Predictors of Linkage to an Opioid Treatment Program and Methadone Treatment Retention following Hospital Discharge in a Safety-Net Setting.

Background: Methadone is increasingly initiated during hospitalization for the treatment of opioid use disorder (OUD). However, little is known about which factors are associated with linkage to opioid treatment programs (OTP) and retention in methadone maintenance therapy (MMT) following hospital discharge. Materials & Methods: This is a retrospective study of adults with OUD hospitalized in an urban, safety-net hospital referred by inpatient clinicians to an onsite OTP for post-discharge MMT follow-up from October 2017 to July 2019. We used multivariable modified Poisson regression models to generate adjusted risk ratios (aRR) for associations of sociodemographic factors, mental health disorders, alcohol use, stimulant use, and prior care engagement with post-discharge OTP enrollment and MMT retention at 30 and 90-days. Results: Of the 125 patients referred, 40% enrolled in the OTP post-discharge. Among enrollees, 74% were retained at 30-days and 52% were retained at 90-days. Patients with co-occurring stimulant use were less likely to enroll in the OTP post-discharge compared to those without stimulant use (aRR 0.65, 95% CI 0.44-0.97). We found no associations with 30-day MMT retention, but patients who reported stable housing were more likely to be retained in MMT at 90-days compared to those without stable housing (aRR 1.66, 95% CI 1.03-2.66). Conclusion: Our findings suggest that hospitalized patients with co-occurring stimulant use may need additional support to optimize post-discharge OTP linkage. Stable housing may improve retention in MMT. Additional research is needed to identify trends in MMT engagement among those referred from the acute hospital setting.

Provision of fertility services to women in same-sex relationships at Catholic and non-Catholic clinics in the United States.

INTRODUCTION: This study addressed deficient information on the provision of infertility care in obstetrics and gynecology clinics. We additionally evaluated the availability of these services based on clinic affiliations or stated sexual orientation. METHODOLOGY: We performed a national cross-sectional "mystery caller" survey of 293 general obstetrics and gynecology clinics in 2017-2018. We matched clinics identified by web-based search engine in a 1:1 ratio by Catholic hospital affiliation, after determining number of clinics based on state-population densities. A standard call script included questions regarding provision of infertility services, ovulation induction methods, and information about the caller's sexual orientation. We performed descriptive frequencies and compared responses based on hospital affiliations. RESULTS: Of the 293 clinics included, 49% were affiliated with Catholic and 17% with academic hospitals. The majority offered infertility care (85%, 248/293), and of these 97% (240/248) offered ovulation induction. Only 3% (6/240) reported they would not provide to women in same-sex relationships. Most clinics not offering infertility evaluations (43/45, 96%) cited it was outside of their scope of care and of these 33% (15/45) did not provide information for self-referral. Clinics affiliated with academic (aOR 0.23) or Catholic (aOR 0.34) hospitals were less likely to provide evaluations. Those with academic affiliation were more likely to provide information for self-referral (aOR 19.2). DISCUSSION: Most general obstetrics and gynecology practices offered appointments for infertility evaluation and ovulation induction. Clinics rarely denied services to women reporting a same-sex partnership, regardless of hospital affiliation. These findings provide reassurance to same-sex couples seeking fertility care.

Risk Factors for Mortality and Pre-ICU Fluid Balance Among Critically Ill Hematopoietic Stem Cell Transplant Patients.

OBJECTIVE: To examine if fluid balance surrounding pediatric intensive care unit (PICU) admission in hematopoietic stem cell transplant (HSCT) patients was associated with mortality, ventilator-free days, and intensive care unit (ICU)-free days. To explore other population-specific factors associated with poor outcome. MATERIALS AND METHODS: Retrospective review of HSCT patients admitted to 2 quaternary PICUs, Children's Hospital Los Angeles and University of California San Francisco Benioff Children's Hospital from January 2009 to December 2014. RESULTS: Of 144 patients, 92 were identified with complete fluid balance data available. No difference in fluid balance between survivors and nonsurvivors in the 24 hours preceding PICU admission (P = .81) or when the first 24 hours of PICU stay were taken into account (P = .48) was identified. There was no difference in ventilator-free or ICU-free days. Comparing Pediatric Index of Mortality (PIM)-2, Pediatric Risk of Mortality (PRISM)-3, and a multivariable model using independent risk factors identified through multivariable analysis, the receiver operating characteristic plot for the multivariable model (area under the curve = 0.844 [95% confidence interval: 0.77-0.92]) was superior to both PIM-2 and PRISM-3 in discriminating mortality. CONCLUSIONS: Fluid balance immediately preceding and early in the course of admission was not associated with mortality in PICU HSCT patients. A subset of variables was identified which better discriminated mortality in this cohort than accepted PICU severity of illness scores.

The dual pathway inhibitor rigosertib is effective in direct patient tumor xenografts of head and neck squamous cell carcinomas.

The dual pathway inhibitor rigosertib inhibits phosphoinositide 3-kinase (PI3K) pathway activation as well as polo-like kinase 1 (PLK1) activity across a broad spectrum of cancer cell lines. The importance of PIK3CA alterations in squamous cell carcinoma of the head and neck (HNSCC) has raised interest in exploring agents targeting PI3K, the product of PIK3CA. The genetic and molecular basis of rigosertib treatment response was investigated in a panel of 16 HNSCC cell lines, and direct patient tumor xenografts from eight patients with HNSCC [four HPV-serotype16 (HPV16)-positive]. HNSCC cell lines and xenografts were characterized by pathway enrichment gene expression analysis, exon sequencing, gene copy number, Western blotting, and immunohistochemistry (IHC). Rigosertib had potent antiproliferative effects on 11 of 16 HPV(-) HNSCC cell lines. Treatment sensitivity was confirmed in two cell lines using an orthotopic in vivo xenograft model. Growth reduction after rigosertib treatment was observed in three of eight HNSCC direct patient tumor lines. The responsive tumor lines carried a combination of a PI3KCA-activating event (amplification or mutation) and a p53-inactivating event (either HPV16- or mutation-mediated TP53 inactivation). In this study, we evaluated the in vitro and in vivo efficacy of rigosertib in both HPV(+) and HPV(-) HNSCCs, focusing on inhibition of the PI3K pathway. Although consistent inhibition of the PI3K pathway was not evident in HNSCC, we identified a combination of PI3K/TP53 events necessary, but not sufficient, for rigosertib sensitivity.

Hedgehog signaling alters reliance on EGF receptor signaling and mediates anti-EGFR therapeutic resistance in head and neck cancer.

The EGF receptor (EGFR)-directed monoclonal antibody cetuximab is the only targeted therapy approved for the treatment of squamous cell carcinoma of the head and neck (HNSCC) but is only effective in a minority of patients. Epithelial-to-mesenchymal transition (EMT) has been implicated as a drug resistance mechanism in multiple cancers, and the EGFR and Hedgehog pathways (HhP) are relevant to this process, but the interplay between the two pathways has not been defined in HNSCC. Here, we show that HNSCC cells that were naturally sensitive to EGFR inhibition over time developed increased expression of the HhP transcription factor GLI1 as they became resistant after long-term EGFR inhibitor exposure. This robustly correlated with an increase in vimentin expression. Conversely, the HhP negatively regulated an EGFR-dependent, EMT-like state in HNSCC cells, and pharmacologic or genetic inhibition of HhP signaling pushed cells further into an EGFR-dependent phenotype, increasing expression of ZEB1 and VIM. In vivo treatment with cetuximab resulted in tumor shrinkage in four of six HNSCC patient-derived xenografts; however, they eventually regrew. Cetuximab in combination with the HhP inhibitor IPI-926 eliminated tumors in two cases and significantly delayed regrowth in the other two cases. Expression of EMT genes TWIST and ZEB2 was increased in sensitive xenografts, suggesting a possible resistant mesenchymal population. In summary, we report that EGFR-dependent HNSCC cells can undergo both EGFR-dependent and -independent EMT and HhP signaling is a regulator in both processes. Cetuximab plus IPI-926 forces tumor cells into an EGFR-dependent state, delaying or completely blocking tumor recurrence.

A patient tumor transplant model of squamous cell cancer identifies PI3K inhibitors as candidate therapeutics in defined molecular bins.

Targeted therapy development in head and neck squamous cell carcinoma (HNSCC) is challenging given the rarity of activating mutations. Additionally, HNSCC incidence is increasing related to human papillomavirus (HPV). We sought to develop an in vivo model derived from patients reflecting the evolving HNSCC epidemiologic landscape, and use it to identify new therapies. Primary and relapsed tumors from HNSCC patients, both HPV+ and HPV-, were implanted on mice, giving rise to 25 strains. Resulting xenografts were characterized by detecting key mutations, measuring protein expression by IHC and gene expression/pathway analysis by mRNA-sequencing. Drug efficacy studies were run with representative xenografts using the approved drug cetuximab as well as the new PI3K inhibitor PX-866. Tumors maintained their original morphology, genetic profiles and drug susceptibilities through serial passaging. The genetic makeup of these tumors was consistent with known frequencies of TP53, PI3KCA, NOTCH1 and NOTCH2 mutations. Because the EGFR inhibitor cetuximab is a standard HNSCC therapy, we tested its efficacy and observed a wide spectrum of efficacy. Cetuximab-resistant strains had higher PI3K/Akt pathway gene expression and protein activation than cetuximab-sensitive strains. The PI3K inhibitor PX-866 had anti-tumor efficacy in HNSCC models with PIK3CA alterations. Finally, PI3K inhibition was effective in two cases with NOTCH1 inactivating mutations. In summary, we have developed an HNSCC model covering its clinical spectrum whose major genetic alterations and susceptibility to anticancer agents represent contemporary HNSCC. This model enables to prospectively test therapeutic-oriented hypotheses leading to personalized medicine.