Characteristics of clients entering women-only substance use treatment services in New South Wales.

BACKGROUND: Women experiencing substance use disorders face barriers to treatment, including childcare, stigma and lack of gender/trauma-informed programming. Several non-government organizations in New South Wales run women-only treatment services to address these needs. OBJECTIVES: We aim to assess characteristics of women entering treatment in these services. DESIGN: Data on client characteristics from six women-only non-government organization substance use disorder treatment services in New South Wales between 2014 and 2018 were extracted from a database containing demographics, drug use and treatment characteristics and psychological distress (Kessler-10 scale) of women entering the services. Logistic regression models were used to estimate unadjusted odds ratio and adjusted odds ratio for treatment completion and different drugs on entry. RESULTS: Data were available for 1357 women. Most (91%) episodes were for residential treatment. Women's mean age was 35.4 years (standard deviation = 9.8; range = 17-67). Residential clients tended to be younger than non-residential clients (35.1 vs 38.5 years, p < 0.001). Methamphetamine (43%) and alcohol (32%) were the most reported principal drug of concern. Women (89%) reported high levels of psychological distress (median Kessler-10 scale score = 27.5, range = 10-50), highest for women reporting alcohol as their principal drug. Overall, 43% of episodes resulted in treatment completion, most commonly for women entering residential treatment (45% vs 22%, p < 0.001) and for alcohol treatment (adjusted odds ratio = 1.42; confidence interval = 1.07-1.90; p < 0.001). Women with Kessler-10 scale scores indicating anxiety or depression at treatment entry were less likely to complete treatment than those with lower scores (adjusted odds ratio = 0.56; confidence interval = 0.38-0.80; p < 0.001). CONCLUSION: Women entering women-only residential treatment tend to be younger and report methamphetamine as principal drug of concern. Women enter treatment with high degrees of psychological distress. Women's services need to ensure their programmes can respond to diverse needs of younger women presenting with methamphetamine use disorder and older women with alcohol use disorder experiencing high levels of psychological distress.

Evaluating immune response and metabolic related biomarkers pre-allogenic hematopoietic stem cell transplant in acute myeloid leukemia.

Although hematopoietic stem cell transplantation (HCT) is the only curative treatment for acute myeloid leukemia (AML), it is associated with significant treatment related morbidity and mortality. There is great need for predictive biomarkers associated with overall survival (OS) and clinical outcomes. We hypothesized that circulating metabolic, inflammatory, and immune molecules have potential as predictive biomarkers for AML patients who receive HCT treatment. This retrospective study was designed with an exploratory approach to comprehensively characterize immune, inflammatory, and metabolomic biomarkers. We identified patients with AML who underwent HCT and had existing baseline plasma samples. Using those samples (n = 34), we studied 65 blood based metabolomic and 61 immune/inflammatory related biomarkers, comparing patients with either long-term OS (≥ 3 years) or short-term OS (OS ≤ 1 years). We also compared the immune/inflammatory response and metabolomic biomarkers in younger vs. older AML patients (≤30 years vs. ≥ 55 years old). In addition, the biomarker profiles were analyzed for their association with clinical outcomes, namely OS, chronic graft versus host disease (cGVHD), acute graft versus host disease (aGVHD), infection and relapse. Several baseline biomarkers were elevated in older versus younger patients, and baseline levels were lower for three markers (IL13, SAA, CRP) in patients with OS ≥ 3 years. We also identified immune/inflammatory response markers associated with aGVHD (IL-9, Eotaxin-3), cGVHD (Flt-1), infection (D-dimer), or relapse (IL-17D, bFGF, Eotaxin-3). Evaluation of metabolic markers demonstrated higher baseline levels of medium- and long-chain acylcarnitines (AC) in older patients, association with aGVHD (lactate, long-chain AC), and cGVHD (medium-chain AC). These differentially expressed profiles merit further evaluation as predictive biomarkers.

Homecare Encounters: An Organizational Response to Innovative Care for Patients Undergoing Hematopoietic Stem Cell Transplantation During COVID-19.

BACKGROUND: Healthcare delivery has been significantly changed because of the COVID-19 pandemic. Patients undergoing hematopoietic stem cell transplantation (HSCT) are vulnerable to infections because of their immunocompromised status. The risk of nosocomial infection may be reduced by providing care to patients at home. OBJECTIVES: This article describes one cancer center's approach for delivering safe patient care through homecare encounters, the benefits of home care for HSCT, and future directions. METHODS: Patients received detailed information on home encounters. Advanced practice providers visited patients daily and then returned to the clinic to formulate a plan of care with the interprofessional care team. Transplantation RNs visited patients on the same day to provide the prescribed care. FINDINGS: Based on evaluations from 32 patients and 12 providers, the results indicated that home care was safe, feasible, and beneficial for patient care post-HSCT during the COVID-19 pandemic.

Female Sex Is Associated with Improved Long-Term Survival Following Allogeneic Hematopoietic Stem Cell Transplantation.

Life expectancy for long-term survivors of allogeneic hematopoietic stem cell transplantation (alloHSCT), defined as those living ≥5 years post-transplantation, is significantly lower compared with that of the age-matched general population despite a relatively low primary disease relapse rate at >2 years post-transplantation. Among several factors, patient sex is increasingly recognized as a prognostic indicator of long-term survival. We examined the influence of patient sex and donor-recipient sex matching on overall survival (OS) in a landmark analysis of long-term survivors. Using our institutional database supplemented with individual patient record review, we retrospectively investigated the relative influence of recipient sex and donor-recipient sex matching on outcomes of long-term survivors of alloHSCT between 1994 and 2014. Over this 20-year period, 247 met inclusion criteria for analysis; males and females had similar demographic and treatment characteristics. However, significantly more deaths after the 5-year landmark occurred in male recipients. Interestingly, donor sex did not have a significant impact on OS in multivariate analysis, and differences in OS of donor-recipient sex pairs was driven by recipient sex. In addition to recipient sex, only chronic graft-versus-host disease (cGVHD) retained significance as a covariate with an impact on OS in multivariate analysis. Men experienced slightly higher, but statistically nonsignificant, rates and increased severity of cGVHD, and had higher cGVHD-related mortality compared with females. In this long-term survival analysis of adult alloHSCT recipients, one of the only to include follow-up to 15 years, our results show that women survive significantly longer than men irrespective of their age at transplantation. This outcome is independent of other common pretransplantation prognostic indicators, such as donor sex or performance status at transplantation. The inferior survival in males is consistent with survival outcomes described in the transplantation literature. Increasing evidence suggests a biological basis for long-term sex-determined outcomes, possibly owing to differing rates or severity of cGVHD or sustained alloimmune tolerance in females. Larger studies are warranted to validate these retrospective clinical results.

Engineering Oncolytic Vaccinia Virus to redirect Macrophages to Tumor Cells.

Oncolytic virotherapy has been tested in numerous early phase clinical studies. However, the antitumor activity of oncolytic viruses thus far has been limited. Numerous strategies are being explored to enhance their antitumor activity by activating the adaptive arm of the immune system. We reasoned that it might also be possible to engineer oncolytic viruses to redirect tumor-associated macrophages to tumor cells for therapeutic benefit. We engineered an oncolytic vaccinia virus (VV) to disrupt the CD47/SIRPα interaction by expressing a chimeric molecule that consists of the ectodomain of SIRPα and the Fc domain of IgG4 (SIRPα-Fc-VV). SIRPα-Fc-VV readily replicated in tumor cells and redirected M1 as well as M2 macrophages to tumor cells in vitro. In contrast, control VVs that either encoded YFP (YFP-VV) or SIRPα (SIRPα-VV) did not. In vivo, SIRPα-Fc-VV had greater antitumor activity than YFP-VV and SIRPα-VV in an immune competent osteosarcoma model resulting in a significant survival advantage. Pretreatment with cytoxan further augmented the antitumor activity of SIRPα-Fc-VV. Thus, arming oncolytic viruses with SIRPα-Fc may present a promising strategy to enhance their antitumor activity for the virotherapy of solid tumors.

Stereotactic Radiosurgery for Carcinoid Brain Metastasis: A Case Report.

Carcinoid brain metastases are extremely rare and are associated with a poor prognosis. Treatment options are variable, ranging from surgery, radiation, or chemotherapy alone or combined. We report on a case of rectal carcinoid metastatic to the cerebellum and review chemotherapeutic regimens for carcinoid tumor treatment, focusing on the potential role of temozolomide or stereotactic radiosurgery.

Optimizing EphA2-CAR T Cells for the Adoptive Immunotherapy of Glioma.

Glioblastoma is the most aggressive primary brain tumor in humans and is virtually incurable with conventional therapies. Chimeric antigen receptor (CAR) T cell therapy targeting the glioblastoma antigen EphA2 is an attractive approach to improve outcomes because EphA2 is expressed highly in glioblastoma but only at low levels in normal brain tissue. Building upon our previous findings in this area, we generated and evaluated a panel of EphA2-specific CARs. We demonstrate here that T cells expressing CD28.ζ and 41BB.ζ CARs with short spacers had similar effector function, resulting in potent antitumor activity. In addition, incorporating the 41BB signaling domain into CD28.ζ CARs did not improve CAR T cell function. While we could not determine functional differences between CD28.ζ, 41BB.ζ, and CD28.41BB.ζ CAR T cells, we selected CD28.ζ CAR T cells for further clinical development based on safety consideration.

Generalized metabolic bone disease and fracture risk in Rothmund-Thomson syndrome.

Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by poikiloderma, small stature, sparse hair, skeletal abnormalities, increased risk of osteosarcoma, and decreased bone mass. To date, there has not been a comprehensive evaluation of the prevalence and extent of metabolic bone disease in RTS. Furthermore, the mechanisms that result in this phenotype are largely unknown. In this report, we provide a detailed evaluation of 29 individuals with RTS with respect to their metabolic bone status including bone mineral density, calcium kinetics studies, and markers of bone remodeling. We show that individuals with RTS have decreased areal bone mineral density. Additionally, we demonstrate that the presence of pathogenic variants in RECQL4 and low bone mineral density correlate with the history of increased risk of fractures. Using a RECQL4-deficient mouse model that recapitulates skeletal abnormalities seen in individuals with RTS, we demonstrate that generalized skeletal involvement is likely due to decreased osteogenesis. Our findings are clinically relevant as they may help in the risk stratification of patients with RTS and also in the identification of individuals who may benefit from additional surveillance and management of metabolic bone disease.

Synergistic effect of allyl isothiocyanate (AITC) on cisplatin efficacy in vitro and in vivo.

Although in vitro studies have shown that isothiocyanates (ITCs) can synergistically sensitize cancer cells to cisplatin treatment, the underlying mechanisms have not been well defined, and there are no in vivo demonstrations of this synergy. Here, we report the in vitro and in vivo data for the combination of allyl isothiocyanate (AITC), one of the most common naturally occurring ITCs, with cisplatin. Our study revealed that cisplatin and AITC combination synergistically inhibits cancer cell growth and colony formation, and enhances apoptosis in association with the downregulation of antiapoptotic proteins Bcl-2 and survivin. Importantly, the in vivo combination treatment suppresses human tumor growth in animal models without observable increases in toxicity (body weight loss) in comparison with single agent treatment. Furthermore, our data revealed that addition of AITC to cisplatin treatment changes the profile of G2/M arrest (e.g. increase in M phase cell number) and significantly extends the duration of G2/M arrest in comparison with cisplatin treatment alone. To explore the underlying mechanism, we found that AITC treatment rapidly depletes b-tubulin. Combination of AITC and cisplatin inhibits the expression of G2/M checkpoint-relevant proteins including CDC2, cyclin B1 and CDC25. Together, our findings reveal a novel mechanism for AITC enhancing cisplatin efficacy and provides the first in vivo evidence to support ITCs as potential candidates for developing new regimens to overcome platinum resistance.

MHC class II regulation by epigenetic agents and microRNAs.

MicroRNAs have been shown to regulate gene expression both transcriptionally and translationally. Here, we examine evidence that various stresses regulate miRNAs which, in turn, regulate immune gene levels. Multiple studies are reviewed showing altered microRNA levels in normal cells under stress and in various disease states, including cancer. Unexpected was the finding that Dicer expression is altered by treatments with several agents, such as interferons and cortisone, employed in the treatment of immune disorders. Potential signal transduction pathways, including JAK/Stat, PI3K and PKR, that may regulate Dicer and microRNA levels in normal and stressed mammalian cells are discussed.

Enhancing effectiveness of the MDR-sensitive compound T138067 using advanced treatment with negative modulators of the drug-resistant protein survivin.

Growing evidence indicates that the antiapoptotic protein survivin is a major factor of drug and radiation resistance in cancer cells. However, application of this finding to therapeutic drug combination is largely unexplored. In this study, breast cancer cells were used for treatment with anticancer compounds alone or in combination. We report that T138067, a better drug against multiple drug resistance (MDR) tumor cells than taxol (Shan et al., PNAS 96:5686-91,1999), induces survivin expression and consequently decreases its effectiveness on the induction of cancer cell death. Treatment of breast cancer cells with T138067 induced survivin expression in these cells while showing no effect on Bcl-2, indicating its specificity. Upregulation of survivin by T138067 was concomitant with an increased drug resistance and associated with an increased phosphorylation of Akt and Erk1/2 MAPK, and a decreased phosphorylation of p38 MAPK without affecting the phosphorylation of ErbB2. Therefore, it is possible that inhibition of T138067-induced survivin expression by alternative approaches may sensitize cells to T138067-induced cell death. We found that treatment of breast cancer cells with SN38, the active metabolite of irinotecan, inhibits survivin expression. Intriguingly, inhibition of survivin expression by SN38 was more effective at a low concentration than at the high concentration, which makes SN38 a good survivin modulator. Furthermore, in contrast with the decreased phosphorylation of p38 MAPK after T138067 treatment, inhibition of survivin expression by SN38 was associated with an increased phosphorylation of the p38 MAPK, suggesting opposing signals converging to survivin. Consistent with these observations, T138067 in combination with SN38 strongly induced cell death in comparison with each drug alone. Similarly, sequential combination of resveratrol, a component of red grapes that inhibits survivin expression, with T138067 also provoked massive breast cancer cell death compared with T138067 alone. Together, these results highlight a new concept that unique signaling cross talk converged to survivin may be considered for rational drug combination in the clinic.