KLRG1 Cell Depletion As A Novel Therapeutic Strategy In Patients With Mature T-cell lymphoma Subtypes.

PURPOSE: Develop a novel therapeutic strategy for patients with subtypes of mature T-cell and NK-cell neoplasms. EXPERIMENTAL DESIGN: Primary specimens, cell lines, patient-derived xenograft models, commercially available and proprietary anti-KLRG1 antibodies were used for screening, target, and functional validation. RESULTS: Here we demonstrate that surface KLRG1 is highly expressed on tumor cells in subsets of patients with extranodal NK/T-cell lymphoma (ENKTCL), T-prolymphocytic leukemia (T-PLL) and gamma/delta T-cell lymphoma (G/D TCL). The majority of the CD8+/CD57+ or CD3-/CD56+ leukemic cells derived from patients with T- and NK-large granular lymphocytic leukemia (T-LGLL and NK-LGLL) respectively expressed surface KLRG1. The humanized afucosylated anti-KLRG1 monoclonal antibody (mAb208) optimized for mouse in vivo use depleted KLRG1+ TCL cells by mechanisms of ADCC, ADCP and CDC rather than apoptosis. mAb208 induced ADCC and ADCP of T-LGLL patient-derived CD8+/CD57+ cells ex vivo. mAb208 effected ADCC of subsets of healthy donor-derived KLRG1+ NK, CD4+, CD8+ Tem and TemRA cells while sparing KLRG1- naive and CD8+ Tcm cells. Treatment of cell line and TCL patient-derived xenografts with mAb208 or anti-CD47 mAb alone and in combination with the PI3K-δ/γ inhibitor, duvelisib extended survival. The depletion of macrophages in vivo antagonized mAb208 efficacy. CONCLUSIONS: Our findings suggest the potential benefit of a broader treatment strategy combining therapeutic antibodies with PI3Ki for the treatment of patients with mature T-cell and NK-cell neoplasms.

Overcoming IMiD resistance in T-cell lymphomas through potent degradation of ZFP91 and IKZF1.

Immunomodulatory (IMiD) agents like lenalidomide and pomalidomide induce the recruitment of IKZF1 and other targets to the CRL4CRBN E3 ubiquitin ligase, resulting in their ubiquitination and degradation. These agents are highly active in B-cell lymphomas and a subset of myeloid diseases but have compromised effects in T-cell lymphomas (TCLs). Here, we show that 2 factors determine resistance to IMiDs among TCLs. First, limited CRBN expression reduces IMiD activity in TCLs but can be overcome by newer-generation degrader CC-92480. Using mass spectrometry, we show that CC-92480 selectively degrades IKZF1 and ZFP91 in TCL cells with greater potency than pomalidomide. As a result, CC-92480 is highly active against multiple TCL subtypes and showed greater efficacy than pomalidomide across 4 in vivo TCL models. Second, we demonstrate that ZFP91 functions as a bona fide transcription factor that coregulates cell survival with IKZF1 in IMiD-resistant TCLs. By activating keynote genes from WNT, NF-kB, and MAP kinase signaling, ZFP91 directly promotes resistance to IKZF1 loss. Moreover, lenalidomide-sensitive TCLs can acquire stable resistance via ZFP91 rewiring, which involves casein kinase 2-mediated c-Jun inactivation. Overall, these findings identify a critical transcription factor network within TCLs and provide clinical proof of concept for the novel therapy using next-generation degraders.

Characterizing cesium sorption in freshwater settings using fluvial sediments and characteristic water chemistries.

Cesium-137 (137Cs) is a persistent contaminant that poses a significant risk to human health and the environment. Understanding the fate and transport of 137Cs following a contamination incident is necessary for effective containment and remediation. In this study, we performed experiments to investigate how Cs+ sorption processes are affected by sediment type and varying water chemistries to better understand how Cs+ is transported in freshwater settings. Sediment was collected from various river deposits along the Susquehanna River adjacent to the Safety Light Corporation United States Environmental Protection Agency (US EPA) Superfund site (Bloomsburg, PA) and characterized prior to being used in batch reactor experiments with waters characteristic of different regions in the US (Central US and Northeast US) and with three different cation types (Mg2+, Na+, and K+) over a range of ionic strengths. Greater amounts of Cs+ sorption occurred with increasing sediment mud (silt and clay) content, although no major differences in sorption between the Central and Northeast US water types were observed. At an ionic strength (I) of 10 mM, K+ inhibited Cs+ sorption most effectively, followed by Mg2+, with Na+ having little effect on Cs+ sorption over the range of ionic strengths tested (I = 0.1, 1, and 10 mM). Our findings indicate that for the representative freshwater conditions tested here, sediment type (e.g., clay fraction) has a greater influence on Cs+ sorption processes than water chemistry. Additional reactions or processes occurring in relatively fresh water could buffer cation competition for sorption sites. Conducting experiments using site-specific sediment samples and water chemistries is useful for predicting Cs+ sorption and mobility in distinct environmental settings, particularly when the level of Cs+ contamination is high and if the waste or contaminated (or receiving) waters have a relatively high ionic strength.

Implementing a telephone based peer support intervention for women with a BRCA1/2 mutation.

Women with a BRCA1/2 gene mutation face complex risk management decisions and communication issues that can lead to increased levels of distress and unmet needs. We describe the implementation of a peer-support program that aims to reduce distress among women with a BRCA1/2 mutation, including peer and support recipient satisfaction with the program, challenges and lessons learnt. Participants with a BRCA1/2 mutation were matched with a trained peer volunteer (also a mutation carrier) to have regular one-on-one phone calls, over 4 months. Details of the calls, including topics discussed, time spent and number, were collected. Peers and recipients completed surveys assessing how they felt the contact went, satisfaction with the program, and preferences for matching. Satisfaction with the program was high for both peers and recipients. 80% of pairs ended contact through mutual agreement. Peers and recipients differed in the importance placed on age and surgery experience to determine matches. The most challenging aspect of the program for peers was difficulty in contacting recipients. Peer support for women with a BRCA1/2 mutation is feasible. However, to encourage continued involvement by peers and recipients greater flexibility in the method and delivery of contact is needed. We advocate the use of text-messaging and/or email as mechanisms for pairs to arrange and maintain contact. These strategies should be in addition to, rather than replacing, calls. A mixed medium intervention, where recipients can tailor the method of communication to suit their needs, may be preferable and effective, though this would need to be tested.

Through the looking glass: an exploratory study of the lived experiences and unmet needs of families affected by Von Hippel-Lindau disease.

Despite well-established protocols for the medical management of Von Hippel-Lindau disease (VHL), families affected by this rare tumour syndrome continue to face numerous psychological, social, and practical challenges. To our knowledge, this is one of the first qualitative studies to explore the psychosocial difficulties experienced by families affected by VHL. A semi-structured interview was developed to explore patients' and carers' experiences of VHL along several life domains, including: self-identity and self-esteem, interpersonal relationships, education and career opportunities, family communication, physical health and emotional well-being, and supportive care needs. Quantitative measures were also used to examine the prevalence of anxiety, depression, and disease-specific distress in this sample. Participants were recruited via the Hereditary Cancer Clinic at the Prince of Wales Hospital in Sydney, Australia. A total of 23 individual telephone interviews were conducted (15 patients, 8 carers), yielding a response rate of 75%. A diverse range of experiences were reported, including: sustained uncertainty about future tumour development, frustration regarding the need for lifelong medical screening, strained family relationships, difficulties communicating with others about VHL, perceived social isolation and limited career opportunities, financial and care-giving burdens, complex decisions in relation to childbearing, and difficulties accessing expert medical and psychosocial care. Participants also provided examples of psychological growth and resilience, and voiced support for continued efforts to improve supportive care services. More sophisticated systems for connecting VHL patients and their families with holistic, empathic, and person-centred medical and psychosocial care are urgently needed.

Randomized controlled trial of a telephone-based peer-support program for women carrying a BRCA1 or BRCA2 mutation: impact on psychological distress.

PURPOSE: To assess the effectiveness of a telephone-based peer-delivered intervention in reducing distress among women with a BRCA1 or BRCA2 gene mutation. The intervention involved trained peer volunteers contacting women multiple times over a 4-month period to provide informational, emotional, and practical support. METHODS: Three hundred thirty-seven participants completed the baseline questionnaire, and those reporting interest in talking to other mutation carriers were randomly assigned to either the usual care group (UCG; n = 102) or the intervention group (IG; n = 105). Participants and researchers were not blinded to group allocation. Two follow-up questionnaires were completed, one at the end of the intervention (4 months after random assignment, time 2) and one 2 months later (time 3). Outcomes included breast cancer distress (primary outcome), unmet information needs, cognitive appraisals about mutation testing, and feelings of isolation. RESULTS: There was a greater decrease in breast cancer distress scores in the IG than UCG at time 2 (mean difference, -5.96; 95% CI, -9.80 to -2.12; P = .002) and time 3 (mean difference, -3.94; 95% CI, -7.70 to -0.17; P = .04). There was a greater reduction in unmet information needs in the IG than UCG (P < .01), with unmet needs being lower in the IG than UCG at time 2. There was a greater reduction in Cognitive Appraisals About Genetic Testing stress subscale scores in the IG than UCG (P = .02), with significantly lower scores among the IG than UCG at time 2 (P < .01). CONCLUSION: The intervention is effective in reducing distress and unmet information needs for this group of women. Identifying strategies for prolonging intervention effects is warranted.

Unmet support needs and distress among women with a BRCA1/2 mutation.

Distress levels among female BRCA1/2 mutation carriers can be similar to levels found among breast cancer patients. While psychological distress has been associated with unmet needs among cancer patients no study has examined this among BRCA1/2 mutation carriers. The objectives of this study were to: (1) describe the unmet support needs of women with a known BRCA1/2 mutation, (2) determine how unmet needs are related to psychological distress, and (3) identify variables that predict level of unmet need and distress. Female BRCA1/2 mutation carriers were identified through Familial Cancer Centers in 3 Australian states. Two-hundred and seventy-nine participants completed surveys assessing need for help on 16 information and support items. The Impact of Events Scale assessed genetic test related distress. Participants reported an average of 5.4 (SD = 4.9) moderate to very high unmet needs. Twenty-one percent had scores indicating moderate distress, and 13 % indicating severe distress. Younger age (t = -3.34; p < 0.01), not having someone to confide in about the gene mutation (t = 2.57; p = 0.01) and shorter time since notification of mutation status (t = -2.49; p = 0.01) were associated with higher unmet need scores in linear regression analyses. Greater number of unmet needs was associated with a greater likelihood of moderate to severe levels of distress (OR = 1.19; p < 0.01) in logistic regression analyses. Identifying appropriate interventions that target unmet needs among younger women and those with no confidante may help to reduce distress. Interventions that provide an opportunity for women to confide in someone, such as Peer support programs, may be one way of meeting the emotional needs of this population.

How should we discuss genetic testing with women newly diagnosed with breast cancer? Design and implementation of a randomized controlled trial of two models of delivering education about treatment-focused genetic testing to younger women newly diagnosed with breast cancer.

BACKGROUND: Germline BRCA1 and BRCA2 mutation testing offered shortly after a breast cancer diagnosis to inform women's treatment choices - treatment-focused genetic testing 'TFGT' - has entered clinical practice in specialist centers and is likely to be soon commonplace in acute breast cancer management, especially for younger women. Yet the optimal way to deliver information about TFGT to younger women newly diagnosed with breast cancer is not known, particularly for those who were not suspected of having a hereditary breast cancer syndrome prior to their cancer diagnosis. Also, little is known about the behavioral and psychosocial impact or cost effectiveness of educating patients about TFGT. This trial aims to examine the impact and efficiency of two models of educating younger women newly diagnosed with breast cancer about genetic testing in order to provide evidence for a safe and effective future clinical pathway for this service. DESIGN/METHODS: In this non-inferiority randomized controlled trial, 140 women newly diagnosed with breast cancer (aged less than 50 years) are being recruited from nine cancer centers in Australia. Eligible women with either a significant family history of breast and/or ovarian cancer or with other high risk features suggestive of a mutation detection rate of > 10% are invited by their surgeon prior to mastectomy or radiotherapy. After completing the first questionnaire, participants are randomized to receive either: (a) an educational pamphlet about genetic testing (intervention) or (b) a genetic counseling appointment at a family cancer center (standard care). Each participant is offered genetic testing for germline BRCA mutations. Decision-related and psychosocial outcomes are assessed over 12 months and include decisional conflict (primary outcome);uptake of bilateral mastectomy and/or risk-reducing salpingo-oophorectomy; cancer-specific- and general distress; family involvement in decision making; and decision regret. A process-oriented retrospective online survey will examine health professionals' attitudes toward TFGT; a health economic analysis will determine the cost effectiveness of the intervention. DISCUSSION: This trial will provide crucial information about the impact, efficiency and cost effectiveness of an educational pamphlet designed to inform younger women newly diagnosed with breast cancer about genetic testing. Issues regarding implementation of the trial are discussed.

"For all my family's sake, I should go and find out": an Australian report on genetic counseling and testing uptake in individuals at high risk of breast and/or ovarian cancer.

CONTEXT: Despite proven benefits, the uptake of genetic counseling and testing by at-risk family members of BRCA1 and BRCA2 mutation carriers remains low. AIMS: This study aimed to examine at-risk individuals' reported reasons for and against familial cancer clinic (FCC) attendance and genetic testing. METHODS: Thirty-nine telephone interviews were conducted with relatives of high-risk mutation carriers, 23% (n = 9) of whom had not previously attended an FCC. Interview responses were analyzed using the frameworks of Miles and Huberman. RESULTS: The reasons most commonly reported for FCC attendance were for clarification of risk status and to gain access to testing. While disinterest in testing was one reason for FCC nonattendance, several individuals were unaware of their risk (n = 3) or their eligibility to attend an FCC (n = 2), despite being notified of their risk status through their participation in a large-scale research project. Individuals' reasons for undergoing testing were in line with that reported elsewhere; however, concerns about discrimination and insurance were not reported in nontestees. CONCLUSIONS: Current guidelines regarding notifying individuals discovered to be at increased risk in a research, rather than clinical setting, take a largely nondirective approach. However, this study demonstrates that individuals who receive a single letter notifying them of their risk may not understand/value the information they receive.

An exploration of the communication preferences regarding genetic testing in individuals from families with identified breast/ovarian cancer mutations.

The responsibility for informing at-risk relatives of the availability of genetic testing for breast/ovarian cancer gene (BRCA1 or BRCA2) mutations currently falls on the probands. This study explored the support needs of individuals from families with identified BRCA1 or BRCA2 mutations when communicating about genetic risk and genetic testing with at-risk family members. Thirty-nine semi-structured telephone interviews were conducted with individuals from families with identified BRCA mutations. Interview responses were cross-tabulated by sample characteristics using the qualitative research analysis software NVivo8. The development of educational materials, which individuals could use when communicating the risks of carrying a BRCA gene mutation with their relatives, was identified as a specific need. Many participants expressed a preference for a staged approach, where relatives are notified of their increased risk and the availability of genetic testing risk either face-to-face or via a letter, with additional educational sources, including brief written information or access to a website, made available for those wishing to access more in-depth information. This research identified a need for the development of educational/informational resources to support individuals with identified breast/ovarian cancer mutations to communicate with their at-risk relatives about genetic risk and genetic testing availability.

The Relationship Between Noncoplanar PCB-Induced Immunotoxicity and Hepatic CYP1A Induction in a Fish Model.

Abundant literature exists demonstrating the immunomodulating effects of polychlorinated biphenyls (PCBs). To date, most of the research has focused on dioxin-like coplanar PCB congeners because of their high affinity for the aryl hydrocarbon receptor (AhR) and cytochrome P450-inducing capability. For this study, the impact of two structurally different PCB congeners on the immune responsiveness of bluegill sunfish (Lepomis macrochirus) was examined to evaluate the immunotoxic potential of each congener (as separate entities) and to relate effects on immune function with hepatic CYP1A induction. Fish received a single intraperitoneal injection of the: coplanar congener, PCB 126 (0.01 or 1.0 mug/g BW); noncoplanar PCB 153 (5.0 or 50.0 mug/g BW); or, the corn oil vehicle. PCB-induced effects on innate and cell-mediated immune parameters, and on hepatic CYP1A protein induction were evaluated in fish sacrificed 1, 3, 7, 14 or 21 days post-injection. In the absence of CYP1A induction, PCB 153 increased kidney phagocyte-mediated superoxide production 3 d post-injection, and at the highest dose suppressed B- and T-lymphocyte proliferation after 3 and 7 days, respectively. Treatment of fish with PCB 126 had no effect on oxyradical production, but altered B-lymphocyte proliferation after 1 day, also in the absence of CYP1A induction. Hepatic CYP1A was only induced in fish exposed to the highest PCB 126 dose; protein induction appeared at 3 d post-injection and persisted for up to 21 days. Taken together, these results demonstrate that exposure to different PCB congeners can alter immune function in the absence of CYP1A induction, suggesting that mechanisms other than the AhR pathway may play a role in PCB-induced immunotoxicity, particularly for the noncoplanar congeners.