Patterns and kinetics of hepatocellular carcinoma relapse post-liver transplantation: oligorecurrence and role of local therapies.

Background: Amongst patients with recurrent hepatocellular carcinoma (HCC) post-liver transplantation, systemic therapy options may be limited by immunosuppression or poor performance status. Thus, we aimed to assess the impact of metastasis-directed therapy to all sites of disease (MDT-All) in HCC patients with limited disease recurrence [i.e., oligorecurrence (oligoM1)] post-transplantation and characterize pre-transplant characteristics associated with oligoM1. Methods: In this retrospective cohort study, patients at a single institution with recurrent HCC post-liver transplantation were identified. OligoM1 disease was defined as ≤3 lesions at recurrence, while polyrecurrent (polyM1) disease was defined as >3 lesions. Outcomes were compared in patients with oligoM1 disease by receipt of MDT-All. Regression analyses were used to identify predictors of polyM1 disease and characteristics associated with post-recurrence outcomes. Results: Forty-three patients with recurrent HCC post-liver transplantation from 2005-2022 were identified. Twenty-seven (63%) patients had oligoM1. Microvascular invasion was independently associated with polyM1 [odds ratio (OR): 14.64; 95% confidence interval (CI): 1.48-144.77; P=0.022]. Elevated alpha-fetoprotein (AFP) ≥400 ng/mL [hazard ratio (HR): 2.44; 95% CI: 1.08, 5.52; P=0.033] at recurrence was independently associated with inferior overall survival (OS), while oligoM1 (HR: 0.42; 95% CI: 0.21, 0.87; P=0.018) was independently associated with favorable OS. Amongst patients with oligoM1 who received MDT-All (n=15) median OS was 38.4 vs. 16.1 months for those who did not receive MDT-All (log-rank P=0.021). There was a non-significant improvement in polyprogression-free survival (polyPFS) (median 14.0 vs. 10.7 months, P=0.1) amongst oligoM1 patients who received MDT-All compared to those who did not. Conclusions: Receipt of MDT-All was associated with improved OS amongst patients with limited HCC disease recurrence following liver transplantation.

Cavitary lung nodules as an extraintestinal manifestation of ulcerative colitis.

A man in his 30s with ulcerative colitis (UC) on immunosuppressive agents and extensive travel history presented with subacute dyspnoea and dry cough. CT of the chest demonstrated numerous cavitary pulmonary nodules. An extensive infectious, malignant and autoimmune evaluation was pursued, ultimately with histopathology most consistent with necrobiotic lung nodules as an extraintestinal manifestation of UC. Steroids and ustekinumab were initiated with improvement in symptoms and resolution of cavitary lesions on follow-up imaging. In a patient with inflammatory bowel disease and cavitary lung lesions, necrobiotic lung nodules should be considered, particularly when evaluation for infectious causes is negative.

Provider perceptions of medication for opioid used disorder (MOUD): A qualitative study in communities with high opioid overdose death rates.

BACKGROUND: Medication for Opioid Use Disorder (MOUD) has been shown to be a safe, cost-effective intervention that successfully lowers risk of opioid overdose. However, access to and use of MOUD has been limited. Our objective was to explore attitudes, opinions, and beliefs regarding MOUD among healthcare and social service providers in a community highly impacted by the opioid overdose epidemic. METHODS: As part of a larger ethnographic study examining neighborhoods in Allegheny County, PA, with the highest opioid overdose death rates, semi-structured qualitative in-person and telephone interviews were conducted with forty-five providers treating persons with opioid use disorders in these communities. An open coding approach was used to code interview transcripts followed by thematic analysis. RESULTS: Three major themes were identified related to MOUD from the perspectives of our provider participants. Within a variety of health and substance use service roles and settings, provider reflections revealed: (1) different opinions about MOUD as a transition to abstinence or as a long-term treatment; (2) perceived lack of uniformity and dissemination of accurate information of MOUD care, permitting differences in care, and (3) observed barriers to entry and navigation of MOUD, including referrals as a "word-of-mouth insider system" and challenges of getting patients MOUD services when they need it. CONCLUSIONS: Even in communities hard hit by the opioid overdose epidemic, healthcare providers' disagreement about the standard of care for MOUD can be a relevant obstacle. These insights can inform efforts to improve MOUD treatment and access for people with opioid use disorders.

A rapid-cycle assessment strategy for understanding the opioid overdose epidemic in local communities.

Background: Certain communities in the United States experience greater opioid-involved overdose mortality than others. Interventions to stem overdose benefit from contextual understandings of communities' needs and strengths in addressing the opioid crisis. This project aims to understand multiple stakeholder perspectives on the opioid epidemic in communities disproportionately affected by opioid-involved overdose mortality. Methods: We performed a rapid-cycle qualitative assessment study utilizing in-depth interviews with community stakeholders and observations of community meetings in eight communities in Allegheny County, Pennsylvania, USA, disproportionately impacted by opioid-involved overdose mortality. Stakeholder categories included: current and past illicit users of opioids; medical and social service providers; emergency medical services; law enforcement; spouse or other family members of illicit users/former users of opioids; government officials; school officials; community members. Content analysis was utilized to identify themes and answer study questions. Regular feedback to stakeholders was provided to support targeted interventions. Results: We performed semi-structured, in-depth interviews with 130 community stakeholders and 29 community meeting observations in 2018-2019. Participants perceived similar economic and social determinants as origins of the opioid overdose epidemic including lack of economic resources, loss of jobs, transient populations and dilapidated housing. However, they differed in their awareness of and attention to the epidemic. Awareness was dependent on the visibility of opioid use (presence of paraphernalia litter, location of drug users, media coverage, and relationship to users). Overall, there was good knowledge of naloxone for opioid overdose reversal but less knowledge about local syringe services programs. Perceptions of harm reduction efforts were ambivalent. Conclusions: Members of communities impacted by the opioid epidemic perceived that economic downturn was a major factor in the opioid overdose epidemic. However, the varied beliefs within and between communities suggest that interventions need to be tailored according to the cultural norms of place.

Polysubstance Use Among Pregnant Women With Opioid Use Disorder in the United States, 2007-2016.

OBJECTIVE: To assess trends in polysubstance use among pregnant women with opioid use disorder in the United States. METHODS: We conducted a time trend analysis of pooled, cross-sectional data from the National Inpatient Sample, an annual nationally representative sample of U.S. hospital discharge data. Among 38.0 million females aged 15-44 years with a hospitalization for delivery from 2007 to 2016, we identified 172,335 pregnant women with an International Classification of Diseases, Ninth Revision, Clinical Modification or International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis of opioid use disorder. Polysubstance use among pregnant women with opioid use disorder was defined as at least one co-occurring diagnosis of other substance use, including alcohol, amphetamine, cannabis, cocaine, sedative, or tobacco. We fit weighted multivariable logistic regression models to produce nationally representative estimates, including an interaction between year and rural compared with urban county of residence; controlled for age, race, and insurance type. Average predicted probabilities and 95% CIs were derived from regression results. RESULTS: Polysubstance use among women with opioid use disorder increased from 60.5% (95% CI 58.3-62.8%) to 64.1% (95% CI 62.8%-65.3%). Differential time trends in polysubstance use among women with opioid use disorder were found in rural compared with urban counties. Large increases in amphetamine use occurred among those in both rural and urban counties (255.4%; 95% CI 90.5-562.9% and 150.7%; 95% CI 78.2-52.7%, respectively), similarly to tobacco use (30.4%; 95% CI 16.9-45.4% and 23.2%; 95% CI 15.3-31.6%, respectively). Cocaine use diagnoses declined among women with opioid use disorder at delivery in rural (-70.5%; 95% CI -80.4% to -55.5%) and urban (-61.9%; 95% CI -67.6% to -55.1%) counties. Alcohol use diagnoses among those with opioid use disorder declined -57% (95% CI -70.8% to -37.7%) in urban counties but did not change among those in rural counties. CONCLUSION: Over the past decade, polysubstance use among pregnant women with opioid use disorder has increased more rapidly in rural compared with urban counties in the United States, with amphetamines and tobacco use increasing most rapidly.

Trends in Surgical Indications for Major Lower Limb Amputation in the USA from 2000 to 2016.

OBJECTIVE: Major lower limb amputation is an important cause of morbidity and mortality in the USA. Little is known about the prevalence of the various indications for amputation, or if these indications have changed over time. The purpose of this study was to assess the indications for major amputation over a 17 year period and to determine whether surgical indications have shifted over this time period. METHODS: A retrospective, population based analysis of patients undergoing major amputation between 2000 and 2016 was performed using the National Inpatient Sample. Surgical indications for major amputation were classified as chronic ischaemia, acute limb ischaemia (ALI), infection, oncological, trauma, other, or any combination of these indications. Prevalence rates of surgical indications were calculated using logistic regression. Prevalence differences across years were assessed using likelihood ratio tests to determine statistical significance. RESULTS: Of 1 002 119 weighted hospitalisations for patients undergoing major amputation during the study period, the majority had chronic ischaemia (72%) or infection (15%) as the primary indication for amputation. Patients were predominantly male (60%) and diabetic (61%). Renal insufficiency was the only measured comorbidity that changed significantly over time (from 6% to 39%), although changes in coding procedures are partially responsible for the increase. From 2000 to 2016, the proportion of amputations done for chronic ischaemia alone decreased from 60% to 40% (p < .001), while the proportion of amputations that included infection in the presence of chronic ischaemia nearly doubled from 20% to 40% (p < .001). Major amputation due to ALI, oncology, or trauma was stable across the study period. CONCLUSION: Surgical indications for major amputation have changed between 2000 and 2016. Infection related amputations increased significantly during the study period. Further evaluation and modification of treatment protocols for limb infection are crucial to decreasing infection related major limb amputation.

Cigarette smoking intensity informs outcomes after open revascularization for peripheral artery disease.

OBJECTIVE: Cigarette smoking is the leading risk factor for peripheral artery disease (PAD). Existing literature often defines smoking history in broad categories of current, former, and never smokers, which may not sufficiently identify patients at the highest risk for poor outcomes. The purpose of this study was to examine the use of more informative categorization of smoking and to determine the association with important revascularization outcomes. METHODS: We conducted a retrospective review of all patients undergoing open lower extremity revascularization for symptomatic PAD, defined as claudication (Rutherford 3) or critical limb ischemia (Rutherford 4-6), during a 5-year period (2013-2017). Smoking history, demographics, and comorbidities were abstracted from electronic health records from seven hospitals within our health care system. Smoking history was defined by intensity (packs/day), duration (years), pack-year history, and cessation time. Outcomes included major adverse limb events (MALEs), death, limb loss, and amputation-free survival. Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals (CIs) for each parameter adjusted for patients' demographics and comorbidities. Cumulative incidence is reported for outcomes at 30, 180, and 365 days of follow-up. RESULTS: We identified 693 patients undergoing open lower extremity revascularization for PAD (66% critical limb ischemia; 46% diabetes). The 1-year cumulative incidence of MALEs was 29.9% (95% CI, 26.4-33.9), whereas the 1-year incidence of death was 9.8% (95% CI, 7.5-12.7). The broad classification of current and former smokers identified no statistically significant differences in any measured outcomes. Patients who smoked more than one pack/day had 1.48 (95% CI, 1.01-2.16) times increase in risk of MALEs at 1 year compared with patients who smoked one or fewer packs/day. Patients who smoked more than one pack/day also had the highest 1-year amputation incidence (12.7%). Each of the four parameters was associated with increased risk of poor outcomes, although small sample size limited the precision of our estimates. CONCLUSIONS: We found that smoking intensity is particularly informative of outcomes of patients undergoing open lower extremity revascularization for symptomatic PAD. These findings lay the groundwork for future research on relevant smoking history parameters and benefits of smoking reduction and cessation for clinicians to discuss with patients and to better understand and inform patients of intervention risks and expected outcomes.

Mass cytometry of Hodgkin lymphoma reveals a CD4+ regulatory T-cell-rich and exhausted T-effector microenvironment.

In classical Hodgkin lymphoma (cHL), the host antitumor immune response is ineffective. Hodgkin Reed-Sternberg (HRS) cells have multifaceted mechanisms to evade the immune system, including 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) genetic alterations, overexpression of PD-1 ligands, and associated T-cell exhaustion and additional structural bases of aberrant antigen presentation. The clinical success of PD-1 blockade in cHL suggests that the tumor microenvironment (TME) contains reversibly exhausted T effector cells (Teffs). However, durable responses are observed in patients with ß2-microglobulin/major histocompatibility complex (MHC) class I loss on HRS cells, raising the possibility of non-CD8+ T cell-mediated mechanisms of efficacy of PD-1 blockade. These observations highlight the need for a detailed analysis of the cHL TME. Using a customized time-of-flight mass cytometry panel, we simultaneously assessed cell suspensions from diagnostic cHL biopsies and control reactive lymph node/tonsil (RLNT) samples. Precise phenotyping of immune cell subsets revealed salient differences between cHLs and RLNTs. The TME in cHL is CD4+ T-cell rich, with frequent loss of MHC class I expression on HRS cells. In cHLs, we found concomitant expansion of T helper 1 (Th1)-polarized Teffs and regulatory T cells (Tregs). The cHL Th1 Tregs expressed little or no PD-1, whereas the Th1 Teffs were PD-1+ The differential PD-1 expression and likely functional Th1-polarized CD4+ Tregs and exhausted Teffs may represent complementary mechanisms of immunosuppression in cHL.

Isolation and high-dimensional phenotyping of gastrointestinal immune cells.

The gastrointestinal immune system plays a pivotal role in the host relationship with food antigens, the homeostatic microbiome and enteric pathogens. Here, we describe how to collect and process liver and intestinal samples to efficiently isolate and analyse resident immune cells. Furthermore, we describe a step-by-step methodology showing how to high-dimensionally immunophenotype resident leucocytes using cytometry by time-of-flight, providing a well-characterized antibody platform that allows the identification of every leucocyte subset simultaneously. This protocol also includes instructions to purify and cultivate primary murine hepatocytes, a powerful tool to assess basic cell biology and toxicology assays. Gut and liver samples from the same mouse can be collected, processed and stained in less than 6 hr. This protocol enables the recovery of several populations of purified and viable immune cells from solid and fibrous organs, preventing unwanted loss of adherent cells during isolation.

Low-dose IL-2 selectively activates subsets of CD4+ Tregs and NK cells.

CD4+ regulatory T cells (CD4Tregs) play a critical role in the maintenance of immune tolerance and prevention of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. IL-2 supports the proliferation and survival of CD4Tregs and previous studies have demonstrated that IL-2 induces selective expansion of CD4Tregs and improves clinical manifestations of chronic GVHD. However, mechanisms for selective activation of CD4Tregs and the effects of low-dose IL-2 on other immune cells are not well understood. Using mass cytometry, we demonstrate that low concentrations of IL-2 selectively induce STAT5 phosphorylation in Helios+ CD4Tregs and CD56brightCD16- NK cells in vitro. Preferential activation and expansion of Helios+ CD4Tregs and CD56brightCD16- NK cells was also demonstrated in patients with chronic GVHD receiving low-dose IL-2. With prolonged IL-2 treatment for 48 weeks, phenotypic changes were also observed in Helios- CD4Tregs. The effects of low-dose IL-2 therapy on conventional CD4+ T cells and CD8+ T cells were limited to increased expression of PD-1 on effector memory T cells. These studies reveal the selective effects of low-dose IL-2 therapy on Helios+ CD4Tregs and CD56bright NK cells that constitutively express high-affinity IL-2 receptors as well as the indirect effects of prolonged exposure to low concentrations of IL-2 in vivo.

Chronic headache and backache are long-term sequelae of unintentional dural puncture in the obstetric population.

INTRODUCTION: Unintentional dural puncture (UDP) and postdural puncture headache (PDPH) occur during the course of epidural catheter placement for labor analgesia with a reported incidence of 1%-5%. After UDP with an epidural needle, 80%-86% of patients develop PDPH. Acute symptoms after UDP are well known. However, few studies have evaluated the long-term complications of UDP, which is important in assisting parturients in the decision-making informed consent process. We sought to elucidate the long-term (>6 weeks) sequelae of PDPH by examining parturients who had UDP (both recognized and unrecognized) associated with labor epidural analgesia. METHODS: Parturients with a documented UDP (n = 308) over a 5-year period were followed up for acute and long-term residual symptoms (lasting >6 weeks) and compared with a control group (no documented UDP, n = 50) in the same period. Specific symptoms included headache, backache, neck ache, auditory symptoms, and visual symptoms. RESULTS: In comparing parturients with a UDP with control group (no UDP), differences were noted in overall acute symptoms (75.9% vs 21.7%, P < .001), specifically headache (87.0% vs 8.7%, P < .001), backache (47.2% vs 19.6%, P = .002), neck ache (30.1% vs 2.2%, P < .001), auditory (13.8% vs 0%, P = .02), and visual symptoms (19.5% vs 0%, P = .002). Differences were also noted in comparing chronic symptoms (26.5% vs 10.9%, P = .04) and specifically with respect to chronic headache (34.9% vs 2.2%, P < .001), backache (58.1% vs 4.4%, P < .001), and neck ache (14.0% vs 0%, P = .02). No differences were noted between groups in comparing chronic auditory and visual symptoms. CONCLUSION: Chronic headache and backache sequelae persist in the obstetrical population after UDP. When parturients are considering labor epidural analgesia, long-term sequelae should be discussed in the informed consent decision-making process.