PFS was 53%. Eleven (29%) men experienced G3 toxicities, and there were no G4-5 or unexpected toxicities. QOL data suggest modest worsening of bowel, bladder, and hormonal symptoms at 3 mo, with recovery by 24 mo in most men. CONCLUSIONS: Salvage RT with enzalutamide and ADT following RP for men with PSA recurrent high-risk PC is safe and demonstrates encouraging efficacy, warranting prospective controlled phase 3 trials of ADT with or without potent androgen receptor inhibition in this curative-intent setting. PATIENT SUMMARY: Addition of 6 mo of oral daily enzalutamide to standard salvage radiation and hormone therapy is safe and may improve prostate cancer remission rates at 2 and 3 yr.