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Purpose: The Radiation Therapy Oncology Group (RTOG) 0215 investigated the efficacy of sildenafil in improving erectile dysfunction following radiotherapy and neoadjuvant/concurrent androgen deprivation therapy among prostate cancer patients and found a significant improvement on drug but only in 21% of study participants. This paper reports on a secondary aim to investigate the effect of sildenafil on overall sexual and marital adjustment among both patients and their wives.Methods: RTOG 0215 was a placebo-controlled, double-blind, crossover trial of sildenafil. Participation of wives was optional. Twenty-four married heterosexual couples (33% of heterosexual couples in study) completed the Sexual Adjustment Questionnaire and Locke's Marital Adjustment Test. Treatment differences in mean change scores were evaluated by paired t-tests, and the proportion of patients achieving a clinically meaningful change was evaluated using chi-square tests. Spearman's correlation coefficients were used to determine the association of adjustment between patients and wives.Results: There was no significant change in either sexual or marital adjustment for patients. For wives, there was a trend for improvement in sexual adjustment but no significant change in marital adjustment. Change in marital adjustment between patients and wives was weakly related (r(s) = 0.15, p = 0.48), and for sexual adjustment, there was a moderate, but nonsignificant relationship (r(s) = 0.40, p = 0.09).Conclusions: Larger studies are warranted to further examine possible differences in sexual experiences and treatment needs between prostate cancer patients and their wives, as well as to assess predictors of sildenafil response. [ABSTRACT FROM AUTHOR]

Selective binding of TCR-like antibodies that target a single tumour-specific peptide antigen presented by human leukocyte antigens (HLA) is the absolute prerequisite for their therapeutic suitability and patient safety. To date, selectivity assessment has been limited to peptide library screening and predictive modeling. We developed an experimental platform to de novo identify interactomes of TCR-like antibodies directly in human tissues using mass spectrometry. As proof of concept, we confirm the target epitope of a MAGE-A4-specific TCR-like antibody. We further determine cross-reactive peptide sequences for ESK1, a TCR-like antibody with known off-target activity, in human liver tissue. We confirm off-target-induced T cell activation and ESK1-mediated liver spheroid killing. Off-target sequences feature an amino acid motif that allows a structural groove-coordination mimicking that of the target peptide, therefore allowing the interaction with the engager molecule. We conclude that our strategy offers an accurate, scalable route for evaluating the non-clinical safety profile of TCR-like antibody therapeutics prior to first-in-human clinical application., (© 2024. The Author(s).)

Antibody-based immunotherapy is a promising strategy for targeting chemoresistant leukemic cells. However, classical antibody-based approaches are restricted to targeting lineage-specific cell surface antigens. By targeting intracellular antigens, a large number of other leukemia-associated targets would become accessible. In this study, we evaluated a novel T-cell bispecific (TCB) antibody, generated by using CrossMAb and knob-into-holes technology, containing a bivalent T-cell receptor-like binding domain that recognizes the RMFPNAPYL peptide derived from the intracellular tumor antigen Wilms tumor protein (WT1) in the context of HLA-A*02. Binding to CD3ε recruits T cells irrespective of their T-cell receptor specificity. WT1-TCB elicited antibody-mediated T-cell cytotoxicity against AML cell lines in a WT1- and HLA-restricted manner. Specific lysis of primary acute myeloid leukemia (AML) cells was mediated in ex vivo long-term cocultures by using allogeneic (mean ± standard error of the mean [SEM] specific lysis, 67 ± 6% after 13-14 days; n = 18) or autologous, patient-derived T cells (mean ± SEM specific lysis, 54 ± 12% after 11-14 days; n = 8). WT1-TCB-treated T cells exhibited higher cytotoxicity against primary AML cells than an HLA-A*02 RMF-specific T-cell clone. Combining WT1-TCB with the immunomodulatory drug lenalidomide further enhanced antibody-mediated T-cell cytotoxicity against primary AML cells (mean ± SEM specific lysis on days 3-4, 45.4 ± 9.0% vs 70.8 ± 8.3%; P = .015; n = 9-10). In vivo, WT1-TCB-treated humanized mice bearing SKM-1 tumors exhibited a significant and dose-dependent reduction in tumor growth. In summary, we show that WT1-TCB facilitates potent in vitro, ex vivo, and in vivo killing of AML cell lines and primary AML cells; these results led to the initiation of a phase 1 trial in patients with relapsed/refractory AML (#NCT04580121)., (© 2021 by The American Society of Hematology.)

T-cell bispecific antibodies (TCBs) are a novel class of engineered immunoglobulins that unite monovalent binding to the T-cell receptor (TCR) CD3e chain and bivalent binding to tumor-associated antigens in order to recruit and activate T-cells for tumor cell killing. In vivo, T-cell activation is usually initiated via the interaction of the TCR with the peptide-HLA complex formed by the human leukocyte antigen (HLA) and peptides derived from intracellular proteins. TCR-like antibodies (TCRLs) that recognize pHLA-epitopes extend the target space of TCBs to peptides derived from intracellular proteins, such as those overexpressed during oncogenesis or created via mutations found in cancer. One challenge during lead identification of TCRL-TCBs is to identify TCRLs that specifically, and ideally exclusively, recognize the desired pHLA, but not unrelated pHLAs. In order to identify TCRLs suitable for TCRL-TCBs, large numbers of TCRLs have to be tested in the TCB format. Here, we propose a novel approach using chimeric antigen receptors (CARs) to facilitate the identification of highly selective TCRLs. In this new so-called TCRL-CAR-J approach, TCRL-candidates are transduced as CARs into Jurkat reporter-cells, and subsequently assessed for their specificity profile. This work demonstrates that the CAR-J reporter-cell assay can be applied to predict the profile of TCRL-TCBs without the need to produce each candidate in the final TCB format. It is therefore useful in streamlining the identification of TCRL-TCBs.

An increasing number of applications require the expression of single-chain variable fragments (scFv) fusion proteins in mammalian cells at the cell surface membrane. Here we assessed the CD30-specific scFv HRS3, which is used in immunotherapy, for its ability to retarget lentiviral vectors (LVs) to CD30 and to mediate selective gene transfer into CD30-positive cells. Fused to the C-terminus of the type-II transmembrane protein hemagglutinin (H) of measles virus and expressed in LV packaging cells, gene transfer mediated by the released LV particles was inefficient. A series of point mutations in the scFv framework regions addressing its biophysical properties, which substantially improved production and increased the melting temperature without impairing its kinetic binding behavior to CD30, also improved the performance of LV particles. Gene transfer into CD30-positive cells increased ∼100-fold due to improved transport of the H-scFv protein to the plasma membrane. Concomitantly, LV particle aggregation and syncytia formation in packaging cells were substantially reduced. The data suggest that syncytia formation can be triggered by trans-cellular dimerization of H-scFv proteins displayed on adjacent cells. Taken together, we show that the biophysical properties of the targeting ligand have a decisive role for the gene transfer efficiency of receptor-targeted LVs., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

A limited body of evidence suggests that sleep problems are common in prostate cancer patients undergoing androgen deprivation therapy, yet little is known about sleep characteristics and the effects of poor sleep on daily functioning in this population. This study assessed sleep in 60 prostate cancer patients taking androgen deprivation therapy with wrist actigraphy and daily diaries for 7 days. The Epworth Sleepiness Scale and the general version of the Functional Assessment of Cancer Therapy scale were also administered. On average, total sleep time was 5.9 (SD = 1.4) h, and sleep efficiency was 75% (SD = 12.0) as assessed by actigraphy. There was generally poor concordance between actigraphy and daily diary for most sleep metrics. Subjects reported awakening, on average, 2.7 times per night, most commonly for nocturia and hot flashes. Assessment of daily functioning showed that participants had mild daytime sleepiness, which was predicted by total sleep time (F(1,47) = 4.5, P= 0.04) General quality of life was not impaired. This study supports more research on the predictors of poor sleep in order to identify effective interventions., (© 2010 Blackwell Publishing Ltd.)

The National Cancer Institute (NCI) is developing a patient-reported version of its Common Terminology Criteria for Adverse Events, called the "PRO-CTCAE." The PRO-CTCAE consists of a library of patient-reported items which can be administered in clinical trials to directly capture the patient experience of adverse events during cancer treatment, as well as a software platform for administering these items via computer or telephone. In order to better understand the impressions of stakeholders involved in cancer clinical research about the potential value of the PRO-CTCAE approach to capturing adverse event information in clinical research, as well as their perspectives about barriers and strategies for implementing the PRO-CTCAE in NCI-sponsored cancer trials, a survey was conducted. A survey including structured and open-ended questions was developed to elicit perceptions about the use of patient-reported outcomes (PROs) for adverse event reporting, and to explore logistical considerations for implementing the PRO-CTCAE in cancer trials. The survey was distributed electronically and by paper to a convenience sample of leadership and committee members in the NCI's cooperative group network, including principal investigators, clinical investigators, research nurses, data managers, patient advocates, and representatives of the NCI and Food and Drug Administration. Between October, 2008 through February, 2009, 727 surveys were collected. Most respondents (93%) agreed that patient reporting of adverse symptoms would be useful for improving understanding of the patient experience with treatment in cancer trials, and 88%, 80%, and 76%, respectively, endorsed that administration of PRO-CTCAE items in clinical trials would improve the completeness, accuracy, and efficiency of symptom data collection. More than three fourths believed that patient reports would be useful for informing treatment dose modifications and towards FDA regulatory evaluation of drugs. Eighty-eight percent felt that patients in clinical trials would be willing to self-report adverse symptoms at clinic visits via computer, and 68% felt patients would self-report weekly from home via the internet or an automated telephone system. Lack of computers and limited space and personnel were seen as potential barriers to in-clinic self-reporting, but these were judged to be surmountable with adequate funding. The PRO-CTCAE items and software are viewed by a majority of survey respondents as a means to improve adverse event data quality and comprehensiveness, enhance clinical decision-making, and foster patient-clinician communication. Research is ongoing to assess the measurement properties and feasibility of implementing this measure in cancer clinical trials.

Objective: To conduct a preliminary study assessing the association of hot flashes with pregnancy., Study Design: 268 pregnant and non-pregnant women matched on age and race completed a written questionnaire on sociodemographic and clinical information and the experiences of hot flashes. Binary logistic regressions were used to determine predictors of hot flashes., Results: While controlling for significant bivariate associations, pregnant women were more likely to report hot flashes than non-pregnant women (odds ratio 5.22; confidence interval 2.75-9.89; p<0.001). Hot flashes during pregnancy typically first occurred before the third trimester and were experienced on a weekly basis. Most pregnant women reported that their hot flashes were not severe or bothersome., Conclusions: Findings suggest that hot flashes are common during pregnancy. Studies of hot flashes during pregnancy may further elucidate the causal mechanisms of hot flashes in other populations., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Hot flashes are one of the bothersome symptoms frequently experienced after endocrine treatments for breast and prostate cancers. Many studies have evaluated interventions for hot flashes, but results are obscured by methodologic limitations. We compared the performance of three techniques to measure hot flashes over 48 hours among 47 patients with prostate cancer undergoing androgen deprivation therapy to determine the feasibility and accuracy of each measure. Sternal skin conductance, electronic event marking, and twice daily diaries identified 478, 410, and 285 hot flashes, respectively. Diaries produced the lowest hourly hot flash rate (M = 0.17), which was significantly different from the rates of the objective profile (M = 0.28) and event marks (M = 0.23).The sensitivity and positive predictive value of the three measures demonstrated that the diaries underperformed, but these values did not exceed moderate levels for any measure (% = 28-59). Study results suggest the combined use of sternal skin conductance and event marking for the measurement of hot flash frequency in pathophysiologic studies and clinical trials with prostate cancer patients. Conversely, the use of retrospective diaries may be adequate for clinical practice to determine clinically significant changes in salient events.

Objective: An effective and safe alternative treatment to hormone replacement therapy for hot flashes is needed for cancer patients. Interventions targeting the triggering mechanisms of hot flashes hold promise. Increases in core body temperature are a precursor of most hot flashes in women, and similar findings in prostate cancer patients undergoing androgen deprivation therapy would support further research in this area. We present preliminary findings of physiological changes in a prostate cancer patient with frequent hot flashes., Methods: Physiological changes in sternal skin conductance, heart rate, and core body temperature were continuously measured during two 3.5 h laboratory sessions. Perceived characteristics of hot flashes were recorded in a diary., Results: Five hot flashes were reported during laboratory sessions. Severity and bother ratings were low. All hot flashes were accompanied by large increases in sternal skin conductance and moderate increases in heart rate. Core body temperature increased 0.11-0.32 degrees C prior to and fell 0.23-0.44 degrees C following the peak increase in skin conductance., Conclusions: This case study suggests that hot flashes in men may be preceded by increases in core body temperature. Identification of behavioral factors that raise core body temperature may lead to specific treatment strategies to reduce the frequency of hot flashes., (Copyright (c) 2008 John Wiley & Sons, Ltd.)

Despite decades of research, the causal mechanisms of hot flashes are not adequately understood, and a biopsychosocial perspective on hot flashes remains underdeveloped. This article explores overlooked parallels between hot flashes and panic attacks within 5 areas: course and symptomatology, physiological indicators, neurocircuitry and biochemical mechanisms, pharmacotherapy, and psychological treatment, noting both similarities and important differences between the 2 events. An integrative conceptual model is presented that identifies key ways in which psychological factors may influence the experience of hot flashes, with clinical implications and areas of future research. This model yields readily testable hypotheses and may provide a template for exploring the role of cognition in the frequency and severity of hot flashes and, in turn, a basis for the development of nonpharmacological treatments., ((c) 2008 APA, all rights reserved.)

The gold standard for objectively measuring hot flashes in women is an increased sternal skin conductance level (SCL), but validation studies in prostate cancer patients are lacking. In the laboratory, an SCL increase of > or = 1.78 micro-mho in 45 s had a sensitivity of 68% and a positive predictive value of 100% in detecting self-reported hot flashes among prostate cancer patients. Outside the laboratory, 71% of the objective markers of hot flashes were accompanied by a subjective report of a hot flash, and 65% of subjective reports occurred in the absence of an objective criterion. This study demonstrates that sternal skin conductance can be used to detect hot flashes in men in a manner analogous to its utilization among women. Such use would improve outcome analysis of treatment studies.