Correlation of MET-Receptor Overexpression with MET Gene Amplification and Patient Outcome in Malignant Mesothelioma

Thanks to clinically newly introduced inhibitors of the mesenchymal–epithelial transition (MET) receptor tyrosine-kinase, MET-gene copy number gain/amplification (MET-GCNG/GA) and increased expression of the MET protein are considered very promising therapeutic targets in lung cancer and other malignancies. However, to which extent these MET alterations occur in malignant mesothelioma (MM) remains unclear. Thus, we investigated by well-established immunohistochemistry and fluorescence in situ hybridization methods, the frequency of these alterations in specimens from 155 consecutive MMs of different subtypes obtained from pleural or peritoneal biopsies and pleurectomies. Thirty-three benign reactive mesothelial proliferations (RMPs) were used as controls. MET-protein upregulation was observed in 35% of all MM-cases, though restricted to predominantly epithelioid MMs. We detected low-/intermediate-level MET-GCNG/GA in 22.2% of MET-overexpressing MMs (7.8% of whole MM-cohort) and no MET-GCNG/GA in the other 77.8%, suggesting other upregulating mechanisms. In contrast, 100% of RMPs exhibited no MET-upregulation or MET-GCNG/-GA. Neither MET exon 14 skipping mutations nor MET-fusions were detected as mechanisms of MET overexpression in MM using RNA next-generation sequencing. Finally, in two cohorts of 30 MM patients with or without MET overexpression (MET-positive/-negative) that were matched for several variables and received the same standard chemotherapy, the MET-positive cases showed a significantly lower response rate, but no significant difference in progression-free or overall survival. Our results imply that MET overexpression occurs in a substantial fraction of predominantly epithelioid MMs, but correlates poorly with MET-amplification status, and may impact the likelihood of response to mesothelioma standard chemotherapy. The predictive significance of MET-IHC and -FISH for possible MET-targeted therapy of MM remains to be elucidated.

Effect of prenotification on the response rate of a postal survey of emergency physicians: a randomised, controlled, assessor-blind trial

ObjectivesResponse rates to physician surveys are typically low. The objective of this study was to determine the effect of a prenotification letter on the response rate of a postal survey of emergency physicians.DesignThis was a substudy of a national, cross-sectional postal survey sent to emergency physicians in Canada. We randomised participants to either receive a postal prenotification letter prior to the survey, or to no prenotification letter.ParticipantsA random sample of 500 emergency physicians in Canada. Participants were selected from the Canadian Medical Directory, a national medical directory which lists more than 99% of practising physicians in Canada.InterventionsUsing computer-generated randomisation, physicians were randomised in a concealed fashion to receive a prenotification letter approximately 1 week prior to the survey, or to not receive a prenotification letter. All physicians received an unconditional incentive of a $3 coffee card with the survey instrument. In both groups, non-respondents were sent reminder surveys approximately every 14 days and a special contact using Xpresspost during the final contact attempt.OutcomeThe primary outcome was the survey response rate.Results201 of 447 eligible physicians returned the survey (45.0%). Of 231 eligible physicians contacted in the prenotification group, 80 (34.6%) returned the survey and among 237 eligible physicians contacted in the no-prenotification group, 121 (51.1%) returned the survey (absolute difference in proportions 16.5%, 95% CI 2.5 to 30.5, p=0.01).ConclusionInclusion of a prenotification letter resulted in a lower response rate in this postal survey of emergency physicians. Given the added costs, time and effort required to send a prenotification letter, this study suggests that it may be more effective to omit the prenotification letter in physician postal surveys.

Predisposing factors of long-term responsiveness in a cardio-metabolic cohort: Tehran Lipid and Glucose Study

Background Non-participation in cohort studies, if associated with both the exposure and occurrence of the event, can introduce bias in the estimates of interest. This study aims to identify factors associated with follow-up participation in Tehran Lipid and Glucose Study, a large-scale community-based prospective study in West Asia. Methods A sample of 10,368 adults from TLGS was included in the analysis. All analyses were split according to sex and age groups (20–39, 40–59, and 60 years). The associations between socio-demographic, health, and lifestyle factors with response rate were identified using the Generalized Estimating Equations model. Results Over the median of 15.7 years of follow up the response rate was 64.5%. The highest response rate was observed in those aged 40–59 years for both sexes. Current smokers had lower odds of response in both sexes for all age groups, ranging from 0.51 to 0.74, p < 0.01. In young adults, being single (OR = 0.79, OR = 0.57, p ≤ 0.01, respectively for men and women) and unemployed (OR = 0.73, OR = 0.76, p ≤ 0.01, respectively for men and women) in both sexes, high physical activity in men (OR = 0.77, p < 0.01), high education (OR = 0.75, p = 0.02) and obesity (OR = 0.85, p = 0.05) in women were associated with lower response rate. For the middle-aged group, diabetes in men (OR = 0.77, p = 0.05) and hypertension (OR = 0.84, p = 0.05), and having a history of cancer (OR = 0.43, p = 0.03) in women were factors associated with lower response rates. Finally, interventions for both sexes (OR = 0.75, OR = 0.77, p ≤ 0.05, respectively for men and women) and being divorced/widow in women (OR = 0.77, p = 0.05) were the factors associated with the lower response rate in the elderly. Conclusions Long-term participation was influenced by socio-demographic, health, and lifestyle factors in different sex- and age-specific patterns in TLGS. Recruitment strategies targeting these factors may improve participant follow-up in longitudinal studies.

ERO1L Is a Novel and Potential Biomarker in Lung Adenocarcinoma and Shapes the Immune-Suppressive Tumor Microenvironment

BackgroundThe endoplasmic reticulum oxidoreductin-1-like (ERO1L) gene encodes an endoplasmic reticulum luminal localized glycoprotein known to associated with hypoxia, however, the role of ERO1L in shaping the tumor immune microenvironment (TIME) is yet to be elucidated in lung adenocarcinoma (LUAD).MethodsIn this study, raw datasets (including RNA-seq, methylation, sgRNA-seq, phenotype, and survival data) were obtained from public databases. This data was analyzed and used to explore the biological landscape of ERO1L in immune infiltration. Expression data was used to characterize samples. Using gene signatures and cell quantification, stromal and immune infiltration was determined. These findings were used to predict sensitivity to immunotherapy.ResultsThis study found that ERO1L was significantly overexpressed in LUAD in comparison to normal tissue. This overexpression was found to be a result of hypomethylation of the ERO1L promoter. Overexpression of ERO1L resulted in an immune-suppressive TIME via the recruitment of immune-suppressive cells including regulatory T cells (Tregs), cancer associated fibroblasts, M2-type macrophages, and myeloid-derived suppressor cells. Using the Tumor Immune Dysfunction and Exclusion (TIDE) framework, it was identified that patients in the ERO1Lhigh group possessed a significantly lower response rate to immunotherapy in comparison to the ERO1Llow group. Mechanistic analysis revealed that overexpression of ERO1L was associated with the upregulation of JAK-STAT and NF-κB signaling pathways, thus affecting chemokine and cytokine patterns in the TIME.ConclusionsThis study found that overexpression of ERO1L was associated with poor prognoses in patients with LUAD. Overexpression of ERO1L was indicative of a hypoxia-induced immune-suppressive TIME, which was shown to confer resistance to immunotherapy in patients with LUAD. Further studies are required to assess the potential role of ERO1L as a biomarker for immunotherapy efficacy in LUAD.

COVID -19 Vaccination in Patients with End Stage Kidney Disease. Early Results for an mRNA Vaccine in a Vulnerable Population

Patients with end stage kidney disease receiving dialysis treatment are at increased risk of COVID-19 infection. These patients have also higher rates of complications and mortality. The vulnerability may in part be explained by the profound changes in the immune system that are associated with impaired renal function. At the time of approval of the first vaccine for COVID-19, the BNT162b2 mRNA vaccine, there was no information on the efficacy and safety of the vaccine in dialysis patients. Preliminary reports on outcomes with the vaccine in the dialysis population have been published recently and the results are, in general, encouraging. However, these results indicate a lower response rate, a longer time to mount antibody response, lower antibody levels and possibly higher rate of COVID-19 breakthrough infection in the dialysis population. These results raise several questions that await further data to be reported. Meanwhile the dialysis patient’s population may still need special attention. Lessons learnt in this special population may also be applicable for other vulnerable patient groups.

During Vigilance to Painful Stimuli: Slower Response Rate Related to High Trait Anxiety, whereas a Faster Response Rate is related to High State Anxiety

A pathological increase in vigilance, or hypervigilance, may be related to pain intensity in some clinical pain syndromes and may result from attention bias to salient stimuli mediated by anxiety. During a continuous performance task where subjects discriminated painful target stimuli from painful nontargets, we measured detected targets (hits), nondetected targets (misses), nondetected nontargets (correct rejections), and detected nontargets (false alarms). Using signal detection theory, we calculated response bias, the tendency to endorse a stimulus as a target, and discriminability, the ability to discriminate a target from nontarget. Due to the relatively slow rate of stimulus presentation our primary hypothesis was that sustained performance would result in a more conservative response bias reflecting a lower response rate over time on task. We found a more conservative response bias with time on task and no change in discriminability. We predicted that greater state and trait anxiety would lead to a more liberal response bias. A multivariable model provided partial support for our prediction; high trait anxiety related to a more conservative response bias (lower response rate), while high state anxiety related to a more liberal bias. This inverse relationship of state and trait anxiety is consistent with reports of effects of state and trait anxiety on reaction times to threatening stimuli. In sum, we report that sustained attention to painful stimuli was associated with a decrease in the tendency of the subject to respond to any stimulus over time on task, while the ability to discriminate target from nontarget is unchanged.

Integrative multi-omics analysis of muscle-invasive bladder cancer identifies prognostic biomarkers for frontline chemotherapy and immunotherapy

Only a subgroup of patients with muscle-invasive bladder cancer (MIBC) are responders toward cisplatin-based chemotherapy and PD-L1 blockade immunotherapy. There is a clinical need to identify MIBC molecular subtypes and biomarkers for patient stratification toward the therapies. Here, we performed an integrative clustering analysis of 388 MIBC samples with multi-omics data and identified basal and luminal/differentiated integrative subtypes and derived a 42 gene panel for classification of MIBC. Using nine additional gene expression data (n = 844), we demonstrated the prognostic value of the 42 basal-luminal genes. The basal subtype was associated with worse overall survival in patients receiving no neoadjuvant chemotherapy (NAC), but better overall survival in patients receiving NAC in two clinical trials. Each of the subtypes could be further divided into chr9 p21.3 normal or loss subgroup. The patients with low expression of MTAP/CDKN2A/2B (indicative of chr9 p21.3 loss) had a significantly lower response rate to anti-PD-L1 immunotherapy and worse survival than the patients with high expression of MTAP/CDKN2A/2B. This integrative analysis reveals intrinsic MIBC subtypes and biomarkers with prognostic value for the frontline therapies.

Worse Response to Ursodeoxycholic Acid in Primary Biliary Cholangitis Patients with Autoimmune Hepatitis Features

Background: There is limited evidence on the treatment response of primary biliary cholangitis (PBC) with autoimmune hepatitis (AIH) features but not meet the criteria of PBC-AIH syndromes. This study was to elucidate the clinical characteristics of PBC patients with features of AIH. Methods: We included patients with diagnostic criteria of PBC. All patients were treated with ursodeoxycholic acid (UDCA) and without immunosuppressive agents for more than one year. The biochemical response was evaluated at one year after treatment of UCDA. Results: Among 432 patients with PBC, 166 (38.4%) patients did not achieve biochemical response within one year of UDCA treatment. Non-responders had lower albumin (ALB) level and higher immunoglobulin G (IgG), alanine transaminase (ALT), alanine aminotransferase (AST), alkaline phosphatase (ALP), glutamyl transpeptidase (GGT) and total bilirubin (TB) levels (P < 0.05). The response rates were significantly lower in patients with elevated level of IgG or ALT or AST. Moreover, the higher the IgG or AST level was, the lower the response rate was in patients with PBC regardless of cirrhosis. For patients with cirrhosis, there was no differences among patients with different level of ALT. Patients in the PBC with AIH features group had a significant lower response rate than patients in the PBC-only group. Among the 139 patients who underwent liver biopsy, 54 were non-responsive to UDCA and 48 (88.9%) shown mild interface hepatitis. Conclusion: In conclusion, PBC patients with AIH features had a worse response to UDCA therapy.

Outcomes of Therapy with Venetoclax Combined with Hypomethylating Agents in Favorable-Risk Acute Myeloid Leukemia (AML)

Introduction: Venetoclax (VEN) in combination with a hypomethylating agents (HMA) is associated with a high rate of composite remission (complete remission [CR] and complete remission with incomplete recovery [CRi]) among older and unfit patients with untreated AML. However, data regarding the activity of VEN-HMA in those patients with favorable-risk AML is limited, particularly in those with core-binding factor (CBF) alterations. Although more frequent among younger patients, favorable-risk alterations are also observed among older patients, often unfit for intensive regimens. Even among the subset of older patients (&gt;60 years) with favorable-risk AML eligible for intensive regimens, long-term outcomes are poorer in comparison to younger patients. Methods: We retrospectively analyzed outcomes of 46 patients with favorable-risk AML who underwent therapy with VEN-HMA between 2016-2020 at 4 academic cancer centers in US. Favorable-risk AML was defined by the presence of either CBF [t(8;21) and inv(16) or t(16;16)], NPM1 mutation in the absence of FLT-3 ITD mutations; or bi-allelic CEBPA mutations. Results: Forty-six patients with favorable risk AML were treated with HMA-VEN, including 26 (57%) with newly diagnosed (ND) and 20 (43%) with relapsed/refractory (R/R) AML (Table1). Ten (22%) patients had CBF, 21 (46%) had NPM1 mutations (NPM1m), and 13 (28%) had bi-allelic CEBPA mutations (CEBPAm). The median age was 70 years, and 54% were females. Patients with R/R AML were younger than ND patients (56 vs. 72 yrs, p=0.003). Twenty (44%) patients had secondary or therapy-related AML, including half of ND patients. The median lines of prior therapy were 2(1-4) in patients with R/R AML, including 6 (30%) who had failed prior allogeneic HCT. Eleven (24%) patients had received HMA prior to HMA-VEN therapy, including 1 patient in the ND cohort for prior MDS. Eleven (24%) patients received azacitidine in combination with VEN, while the rest (76%) of patients received decitabine, including 14 patients who received 10-day decitabine during the first cycle. The CR/CRi rate among the whole cohort was 80%, including 52% CR and 28% CRi. There was no statistically significant difference in CR/CRi rate between ND and R/R patients (88% vs. 70%, P =0.15). However, patients with history of prior HMA exposure had lower response rate compared to HMA-naïve patients (55% vs. 88%, p= 0.025). No difference in response was observed based on the favorable genetic alteration subgroups (80% in CBF vs. 86% in NPM1m vs. 77% in CEBPAm, p=0.44). Furthermore, no difference in response was observed according to patient age (p= 0.83), AML types (de novo vs. secondary; p= 0.47), prior transplant (p=1.00), or the type and schedule of HMA (P=0.66). Among the responders who had MRD assessment done (n= 26), 22 (85%) achieved MRD negativity by multicolor flow cytometry. Post response, 13 (35%) patients underwent allogeneic transplant consolidation. The median overall survival (OS) for the whole cohort was 18 months (12.5-NA). Median leukemia-free survival (LFS) was 13.2 months (7-20.2) for all responders, 11.2 months (1.7-NA) for ND responders, and 14.0 months (1-NA) for RR responders (p=0.986). The 30- and 60-day mortality for the whole cohort was 0% and 9%, respectively. Conclusion: In patients with favorable-risk AML, VEN-HMA combination is associated with a highly promising CR/CRi rate, with durable responses. The majority of responders achieved MRD negativity. Patients with prior use of HMA had lower response rate with VEN-HMA, nonetheless, over half of these patients responded despite most being treated in the R/R setting. Disclosures Pullarkat: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dova: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stein:Stemline: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Marcucci:Abbvie: Speakers Bureau; Merck: Other: Research Support (Investigation Initiated Clinical Trial); Novartis: Speakers Bureau; Pfizer: Other: Research Support (Investigation Initiated Clinical Trial); Takeda: Other: Research Support (Investigation Initiated Clinical Trial); Iaso Bio: Membership on an entity's Board of Directors or advisory committees. Yaghmour:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau. Bhatt:Omeros: Consultancy; Agios: Consultancy; Rigel: Consultancy; Tolero: Research Funding; Pfizer: Research Funding; Abbvie: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Partnership for health analytic research: Consultancy; Takeda: Consultancy; Jazz: Research Funding; National Marrow Donor Program: Research Funding; Oncoceutics: Other. Fathi:Takeda: Consultancy, Research Funding; Jazz: Consultancy; Forty Seven: Consultancy; Daiichi Sankyo: Consultancy; Amphivena: Consultancy; Blueprint: Consultancy; Kura Oncology: Consultancy; Boston Biomedical: Consultancy; Astellas: Consultancy; Trovagene: Consultancy; Novartis: Consultancy; PTC Therapeutics: Consultancy; Agios: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Pfizer: Consultancy; Trillium: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy; Newlink Genetics: Consultancy.

Recruitment of Men Into a Pragmatic Rural Primary Care Weight Loss Trial

Men remain underrepresented in behavioral weight loss trials and are more difficult to recruit compared to women. We describe recruitment response of men and women into a mixed-gender behavioral weight loss trial conducted within 36 rural primary care clinics. Participants were recruited through primary care clinics via direct mailings ( n = 15,076) and in-clinic referrals by their primary care provider (PCP). Gender differences were examined in response rate to direct mailings, study referral source, and rates of proceeding to study screening, being eligible, and enrolling. Men had a lower response rate to direct mailings than women (7.8% vs. 17.7%, p < .001). Men (vs. women) responding to the mailing were more likely to respond by opt-in postcard (64.6% vs. 56.8%) and less likely to respond by phone (33.9% vs. 39.6%), p = .002. Among potential participants contacting the study ( n = 2413), men were less likely to report being referred by PCPs (15.2% vs. 21.6%; p < .001), but were just as likely to proceed to screening, be eligible, and enroll. Men and women were more likely to proceed to screening when referred by PCPs (93.3% vs. 95.4%) compared to direct mailings (74.2% vs. 73.9%). Enrolled men were older ( p < .001), more likely to be married ( p = .04), and had higher levels of education ( p = .01). Men were less likely than women to respond to direct mailings and to be referred by their PCP, but after contacting the study, had similar screening, eligibility, and enrollment rates. Encouraging and training providers to refer men during clinic visits may help recruit more men into primary care-based weight loss trials.