Intratumoral Cell Neighborhoods Coordinate Outcomes in Pancreatic Ductal Adenocarcinoma.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDA) is a highly lethal disease characterized by a spatially heterogeneous tumor microenvironment. Within the PDA microenvironment, cells organize into communities where cell fate is influenced by neighboring cells of diverse ontogeny and function. However, it remains unclear how cell neighborhoods in the tumor microenvironment evolve with treatment and impact clinical outcomes. METHODS: Here, using automated chromogenic multiplex immunohistochemistry and unsupervised computational image analysis of human PDA tumors, we investigated cell neighborhoods in surgically resected tumors from patients with chemotherapy-naïve PDA (n = 59) and neoadjuvant chemotherapy-treated PDA (n = 57). Single cells were defined by lineage markers (CD3, CD8, Foxp3, CD68, CK19), proliferation (Ki67), and neighboring cells. RESULTS: Distinct intratumoral immune and tumor cell subsets were defined by neighboring cells. Higher content of stromal-associated macrophages was seen in chemotherapy-naïve tumors from long-term survivors (overall survival >3 years) compared with short-term survivors (overall survival <1 year), whereas immune-excluded tumor cells were higher in short-term survivors. Chemotherapy-treated vs -naïve tumors showed lower content of tumor-associated T cells and macrophages but similar densities of stromal-associated immune cells. However, proliferating tumor cell subsets with immune-rich neighborhoods were higher in chemotherapy-treated tumors. In a blinded analysis of tumors from patients treated with neoadjuvant chemotherapy, a composite index comprising lower quantities of immune-excluded tumor cells and higher spatially distinct immune cell subsets was associated with prolonged survival. CONCLUSIONS: Together, these data provide new insights into discrete cell communities in PDA and show their clinical relevance.

Gut microbiome-brain-cirrhosis axis.

Cirrhosis is characterized by inflammation, degeneration, and fibrosis of liver tissue. Along with being the most common cause of liver failure and liver transplant, cirrhosis is a significant risk factor for several neuropsychiatric conditions. The most common of these is HE, which is characterized by cognitive and ataxic symptoms, resulting from the buildup of metabolic toxins with liver failure. However, cirrhosis patients also show a significantly increased risk for neurodegenerative diseases such as Alzheimer and Parkinson diseases, and for mood disorders such as anxiety and depression. In recent years, more attention has been played to communication between the ways the gut and liver communicate with each other and with the central nervous system, and the way these organs influence each other's function. This bidirectional communication has come to be known as the gut-liver-brain axis. The gut microbiome has emerged as a key mechanism affecting gut-liver, gut-brain, and brain-liver communication. Clinical studies and animal models have demonstrated the significant patterns of gut dysbiosis when cirrhosis is present, both with or without concomitant alcohol use disorder, and have provided compelling evidence that this dysbiosis also influences the cognitive and mood-related behaviors. In this review, we have summarized the pathophysiological and cognitive effects associated with cirrhosis, links to cirrhosis-associated disruption of the gut microbiome, and the current evidence from clinical and preclinical studies for the modulation of the gut microbiome as a treatment for cirrhosis and associated neuropsychiatric conditions.

QuickStroop, a Shortened Version of EncephalApp, Detects Covert Hepatic Encephalopathy With Similar Accuracy Within One Minute.

BACKGROUND & AIMS: Covert hepatic encephalopathy (CHE) is associated with poor outcomes but is often not diagnosed because of the time requirement. Psychometric hepatic encephalopathy score (PHES) is the gold standard against which EncephalApp Stroop has been validated. However, EncephalApp (5 runs each in "Off" and "On" state) can take up to 10 minutes. This study sought to define the smallest number of EncephalApp runs needed for comparable accuracy to the total EncephalApp using CHE on PHES as gold standard. METHODS: A derivation and a validation cohort of outpatients with cirrhosis who underwent PHES (gold standard) and total EncephalApp was recruited. Data were analyzed for individual runs versus total EncephalApp time versus PHES-CHE. The derivation cohort (n = 398) was split into training (n = 299) and test (n = 99) sets. From the training data set a regression model was created with age, gender, education, and various sums of the "Off" settings. After this, a K-fold cross-validation on the test dataset was performed for both total EncephalApp time and individual Off runs and for the validation cohort. RESULTS: In both cohorts, Off runs 1 + 2 had statistically similar area under the receiver operating curve and P value to the total EncephalApp for PHES-CHE prediction. The adjusted (age, gender, education) regression formula from the derivation cohort showed an accuracy of 84% to diagnose PHES-CHE in the validation cohort. Time for CHE diagnosis decreased from 203.7 (67.82) to 36.8 (11.25) seconds in the derivation and from 178.2 (46.19) to 32.9 (9.94) seconds in the validation cohort. CONCLUSIONS: QuickStroop, which is completed within 1 minute, gives an equivalent ability to predict CHE on the gold standard compared with the entire EncephalApp time.

A Pilot E-Cigarette Voucher Scheme in a Rural County of the United Kingdom.

INTRODUCTION: E-Cigarette voucher schemes have been piloted across the UK to support populations to quit smoking. This short report evaluates a scheme that targets vulnerable and disadvantaged smokers who had failed to quit smoking by other means. METHODS: Descriptive summary evaluation of service data on smoking outcomes and qualitative data from selected participants, as "key-informants" (n = 4) and key stakeholders (stop smoking staff, vape shop staff, and general practitioners [GPs]). RESULTS: In total, 668 participants were referred to the scheme, and 340 participants redeemed a voucher. By intention to treat analysis (ITT) 143/668 (21%) were recorded as quit smoking at 4 weeks. At 12 weeks, 7.5% of participants had quit, by ITT. Overall, the pilot project was well received by clients as it offered an affordable route into vaping for smoking cessation. GPs supported the scheme and appreciated being able to offer an alternative to entrenched smokers. CONCLUSIONS: The scheme shows promise in supporting entrenched smokers to quit smoking. The offer of similar voucher schemes across the UK suggests the potential to reduce overall smoking prevalence and associated morbidity and mortality. IMPLICATIONS: Working with GPs in a deprived area, it was possible to set-up a vape shop voucher scheme for smoking cessation. Patients with comorbidities who had tried and failed to quit smoking previously were referred to receive a vape shop voucher to be redeemed for an initial starter kit, alongside support from the stop smoking service. This innovative scheme enabled 42% of entrenched smokers who redeemed a voucher to successfully quit smoking within 4 weeks.

Specific Challenges in Geriatric Cirrhosis and Hepatic Encephalopathy.

As the world's population ages, diseases predominantly found in the elderly now overlap with diseases that were thought to be the purview of younger patients. This includes chronic liver disease, which affects more than 2 billion people worldwide. Owing to the obesity epidemic (and associated metabolic diseases), nonalcoholic fatty liver disease has become the most common cause of chronic liver disease and cirrhosis. A major complication of cirrhosis is hepatic encephalopathy (HE), which becomes challenging to diagnose in elderly patients. HE is usually included in the differential diagnosis of acute delirium but not of reversible dementias. To illustrate this point, we present 2 cases of older patients that were misdiagnosed as having dementia and Parkinson's disease or a parkinsonian syndrome but had contributions from cirrhosis. Both cognitive impairment and tremor resolved with treatment of HE.

A Randomized Clinical Trial of Fecal Microbiota Transplant for Alcohol Use Disorder.

BACKGROUND AND AIMS: Alcohol use disorder (AUD) is associated with microbial alterations that worsen with cirrhosis. Fecal microbiota transplant (FMT) could be a promising approach. APPROACH AND RESULTS: In this phase 1, double-blind, randomized clinical trial, patients with AUD-related cirrhosis with problem drinking (AUDIT-10 > 8) were randomized 1:1 into receiving one placebo or FMT enema from a donor enriched in Lachnospiraceae and Ruminococcaceae. Six-month safety was the primary outcome. Alcohol craving questionnaire, alcohol consumption (urinary ethylglucuronide/creatinine), quality of life, cognition, serum IL-6 and lipopolysaccharide-binding protein, plasma/stool short-chain fatty acids (SCFAs), and stool microbiota were tested at baseline and day 15. A 6-month follow-up with serious adverse event (SAE) analysis was performed. Twenty patients with AUD-related cirrhosis (65 ± 6.4 years, all men, Model for End-Stage Liver Disease 8.9 ± 2.7) with similar demographics, cirrhosis, and AUD severity were included. Craving reduced significantly in 90% of FMT versus 30% in placebo at day 15 (P = 0.02) with lower urinary ethylglucuronide/creatinine (P = 0.03) and improved cognition and psychosocial quality of life. There was reduction in serum IL-6 and lipopolysaccharide-binding protein and increased butyrate/isobutyrate compared with baseline in FMT but not placebo. Microbial diversity increased with higher Ruminococcaceae and other SCFAs, producing taxa following FMT but not placebo, which were linked with SCFA levels. At 6 months, patients with any SAEs (8 vs. 2, P = 0.02), AUD-related SAEs (7 vs. 1, P = 0.02), and SAEs/patient (median [interquartile range], 1.5 [1.25] vs. 0 [0.25] in FMT, P = 0.02) were higher in placebo versus FMT. CONCLUSIONS: This phase 1 trial shows that FMT is safe and associated with short-term reduction in alcohol craving and consumption with favorable microbial changes versus placebo in patients with alcohol-associated cirrhosis with alcohol misuse. There was also a reduction in AUD-related events over 6 months in patients assigned to FMT.

Patient- and provider-level factors that underlie alcohol use disorder treatment offer and acceptance in veterans with cirrhosis.

BACKGROUND: Untreated alcohol use disorder (AUD) is associated with poor cirrhosis outcomes. We evaluated factors associated with AUD treatment discussions and initiation in the Veterans Health Administration. METHODS: Chart reviews were conducted for veterans with International Classification of Diseases codes for both cirrhosis and AUD who were receiving care at one of three large medical centers in 2020. Factors associated with a 1-year offer of AUD treatment and its acceptance were assessed using regression models, which included as covariates demographic characteristics, comorbidities, and depression, as measured by the patient health questionnaire (PHQ-2) from the electronic health record. RESULTS: The cohort included 654 veterans, 68 of whom were engaged in AUD treatment at baseline and 174 who were documented as being in AUD remission. Treatment was offered to 264 (64%) of the 412 veterans with opportunities to initiate it. AUD treatment discussions were most often documented by practitioners in primary care (n = 162), hepatology (n = 45), or both (n = 41). Multivariable logistic regression modeling revealed that treatment was significantly more likely to be offered to patients with co-occurring bipolar disorder (OR 2.94, p = 0.03) or depression (1.50, p = 0.05) or who were younger (0.97, p = 0.01). Of the 264 patients offered AUD treatment, 107 (40%) agreed to initiate it. Acceptance of an offer of treatment was significantly associated with hospitalization in the prior year (OR 1.74, p = 0.05), prior AUD treatment (9.92, p < 0.0001), and a higher PHQ-2 depression score (2.85, p = 0.004). CONCLUSIONS: We identified factors associated with an offer of AUD treatment and its initiation among veterans with cirrhosis. Application of these findings could increase the likelihood that veterans with alcoholic cirrhosis initiate AUD treatment.

Liver-Unrelated Comorbid Conditions Do Not Affect Cognitive Performance or Hepatic Encephalopathy Progression in Cirrhosis.

INTRODUCTION: We aimed to determine the effect of comorbidities on covert hepatic encephalopathy (CHE) diagnosis and overt hepatic encephalopathy (OHE) development. METHODS: Cirrhotic outpatients underwent CHE testing and 2-year follow-up. Cox regression was performed for time to OHE. In total, 700 patients (60 years, 84% men, model for end-stage liver disease 11) and 33% prior OHE underwent testing and follow-up. RESULTS: Major comorbidities were hypertension (54%), diabetes (35%), and depression (29%). Common medications were proton pump inhibitor (49%), beta-blockers (32%), and opioids (21%). Approximately 90 (40%) prior-OHE patients developed recurrence 93 (30,206) days post-testing predicted only by liverrelated variables. DISCUSSION: Demographics, cirrhosis characteristics, and opioid use, but not other comorbid conditions, were associated with CHE diagnosis and OHE progression.

Neuroinflammation in Murine Cirrhosis Is Dependent on the Gut Microbiome and Is Attenuated by Fecal Transplant.

Cirrhosis and hepatic encephalopathy (HE) is associated with an altered gut-liver-brain axis. Fecal microbial transplant (FMT) after antibiotics improves outcomes in HE, but the impact on brain function is unclear. The aim of this study is to determine the effect of colonization using human donors in germ-free (GF) mice on the gut-liver-brain axis. GF and conventional mice were made cirrhotic using carbon tetrachloride and compared with controls in GF and conventional state. Additional GF mice were colonized with stool from controls (Ctrl-Hum) and patients with cirrhosis (Cirr-Hum). Stools from patients with HE cirrhosis after antibiotics were pooled (pre-FMT). Stools from the same patients 15 days after FMT from a healthy donor were also pooled (post-FMT). Sterile supernatants were created from pre-FMT and post-FMT samples. GF mice were colonized using stools/sterile supernatants. For all mice, frontal cortex, liver, and small/large intestines were collected. Cortical inflammation, synaptic plasticity and gamma-aminobutyric acid (GABA) signaling, and liver inflammation and intestinal 16s ribosomal RNA microbiota sequencing were performed. Conventional cirrhotic mice had higher degrees of neuroinflammation, microglial/glial activation, GABA signaling, and intestinal dysbiosis compared with other groups. Cirr-Hum mice had greater neuroinflammation, microglial/glial activation, and GABA signaling and lower synaptic plasticity compared with Ctrl-Hum mice. This was associated with greater dysbiosis but no change in liver histology. Pre-FMT material colonization was associated with neuroinflammation and microglial activation and dysbiosis, which was reduced significantly with post-FMT samples. Sterile pre-FMT and post-FMT supernatants did not affect brain parameters. Liver inflammation was unaffected. Conclusion: Fecal microbial colonization from patients with cirrhosis results in higher degrees of neuroinflammation and activation of GABAergic and neuronal activation in mice regardless of cirrhosis compared with those from healthy humans. Reduction in neuroinflammation by using samples from post-FMT patients to colonize GF mice shows a direct effect of fecal microbiota independent of active liver inflammation or injury.

Focused Education Increases Hepatocellular Cancer Screening in Patients with Cirrhosis Regardless of Functional Health Literacy.

BACKGROUND: Health education interventions are successful in modifying lifestyle. Functional health literacy (FHL) can determine patient adherence to clinic visits and procedures and may adversely impact the success of these interventions. AIMS: We sought to evaluate the hypothesis that a health education intervention would improve compliance with hepatocellular cancer (HCC) screening and that poor FHL would reduce such compliance. METHODS: We assessed FHL using a short version test of functional health literacy in adults (STOFHLA). Cirrhotic patients free of HCC were prospectively enrolled from clinics and provided an educational intervention consisting of focused physician-led discussion regarding cirrhosis and HCC, along with written material on these topics for the subject to review at home. Patients were subsequently followed for 6 months (prospective time period), and the same cohort's clinic/HCC screening behavior between 6 and 12 months prior to the educational intervention (retrospective time period) was compared. RESULTS: In total, 104 cirrhotic patients (age 60.01 ± 8.58 years, 80% men, MELD 12.70 ± 5.76) were included. Of these, 89 (85.57%) of patients had educational level 12th grade and higher. There were 76% (n = 79) with adequate, while 24% (n = 25) had inadequate/marginal FHL on S-TOHFLA. The number of HCC-related imaging increased from 59 (56.7%) to 86 (82.6%, p < 0.0001) post-education in the prospective compared to prior time period which was similar regardless of FHL. CONCLUSIONS: While the educational intervention was successful in improving compliance with HCC screenings, FHL status did not impact the power of this intervention. Hence, the combination of specific verbal information, along with targeted written material, improved compliance with clinic visits and liver imaging for HCC.

Liver Transplant Is Associated with Sustained Improvement in Tandem Gait and Risk of Falls.

BACKGROUND: Cirrhosis is associated with poor health-related quality of life (HRQOL), cognitive dysfunction (CD), and lack of coordination leading to falls. Tandem gait (TG; heel-toe) can be used to assess coordination. The impact and relationship between CD, TG and falls pre-/post-liver transplant (LT) is unclear. We aimed to determine the impact of LT on CD, abnormal TG, and HRQOL in cirrhosis. METHODS: We analyzed patients who underwent complete neurological examination, cognitive testing by psychometric hepatic encephalopathy score (PHES), and HRQOL assessment using sickness impact profile (SIP). All patients were followed for 1 post-LT visit at 6 or 12 months post-LT for clinical course and falls. Change in CD, TD, and falls pre-/post-LT were compared. RESULTS: Off 131 recruited, 61 patients completed all visits. Majority were men (84%), with HCV etiology (34%). Pre-LT: Abnormal TG trended towards increased falls (OR 3.3, P = 0.08). Forty-nine % had abnormal TG, 61% had CD, 32.7% had CD + abnormal TG, 62% had prior OHE, and 14.7% had falls. Abnormal and normal TG patients had similar ages, BMI, sex, education level, and MELD scores. Abnormal TG group had higher prior overt HE (P = 0.03) and worse physical SIP score (P = 0.008). Post-LT: There was sustained improvement in CD, HRQOL, falls, and TG post-LT more at 12 than 6 months in all patients. Patients who had abnormal TG pre-LT continued to have a worse PHES (P = 0.0064) and physical SIP score (P = 0.008) compared to normal pre-LT TG patients. CONCLUSION: After LT, there is a sustained improvement in coordination measured via tandem gait, accompanied by a lower rate of falls.

A randomized phase 2 study of temsirolimus and cetuximab versus temsirolimus alone in recurrent/metastatic, cetuximab-resistant head and neck cancer: The MAESTRO study.

BACKGROUND: Patients with cetuximab-resistant, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) have poor outcomes. This study hypothesized that dual blockade of mammalian target of rapamycin and epidermal growth factor receptor (EGFR) would overcome cetuximab resistance on the basis of the role of phosphoinositide 3-kinase signaling in preclinical models of EGFR resistance. METHODS: In this multicenter, randomized clinical study, patients with recurrent/metastatic HNSCC with documented progression on cetuximab (in any line in the recurrent/metastatic setting) received 25 mg of temsirolimus weekly plus cetuximab at 400/250 mg/m2 weekly (TC) or single-agent temsirolimus (T). The primary outcome was progression-free survival (PFS) in the TC arm versus the T arm. Response rates, overall survival, and toxicity were secondary outcomes. RESULTS: Eighty patients were randomized to therapy with TC or T alone. There was no difference for the primary outcome of median PFS (TC arm, 3.5 months; T arm, 3.5 months). The response rate was 12.5% in the TC arm (5 responses, including 1 complete response [2.5%]) and 2.5% in the T arm (1 partial response; P = .10). Responses were clinically meaningful in the TC arm (range, 3.6-9.1 months) but not in the T-alone arm (1.9 months). Fatigue, electrolyte abnormalities, and leukopenia were the most common grade 3 or higher adverse events and occurred in less than 20% of patients in both arms. CONCLUSIONS: The study did not meet its primary endpoint of improvement in PFS. However, TC induced responses in cetuximab-refractory patients with good tolerability. The post hoc observation of activity in patients with acquired resistance (after prior benefit from cetuximab monotherapy) may warrant further investigation.

Surgical Outcome Results From SWOG S1505: A Randomized Clinical Trial of mFOLFIRINOX Versus Gemcitabine/Nab-paclitaxel for Perioperative Treatment of Resectable Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: The optimal neoadjuvant therapy for resectable pancreatic ductal adenocarcinoma (PDA) and the impact on surgical outcomes remains unclear. METHODS: S1505 (NCT02562716) was a randomized phase II study of perioperative chemotherapy with mFOLFIRINOX (Arm 1) or gemcitabine/nab-paclitaxel (Arm 2). Measured parameters included resection rate, margin positivity, pathologic response, and toxicity. RESULTS: Between 2015 and 2018, 147 patients were randomized. Of these, 44 (30%) were deemed ineligible (43 by central review). Of the 103 eligible patients, 77 (76%) completed preoperative therapy and underwent surgery; reasons patients did not undergo surgery included toxicity related to preoperative therapy (n = 9), progression (n = 9), or other (n = 7). Of the 77, 73 (95%) underwent successful resection; 21 (29%) required vascular reconstruction, 62 (85%) had negative (R0) margins, and 24 (33%) had a complete or major pathologic response to therapy. The grade 3-5 postoperative complication rate was 16%. Of the 73 patients completing surgery, 57 (78%) started and 46 (63%) completed postoperative therapy. This study represents the first prospective trial evaluating modern systemic therapy delivered in a neoadjuvant/perioperative format for resectable PDA. CONCLUSIONS: We have demonstrated: (1) Based on the high percentage of enrolled, but ineligible patients, it is clear that adherence to strict definitions of resectable PDA is challenging; (2) Patients can tolerate modern systemic therapy and undergo successful surgical resection without prohibitive perioperative complications; (3) Completion of adjuvant therapy in the perioperative format is difficult; (4) Major pathologic response rate of 33% is encouraging.

Minimal Hepatic Encephalopathy and Mild Cognitive Impairment Worsen Quality of Life in Elderly Patients With Cirrhosis.

BACKGROUND & AIMS: Patients with cirrhosis are growing older. The overlap between minimal hepatic encephalopathy (MHE) and predementia mild cognitive impairment (MCI) could affect quality of life (QOL). We investigated the performance of elderly patients with cirrhosis on tests for MHE and MCI and their effects on QOL. METHODS: We recruited outpatients with cirrhosis (n = 109) and without cirrhosis (controls, n = 100), 65 years or older, at 4 centers (derivation cohort). All study participants were assessed for psychometric hepatic encephalopathy score (PHES), EncephalApp score, and QOL. MCI was tested in patients with cirrhosis using the repeatable battery for assessment of neuropsychological status and assigned to the following groups: unimpaired, MCI only, MHE only, and MCI+MHE. We created adjusted norms to detect MHE using PHES and EncephalApp scores from the controls. Findings were validated using data from a separate cohort of 77 patients with cirrhosis (mean age, 69.49 ± 4.36 y; 72% men) at the same study sites. RESULTS: Controls were older but were more educated, performed better cognitively, and had better QOL. Among patients with cirrhosis, age, education, model for end-stage liver disease score, EncephalApp score, and QOL were similar, but PHES and repeatable battery for assessment of neuropsychological status differed among sites. In the derivation cohort, the presence of MHE, with or without MCI, was associated with poor QOL, which was lowest in the MCI+MHE group. When we adjusted for age, sex, and education, 49% of patients with cirrhosis had MHE based on the EncephalApp and 8% had MHE based on the PHES. A similar pattern (49% MHE based on EncephalApp and 6% MHE based on PHES) was found in a validation cohort. CONCLUSIONS: In a multicenter study of patients with cirrhosis (>65 y) and controls, the presence of MHE, regardless of MCI, was associated with poor cognition and QOL. We created adjusted norms that defined the high sensitivity of EncephalApp for the detection of MHE in older individuals and validated it in a separate cohort.

Training of hepatology providers improves the screening and resultant interventions for alcohol use disorder.

Alcohol use disorder (AUD) screening is important but focused training with using AUDIT-10 with counselling/mental health (MH) referral may be needed. We aimed to compare the effect of training on AUD screening/intervention in hepatology clinics in pre vs post-training phases of a quality-improvement initiative. Pre-training encounters were evaluated for inquiry into AUD, AUDIT-10 and MH referrals. Dedicated AUD-related training was provided to hepatology providers and analyses repeated post-training. Pre-training (n = 378) and post-training patients(n = 318) had similar demographics and disease characteristics. Post-training there was higher inquiry about alcohol(92% vs 80%, P < .0001), counselling (82% vs 68%, P < .0001). This led to higher diagnosis of drinkers (49% vs 31%, P < .0001) of whom higher proportion had AUDIT-10 administered(91% vs 34%, P < .0001) and referred to MH(29% vs 8%, P < .0001). On regression presumed alcohol-related aetiology, younger age and post-training period were associated with AUDIT-10 administration. AUD-focused training significantly improves rates of screening and MH referral for problem drinking in a hepatology clinic population.

A linear mass concentration detector for solvent gradient polymer separations.

Characterization of copolymers requires the measurement of two distributions-molecular weight (MW) and chemical composition (CC). Molecular weight distributions (MWD) are traditionally determined using size exclusion chromatography (SEC) run under isocratic solvent conditions. Chemical composition distributions (CCD) are often determined using liquid adsorption chromatography (LC) with solvent gradients. The use of solvent gradients, however, often limits options of compatible detectors. A gradient compatible, universal linear mass concentration detector is a longstanding unmet need. Many industrially-relevant polymers lack chromophores or other discriminating moieties requiring detectors with a universal response. Differential refractive index (dRI) is incompatible with gradient elution due to its small dynamic range. Charged aerosol detectors (CAD) and evaporative light scattering detectors (ELSD) are probably the most promising options for gradient elution detection, but both suffer from a nonlinear mass concentration response. Silicon photonic microring resonators are optical sensors that are responsive to changes in the local refractive index (RI). The substantial dynamic range of this technology makes it attractive for refractive index-based detection during solvent gradient elution. Previously, the microring resonator platform was used as a SEC detector to characterize the MWD of broadly dispersed polystyrene (PS) standards. In this study, we demonstrate the gradient compatibility of the microring resonator platform for polymer detection by quantifying the CCD of polymer blend components. Control experiments were run with UV and ELSD detection, highlighting the uniqueness of the platform as a linear mass concentration detector with a universal detector response.

Use of letrozole after aromatase inhibitor-based therapy in postmenopausal breast cancer (NRG Oncology/NSABP B-42): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: The optimal duration of extended therapy with aromatase inhibitors in patients with postmenopausal breast cancer is unknown. In the NSABP B-42 study, we aimed to determine whether extended letrozole treatment improves disease-free survival after 5 years of aromatase inhibitor-based therapy in women with postmenopausal breast cancer. METHODS: This randomised, double-blind, placebo-controlled, phase 3 trial was done in 158 centres in the USA, Canada, and Ireland. Postmenopausal women with stage I-IIIA hormone receptor-positive breast cancer, who were disease-free after about 5 years of treatment with an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor, were randomly assigned (1:1) to receive 5 years of letrozole (2·5 mg orally per day) or placebo. Randomisation was stratified by pathological node status, previous tamoxifen use, and lowest bone mineral density T score in the lumbosacral spine, total hip, or femoral neck. The primary endpoint was disease-free survival, defined as time from randomisation to breast cancer recurrence, second primary malignancy, or death, and was analysed by intention to treat. To adjust for previous interim analyses, the two-sided statistical significance level for disease-free survival was set at 0·0418. This study is registered with ClinicalTrials.gov, number NCT00382070, is active, and is no longer enrolling patients. FINDINGS: Between Sept 28, 2006, and Jan 6, 2010, 3966 patients were randomly assigned to receive letrozole (n=1983) or placebo (n=1983). Follow-up information was available for 3903 patients for the analyses of disease-free survival. Median follow-up was 6·9 years (IQR 6·1-7·5). Letrozole treatment did not significantly improve disease-free survival (339 disease-free survival events were reported in the placebo group and 292 disease-free survival events were reported in the letrozole group; hazard ratio 0·85, 95% CI 0·73-0·999; p=0·048). 7-year disease-free survival estimate was 81·3% (95% CI 79·3-83·1) in the placebo group and 84·7% (82·9-86·4) in the letrozole group. The most common grade 3 adverse events were arthralgia (47 [2%] of 1933 patients in the placebo group vs 50 [3%] of 1941 patients in the letrozole group) and back pain (44 [2%] vs 38 [2%]). The most common grade 4 adverse event in the placebo group was thromboembolic event (eight [<1%]) and the most common grade 4 adverse events in the letrozole group were urinary tract infection, hypokalaemia, and left ventricular systolic dysfunction (four [<1%] each). INTERPRETATION: After 5 years of aromatase inhibitor-based therapy, 5 years of letrozole therapy did not significantly prolong disease-free survival compared with placebo. Careful assessment of potential risks and benefits is required before recommending extended letrozole therapy to patients with early-stage breast cancer. FUNDING: National Cancer Institute, Korea Health Technology R&D Project, Novartis.

Association between body mass index and response to duloxetine for aromatase inhibitor-associated musculoskeletal symptoms in SWOG S1202.

BACKGROUND: Aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS) negatively impact adherence to and persistence with therapy. In SWOG S1202, patients with AIMSS who were treated with duloxetine, a serotonin norepinephrine reuptake inhibitor, reported improvement in pain by 12 weeks compared with placebo. Based on the authors' prior observation that responses to pain interventions differ between obese and nonobese patients, the current study examined whether response to duloxetine therapy differed by obesity status. METHODS: In SWOG S1202, a total of 299 AI-treated postmenopausal women with stage I to III (AJCC 7th Edition) breast cancer who developed new or worsening average pain were enrolled, randomized to duloxetine or placebo, and treated for 12 weeks. Patient-reported outcomes were obtained at baseline and through 12 weeks. Patients were categorized into nonobese (body mass index [BMI] <30 kg/m2 ) or obese (BMI ≥30 kg/m2 ). The authors tested the interaction between intervention and obesity with respect to average pain at 12 weeks in the 289 eligible patients, using a P value of .05 to indicate statistical significance. RESULTS: In approximately 54% of evaluable patients with a BMI ≥30 kg/m2 , the reduction in the mean average pain score between baseline and 12 weeks was statistically significantly greater for patients treated with duloxetine compared with those receiving placebo (-2.73 vs -1.64 points; P = .003). Conversely, in the nonobese patients, the reduction in the mean average pain score was similar in the 2 cohorts (-2.46 vs -2.34 points; P = .75). The P value for interaction was .02, thereby meeting the threshold criteria of the current study. Similar findings were evident for other pain-related patient-reported outcomes. CONCLUSIONS: In this trial, obese patients with AIMSS obtained more analgesic benefit from duloxetine compared with nonobese patients. Additional studies are warranted to determine the biologic basis for these findings.

Posttraumatic stress disorder is associated with altered gut microbiota that modulates cognitive performance in veterans with cirrhosis.

Posttraumatic stress disorder (PTSD) is associated with cirrhosis in veterans, and therapeutic results are suboptimal. An altered gut-liver-brain axis exists in cirrhosis due to hepatic encephalopathy (HE), but the added impact of PTSD is unclear. The aim of this study was to define linkages between gut microbiota and cognition in cirrhosis with/without PTSD. Cirrhotic veterans (with/without prior HE) underwent cognitive testing [PHES, inhibitory control test (ICT), and block design test (BDT)], serum lipopolysaccharide-binding protein (LBP) and stool collection for 16S rRNA microbiota composition, and predicted function analysis (PiCRUST). PTSD was diagnosed using DSM-V criteria. Correlation networks between microbiota and cognition were created. Patients with/without PTSD and with/without HE were compared. Ninety-three combat-exposed male veterans [ (58 yr, MELD 11, 34% HE, 31% combat-PTSD (42 no-HE/PTSD, 19 PTSD-only, 22 HE-only, 10 PTSD+HE)] were included. PTSD patients had similar demographics, alcohol history, MELD, but worse ICT/BDT, and higher antidepressant use and LBP levels. Microbial diversity was lower in PTSD (2.1 ± 0.5 vs. 2.5 ± 0.5, P = 0.03) but unaffected by alcohol/antidepressant use. PTSD (P = 0.02) and MELD (P < 0.001) predicted diversity on regression. PTSD patients showed higher pathobionts (Enterococcus and Escherichia/Shigella) and lower autochthonous genera belonging to Lachnospiraceaeae and Ruminococcaceae regardless of HE. Enterococcus was correlated with poor cognition, while the opposite was true for autochthonous taxa regardless of PTSD/HE. Escherichia/Shigella was only linked with poor cognition in PTSD patients. Gut-brain axis-associated microbiota functionality was altered in PTSD. In male cirrhotic veterans, combat-related PTSD is associated with cognitive impairment, lower microbial diversity, higher pathobionts, and lower autochthonous taxa composition and altered gut-brain axis functionality compared with non-PTSD combat-exposed patients. Cognition was differentially linked to gut microbiota, which could represent a new therapeutic target.NEW & NOTEWORTHY Posttraumatic stress disorder (PTSD) in veterans with cirrhosis was associated with poor cognitive performance. This was associated with lower gut microbial diversity in PTSD with higher pathobionts belonging to Enterococcus and Escherichia/Shigella and lower beneficial taxa belonging to Lachnospiraceaeae and Ruminococcaceae, with functional alterations despite accounting for prior hepatic encephalopathy, psychoactive drug use, or model for end-stage liver disease score. Given the suboptimal response to current therapies for PTSD, targeting the gut microbiota could benefit the altered gut-brain axis in these patients.

Silicon Photonic Microring Resonator Arrays for Mass Concentration Detection of Polymers in Isocratic Separations.

Molecular weight distribution (MWD) is often the most informative analytical parameter in polymer analysis, with gel permeation chromatography (GPC) being the most common approach for determining the MWD for polymer samples. Many industrially relevant polymers lack chromogenic or fluorogenic signatures, precluding use of spectroscopy-based detection. Universal detectors, such as evaporative light scattering and charged aerosol detectors, are nonlinear, limiting quantitative polymer analysis. Differential refractive index (dRI) detectors show linear mass concentration sensitivity but are limited for some analyses given that they are incompatible with gradient-based separations, have a limited dynamic range, and require extended thermal equilibration times. In this study, we investigated the utility of silicon photonic microring resonator arrays as a quantitative mass concentration detector for industrial polymer analysis. Microring resonators have optical properties that are sensitive to changes in refractive index, offer an extended dynamic range, have a broad solvent compatibility, and have a linear mass concentration detection for a range of molecular weights. Linear mass concentration detection for microrings was demonstrated through a series of isocratic GPC separations using narrow MWD polystyrene (PS) standards. This detection technology was then utilized in conjunction with conventional GPC detectors to analyze a series of broad MWD PS standards, with results in good agreement with dRI and UV/visible. These results demonstrate the potential of the microring resonator platform as a detector for industrial polymer analysis.