The Role of Natural Killer Cells in Oncolytic Virotherapy: Friends or Foes?

Oncolytic virotherapy (OVT) has emerged as a promising cancer immunotherapy, and is capable of potentiating other immunotherapies due to its capacity to increase tumor immunogenicity and to boost host antitumor immunity. Natural killer (NK) cells are a critical cellular component for mediating the antitumor response, but hold a mixed reputation for their role in mediating the therapeutic efficacy of OVT. This review will discuss the pros and cons of how NK cells impact OVT, and how to harness this knowledge for the development of effective strategies that could modulate NK cells to improve OVT-based therapeutic outcomes.

Group brief cognitive behavioral therapy for suicide prevention compared to dialectal behavior therapy skills group for military service members: a study protocol of a randomized controlled trial.

BACKGROUND: Suicide is a pressing matter for the military. Not only does it pose a health risk, but suicide also compromises operational readiness. Despite provision of suicide prevention clinical best practices, the Department of Defense suffers several challenges (e.g., clinician shortages) limiting the agency's ability to effectively respond to service member suicide. Implementation of evidence-based suicide-specific group therapy is a possible solution to service member well-being needs and system challenges. Service members can also gain coping skills useful beyond managing suicidal thoughts and behaviors. METHODS: This 2-arm non-inferiority randomized controlled trial compares a group therapy format of Brief Cognitive Behavioral Therapy (i.e., G-BCBT) with Dialectical Behavior Therapy (DBT) Skills Group. Both therapies are delivered in-person at a United States Naval Medical Center. Participants (N = 136) are active-duty service members with recent suicidal thoughts or suicidal behavior. Evaluation features electronically delivered questionnaires at baseline, after each treatment session, and at 3- and 6-month follow-up. DISCUSSION: The primary outcome concerns G-BCBT impacts on suicidal ideation. Secondary outcomes of interest are suicide attempt, psychological distress (e.g., symptoms of depression, anxiety), and self-regulatory skills (e.g., emotion regulation). We also examine self-regulatory skills as treatment moderators. Clinical trial strengths and limitations are reviewed. TRIAL REGISTRATION: This study was registered at Clinicaltrials.gov (protocol NCT05401838).

Structure-Activity Relationship Study of Momordica Saponin II Derivatives as Vaccine Adjuvants.

VSA-2 is a recently developed semisynthetic saponin immunostimulant. It is prepared by incorporating a terminal-functionalized side chain to the branched trisaccharide domain at the C3 position of Momordica saponin II (MS II) isolated from the seeds of perennial Momordica cochinchinensis Spreng. Direct comparison of VSA-2 and the clinically proven saponin adjuvant QS-21 shows that VSA-2 is comparable to QS-21 in enhancing humoral and cellular immune responses. Structure-activity relationship studies show that structural changes in the side chain have a significant impact on saponins' adjuvant activity. However, with the VSA-2 molecular framework intact, the new VSA-2 analogues with various substitution(s) at the terminal benzyl group of the side chain retain the ability of potentiating antigen-specific humoral and cellular responses.

A psychometric assessment of the Military Suicide Attitudes Questionnaire (MSAQ).

Suicide rates remain high among military populations. Stigmatizing beliefs about suicide contribute to the problem of heightened suicide risk as a deterrent for help-seeking. Measurement of military suicide stigma is therefore an important gap in the literature as a necessity toward the development of military suicide prevention programming. This paper assessed the factor structure, reliability, and validity of the Military Suicide Attitudes Questionnaire (MSAQ). Study 1 featured secondary analysis of a suicide risk dataset from active duty treatment-seeking military personnel (N = 200). Study 2 was a secondary analysis of a statewide assessment of Army National Guard service members' beliefs about mental health and suicide (N =1116). Factor analyses results collectively supported a four-factor Military Suicide Attitudes Questionnaire (MSAQ) structure: discomfort, unacceptability, support, and empathic views. Subscale reliabilities ranged from 0.77 to 0.83 across samples. Unacceptability and support displayed significant negative correlations with psychological distress. Men displayed more negative suicide-related beliefs compared to women counterparts. Discomfort and unacceptability beliefs displayed significant positive associations with perceived barriers to care. The final short version of the MSAQ is an efficient, multi-dimensional measure of military suicide-related beliefs. The instrument can be used for public health assessment and program evaluation in military settings.

Preferences in Information Processing: Understanding Suicidal Thoughts and Behaviors among Active Duty Military Service Members.

The present study examined Preferences in Information Processing (PIP), an emerging model of understanding suicidal thoughts and behaviors (STBs), in a clinical military sample for the first time. Constructs of need for affect (NFA; i.e., extent to which one engages or avoids emotional content) and need for cognition (NFC; i.e., extent of preference for and enjoyment of cognitive effort) are central individual differences of the PIP model hypothesized to be associated with STBs. Data (n = 200 active duty personnel) were drawn from medical records and self-report questionnaires from two outpatient treatment settings in a military hospital. Primary findings include: (1) moderate positive bivariate associations of NFA avoidance with mental health symptoms and lifetime STBs; (2) consistent patterns in which NFA approach buffers the negative associations of depression with life STBs, clinical suicide risk, perceived burdensomeness and thwarted belonging. Recommendations are offered for military suicide prevention, and future suicide theory testing.

CD4+ T cells cause renal and placental mitochondrial oxidative stress as mechanisms of hypertension in response to placental ischemia.

The reduced uterine perfusion pressure (RUPP) rat model and normal pregnant (NP) rat recipients of RUPP CD4+ T cells recapitulate many characteristics of preeclampsia such as hypertension and oxidative stress. We have shown an important hypertensive role for natural killer (NK) cells to cause mitochondrial dysfunction in RUPP rats; however, the role for RUPP CD4+ T cells to stimulate NK cells is unknown. Therefore, we hypothesized that RUPP-induced CD4+ T cells activate NK cells to cause mitochondrial dysfunction/reactive oxygen species (ROS) as mechanisms of hypertension during pregnancy. We tested our hypothesis by adoptive transfer of RUPP CD4+ T cells into NP rats or by inhibiting the activation of RUPP CD4+ T cells with Orencia (abatacept) and examining hypertension, NK cells, and mitochondrial function. RUPP was performed on gestation day (GD) 14, and splenic CD4+ T cells were isolated on GD 19 and injected into NP rats on GD 13. In a separate group of rats, Orencia was infused and the RUPP procedure was performed. Mean arterial pressure and placental and renal mitochondrial ROS increased in RUPP (n = 7, P < 0.05) and NP + RUPP CD4+ T-cell recipients (n = 13, P < 0.05) compared with control NP (n = 7) and NP + NP CD4+ T-cell recipients (n = 5) but was reduced with Orencia (n = 13, P < 0.05). Placental and renal respiration was reduced in RUPP (n = 6, P < 0.05) and NP + RUPP CD4+ T-cell recipients (n = 6, state 3 P < 0.05) compared with NP (n = 5) and NP + NP CD4+ T-cell recipients (n = 5) but improved with Orencia (n = 9, n = 8 P < 0.05). These data indicate that CD4+ T cells, independent of NK cells, cause mitochondrial dysfunction/ROS contributing to hypertension in response to placental ischemia during pregnancy.

Insight into chronic pain in the United States: descriptive results from the Prescription Opioid Misuse and Abuse Questionnaire (POMAQ) validation study.

OBJECTIVE: A chronic pain patient sample living in the United States who participated in a cross-sectional study to evaluate the validity and reproducibility of the Prescription Opioid Misuse and Abuse Questionnaire is characterized. METHODS: Patients with chronic pain identified through electronic medical records as refilling at least one opioid prescription within the prior 3 months were recruited from five United States Department of Defense Military Health System clinics. Patients completed the Prescription Opioid Misuse and Abuse Questionnaire, Brief Pain Inventory-Short Form, Medical Outcomes Study: 36-item Short Form, and sociodemographic questions online. Clinical characteristics and electronic medical records for 1 year prior to consent were collected. RESULTS: 809 (86.2%) participants completed the Prescription Opioid Misuse and Abuse Questionnaire. Mean (± standard deviation) age was 55.4 ± 12.7 years; the majority female (55.5%) and white (74.8%). Mean duration of chronic pain was 14.7 ± 10.5 years; the most common pain conditions were lower back pain (76.6%), neck or shoulder pain (60.3%), and osteoarthritis (38.7%). The most commonly prescribed opioids were oxycodone (35.7%), tramadol (34.5%), and hydrocodone (26.9%); 54.8% took one opioid, 44.9% took 2 or more opioids. DISCUSSION: Participants' health status was poor; pain severity and interference were moderate. Electronic medical record data revealed high healthcare resource utilization. This chronic pain population was severely impacted by their pain condition(s).

Psychometric assessment of two suicide screeners when used under routine conditions in military outpatient treatment programs.

Suicide remains a pressing problem among active-duty military personnel. Recent Department of Veterans Affairs and Department of Defense suicide prevention practice guidelines highlight the need for further screening research. The present study assessed the psychometric properties of 2 common self-report suicide screening tools: the Suicidal Behaviors Questionnaire-Revised (SBQ-R) and the Columbia Suicide Severity Rating Scale (C-SSRS) ideation subscale. Data (n = 200 active-duty personnel) were drawn from medical records and self-report questionnaires from 2 outpatient treatment settings in a military hospital. Primary findings include: (a) confirmatory factor analytic support for the SBQ-R but not the self-report version of the C-SSRS ideation severity subscale; and (b) acceptable reliability for both the SBQ-R and C-SSRS ideation severity subscale. Recommendations are offered for military suicide screening practice and research. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Clinical Utility of a Genomic Classifier in Men Undergoing Radical Prostatectomy: The PRO-IMPACT Trial.

PURPOSE: The optimal management of men with prostate cancer at high risk of recurrence postradical prostatectomy is controversial. The clinical utility of the Decipher test was evaluated prospectively on postoperative treatment decisions and patient-reported outcomes. METHODS AND MATERIALS: In the study, 246 eligible men across 19 centers were enrolled. Patients were dichotomized into those considering adjuvant or salvage radiation therapy (ART or SRT). Participating providers submitted a management recommendation before and after receiving the Decipher test results. Treatment received within 12 months and a validated survey on prostate cancer-related anxiety were collected longitudinally. RESULTS: Pre-Decipher, treatment was recommended for 12% and 40% for the ART and SRT arms, respectively. Post-Decipher, 17% and 30% of treatment recommendations changed in the ART and SRT arms, respectively. Post-Decipher treatment recommendation was administered 78% and 76% of the time in the ART and SRT arms, respectively. Multivariable analysis confirmed that the Decipher score was an independent predictor for change in management for both adjuvant and salvage patients. The number needed to test to change management for one patient was 4. Cancer-specific anxiety decreased among Decipher risk categories in both arms. CONCLUSIONS: Use of Decipher postradical prostatectomy test was associated with postoperative treatment decisions. Overall, high Decipher risk was associated with an increase in treatment intensity whereas low risk scores were associated with a decrease in therapy administered independent of clinical and pathologic risk factors.

Blockade of endogenous angiotensin II type I receptor agonistic autoantibody activity improves mitochondrial reactive oxygen species and hypertension in a rat model of preeclampsia.

Preeclampsia (PE) is characterized by new-onset hypertension that usually occurs in the third trimester of pregnancy and is associated with oxidative stress and angiotensin II type 1 receptor agonistic autoantibodies (AT1-AAs). Inhibition of the AT1-AAs in the reduced uterine perfusion pressure (RUPP) rat, a model of PE, attenuates hypertension and many other characteristics of PE. We have previously shown that mitochondrial oxidative stress (mtROS) is a newly described PE characteristic exhibited by the RUPP rat that contributes to hypertension. However, the factors that cause mtROS in PE or RUPP are unknown. Thus, the objective of the current study is to use pharmacologic inhibition of AT1-AAs to examine their role in mtROS in the RUPP rat model of PE. AT1-AA inhibition in RUPP rats was achieved by administration of an epitope-binding peptide ('n7AAc'). Female Sprague-Dawley rats were divided into the following two groups: RUPP and RUPP + AT1-AA inhibition (RUPP + 'n7AAc'). On day 14 of gestation (GD), RUPP surgery was performed; 'n7AAc' peptide (2 µg/µL) was administered by miniosmotic pumps in a subset of RUPP rats; and on GD19, sera, placentas, and kidneys were collected. mitochondrial respiration and mtROS were measured in isolated mitochondria using the Oxygraph 2K and fluorescent microplate reader, respectively. Placental and renal mitochondrial respiration and mtROS were improved in RUPP + 'n7AAc' rats compared with RUPP controls. Moreover, endothelial cells (human umbilical vein endothelial cells) treated with RUPP + 'n7AAc' sera exhibited less mtROS compared with those treated with RUPP sera. Overall, our findings suggest that AT1-AA signaling is one stimulus of mtROS during PE.

The Coping Self-Efficacy Scale: Psychometric properties in an outpatient sample of active duty military personnel.

Active duty military service members endure a unique constellation of stressors while deployed or at home. Yet, assessment of protective factors against these stressors among active duty service members represents an under studied area. The present study advances the assessment of protective factors through the psychometric evaluation of the Coping Self-Efficacy Scale (CSES) in a clinical sample of military service members in mental health or substance abuse treatment (n = 200). Cross-sectional data were drawn from military medical records and a supplemental self-report questionnaire. Data extracted included demographic (e.g., sex, age), military characteristics (e.g., rank, years in service), physical health and mental health (e.g., anxiety, depression), and coping self-efficacy. Findings suggest a 3-factor (i.e., problem-focused coping, thought-stopping, and getting social support) CSES structure with acceptable internal consistency. Further, there were small-to-moderate associations with physical and mental health outcomes, providing evidence of construct validity. There were few significant associations with military-related characteristics. Finally, controlling for covariates, thought-stopping beliefs explained unique variance in suicide-related behaviors. Together, findings support the use of the CSES to measure coping-related beliefs in military service members. Recommendations are offered for future research and practice with active duty service members.

Decipher test impacts decision making among patients considering adjuvant and salvage treatment after radical prostatectomy: Interim results from the Multicenter Prospective PRO-IMPACT study.

BACKGROUND: Patients with prostate cancer and their providers face uncertainty as they consider adjuvant radiotherapy (ART) or salvage radiotherapy (SRT) after undergoing radical prostatectomy. The authors prospectively evaluated the impact of the Decipher test, which predicts metastasis risk after radical prostatectomy, on decision making for ART and SRT. METHODS: A total of 150 patients who were considering ART and 115 who were considering SRT were enrolled. Providers submitted a management recommendation before processing the Decipher test and again at the time of receipt of the test results. Patients completed validated surveys on prostate cancer (PCa)-specific decisional effectiveness and PCa-related anxiety. RESULTS: Before the Decipher test, observation was recommended for 89% of patients considering ART and 58% of patients considering SRT. After Decipher testing, 18% (95% confidence interval [95% CI], 12%-25%) of treatment recommendations changed in the ART arm, including 31% among high-risk patients; and 32% (95% CI, 24%-42%) of management recommendations changed in the salvage arm, including 56% among high-risk patients. Decisional Conflict Scale (DCS) scores were better after viewing Decipher test results (ART arm: median DCS before Decipher, 25 and after Decipher, 19 [P<.001]; SRT arm: median DCS before Decipher, 27 and after Decipher, 23 [P<.001]). PCa-specific anxiety changed after Decipher testing; fear of PCa disease recurrence in the ART arm (P = .02) and PCa-specific anxiety in the SRT arm (P = .05) decreased significantly among low-risk patients. Decipher results reported per 5% increase in 5-year metastasis probability were associated with the decision to pursue ART (odds ratio, 1.48; 95% CI, 1.19-1.85) and SRT (odds ratio, 1.41; 95% CI, 1.09-1.81) in multivariable logistic regression analysis. CONCLUSIONS: Knowledge of Decipher test results was associated with treatment decision making and improved decisional effectiveness among men with PCa who were considering ART and SRT. Cancer 2017;123:2850-59. © 2017 American Cancer Society.

AUA Quality Improvement Summit 2014: Conference Proceedings on Infectious Complications of Transrectal Prostate Needle Biopsy.

INTRODUCTION: The AUA Quality Improvement Summit is a continuing AUA effort to provide education around issues related to quality improvement and patient safety. Due to the rapidly increasing rates of hospitalization following prostate needle biopsy, Infectious Complications of Transrectal Prostate Needle Biopsy was selected as the inaugural topic. METHODS: The information is largely unpublished data provided by the presenting physicians. Infection rates are predominantly self-reported with protocols specified by the physicians' home institutions. Beyond the identified speakers, the open forum of this summit allowed for input from a majority of the participants. RESULTS: Current hospitalization rates for transrectal prostate needle biopsy infections vary widely from 0.5% to 6%. Antibiotic resistance of coliform organisms appears to be a major risk of these infectious complications. Prophylactic protocols also vary widely among the represented institutions. Antibiotic resistance profiles showed extreme regional variation and, as such, a prophylactic antibiotic protocol should be based on the current local antibiogram in order to reduce infection rates. Opinions vary in relation to the specific antibiotics appropriate for an augmented antibiotic prophylaxis, in the use of rectal swab and prebiopsy enema, and povidone-iodine preparation of the rectal vault. Standardization of the transrectal antibiotic prophylaxis across practices has been proven to reduce the infectious complications rates. CONCLUSIONS: Urologists should monitor the prostate biopsy infection rates of the practice and consult the current local antibiogram. Physicians should query patients to assess whether they are at high risk for resistant organisms. If so, prophylactic protocols might be intensified.

Body surface mapping improves diagnosis of acute myocardial infarction in the emergency department.

Traditionally, the diagnosis of acute myocardial infarction (AMI) in emergency departments is done through an assessment of history and presenting symptoms, 12-lead electrocardiogram (ECG), and cardiac biomarkers. The 12-lead ECG is not highly sensitive for detecting ECG changes, and some infarctions may be missed. Failure to identify patients in the early stages of AMI can result in failure to provide beneficial therapies. New technology, the 80-lead ECG, uses body surface mapping to provide a more comprehensive view of cardiac electrical activity. Body surface mapping has greater sensitivity in detecting AMI in the inferoposterior portions of the left ventricle and the right ventricle. Portable hardware and user-friendly software coupled with an easily applied disposable torso vest containing the electrodes produce a 12-lead ECG, 80-lead ECG, and color contour torso or flat map showing ECG changes. Recent studies support the use of 80-lead body surface mapping for detecting AMI in the emergency department.

Gene therapy for bladder overactivity and nociception with herpes simplex virus vectors expressing preproenkephalin.

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a major challenge to treat. We studied the effect of targeted and localized expression of enkephalin in afferent nerves that innervate the bladder by gene transfer using replication-defective herpes simplex virus (HSV) vectors in a rat model of bladder hyperactivity and pain. Replication-deficient HSV vectors encoding preproenkephalin, which is a precursor for Met- and Leu-enkephalin, or control vector encoding the lacZ reporter gene, were injected into the bladder wall of female rats. After viral vector injection, quantitative polymerase chain reaction showed high preproenkephalin transgene levels in bladder and dorsal root ganglia innervating the bladder in enkephalin vector-treated animals. Functionally, enkephalin vector-treated animals showed reductions in bladder hyperactivity and nociceptive behavior induced by intravesical application of capsaicin; however, vector-mediated expression of enkephalin did not alter normal voiding. This antinociceptive effect of enkephalin gene therapy was antagonized by naloxone hydrochloride administration. Together, our results with HSV vectors encoding preproenkephalin demonstrated physiological improvement in visceral pain induced by bladder irritation. Thus, gene therapy may represent a potentially useful treatment modality for bladder hypersensitive disorders such as IC/PBS.

Stuttering priapism associated with hereditary spherocytosis.

Stuttering priapism is a clinical phenomenon that occurs commonly in certain patient populations, including sickle cell anemia and other hematologic dyscrasias. Although the mechanism is still not completely understood, treatment is focused on prevention of recurrence in the outpatient setting, and immediate detumescence and minimizing corporal fibrosis in the acute setting. We present a case of stuttering priapism in a 44 year-old male with hereditary spherocytosis and discuss the pathophysiology and clinical management of this entity.

Hereditary leiomyomatosis and renal cell cancer: a syndrome associated with an aggressive form of inherited renal cancer.

PURPOSE: Hereditary leiomyomatosis and renal cell cancer is a recently described hereditary cancer syndrome in which affected individuals are at risk for cutaneous and uterine leiomyomas, and kidney cancer. Our initial experience revealed the aggressive behavior of these renal tumors, often with early metastasis, despite small primary tumor size. We report the clinical characteristics and urological treatment of patients with hereditary leiomyomatosis and renal cell cancer associated renal tumors. MATERIALS AND METHODS: A total of 19 patients with hereditary leiomyomatosis and renal cell cancer associated renal tumors were evaluated. The 11 women and 8 men had a median age at diagnosis of 39 years (range 22 to 67), and a median clinical and radiological followup of 34 months (range 6 to 141). Hereditary leiomyomatosis and renal cell cancer manifestations in patients with renal tumors included cutaneous leiomyomas in 11 of 17 evaluable patients (65%) and uterine leiomyomas in 7 of 7 evaluable females (100%). RESULTS: Median pathological tumor size was 7.8 cm (range 1.5 to 20). Histological subtypes were consistent with hereditary leiomyomatosis and renal cell cancer renal carcinoma. Four of 7 patients with 2.0 to 6.7 cm T1 tumors had spread to regional lymph nodes or metastases at nephrectomy. Overall 9 of 19 patients (47%) presented with nodal or distant metastases. CONCLUSIONS: Renal tumors in patients with hereditary leiomyomatosis and renal cell cancer syndrome are significantly more aggressive than those in patients with other hereditary renal tumor syndromes. In contrast to other familial renal cancer syndromes, the observation of 3 cm or less renal tumors associated with hereditary leiomyomatosis and renal cell cancer is not recommended. Careful followup of affected and at risk individuals in families is necessary.

Epididymal angiosarcoma.

Sarcomas are rare and account for approximately 1% of all malignancies. The subtype angiosarcoma is derived from vascular and lymphatic tissue and generally has a poor prognosis. Prior radiation therapy is a known risk factor for the development of angiosarcomas. We present what we believe to be the first case of an angiosarcoma arising in the epididymis in an 80-year-old man who presented with right scrotal swelling.

Synchronous unilateral renal cell carcinoma and Kimura disease of the kidney.

Kimura disease (KD) is a rare, benign, chronic inflammatory disorder most often found in young Asian males that can simulate a neoplasm. We report a case of renal cell carcinoma and KD within the same kidney. To our knowledge, this is the first reported case of KD involving the kidney confirmed pathologically, as well as the first association of KD with renal cell carcinoma.

Partial adrenalectomy: the National Cancer Institute experience.

OBJECTIVES: To report our experience of partial adrenalectomy and demonstrate whether adrenal function can be preserved in patients with hereditary adrenal pheochromocytoma. Total adrenalectomy has largely been used in the treatment of patients with hereditary adrenal pheochromocytomas. Adrenal cortical-sparing surgery is an alternative approach that aims to balance tumor removal with preservation of adrenocortical function. METHODS: From 1995 to 2004, 33 patients with hereditary pheochromocytoma presented with adrenal masses. Partial adrenalectomy (open or laparoscopic) was performed if normal adrenocortical tissue was evident on preoperative imaging or intraoperative ultrasonography. Various operative parameters, as well as postoperative function of the residual adrenal remnants, were determined. RESULTS: Of the 33 patients, 8 underwent open partial adrenalectomy and 25 laparoscopic partial adrenalectomy during a 10-year period. Ten patients underwent simultaneous, bilateral partial adrenalectomy and 8 underwent surgery on a solitary adrenal gland, 4 of whom received postoperative steroid replacement (stopped in 3 after 1 to 3 months). All other patients had normal catecholamine levels and remained tumor free by imaging at a mean follow-up of 36 months (range 3 to 102). CONCLUSIONS: Partial adrenalectomy can preserve adrenal function in patients with adrenal masses. The laparoscopic approach is technically safe and associated with less morbidity without compromising tumor removal. With careful surgical planning, especially in patients with tumors in solitary glands, adrenocortical function may be preserved, thereby avoiding the morbidity associated with medical adrenal replacement.