Poor Disease Outcome Research Articles

Copy-number intratumor heterogeneity as high-risk feature of stage II colon cancer†.

Overall, the prognosis of patients suffering from stage II colon cancer is relatively favorable. However, a proportion of patients develop a recurrence following surgery. Clinical and histopathological properties that identify high‐risk patients are of limited value and better biomarkers are urgently required. In a recent issue of The Journal of Pathology, Lahoz et al proposed that copy‐number‐based biomarkers could be employed for patient stratification. The authors studied copy‐number alterations (CNAs) at the genomic scale by measuring the total CNA load (the aberrant genome fraction), and at a smaller scale by identifying common arm‐ or cytoband‐level alterations. Both the overall CNA load and specific chromosomal regions were associated with an increased risk of recurrence. Most interestingly, it was demonstrated that copy‐number intratumor heterogeneity, as defined by subclonal CNAs, is associated with poor disease outcome. This study demonstrates that structural genomic aberrations are promising biomarkers for patient stratification in early colon cancer. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Altered Expression of ACE2 and Co-receptors of SARS-CoV-2 in the Gut Mucosa of the SIV Model of HIV/AIDS.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the cause of the COVID-19 pandemic, is initiated by its binding to the ACE2 receptor and other co-receptors on mucosal epithelial cells. Variable outcomes of the infection and disease severity can be influenced by pre-existing risk factors. Human immunodeficiency virus (HIV), the cause of AIDS, targets the gut mucosal immune system and impairs epithelial barriers and mucosal immunity. We sought to determine the impact and mechanisms of pre-existing HIV infection increasing mucosal vulnerability to SARS-CoV-2 infection and disease. We investigated changes in the expression of ACE2 and other SARS-CoV-2 receptors and related pathways in virally inflamed gut by using the SIV infected rhesus macaque model of HIV/AIDS. Immunohistochemical analysis showed sustained/enhanced ACE2 expression in the gut epithelium of SIV infected animals compared to uninfected controls. Gut mucosal transcriptomic analysis demonstrated enhanced expression of host factors that support SARS-CoV-2 entry, replication, and infection. Metabolomic analysis of gut luminal contents revealed the impact of SIV infection as demonstrated by impaired mitochondrial function and decreased immune response, which render the host more vulnerable to other pathogens. In summary, SIV infection resulted in sustained or increased ACE2 expression in an inflamed and immune-impaired gut mucosal microenvironment. Collectively, these mucosal changes increase the susceptibility to SARS-CoV-2 infection and disease severity and result in ineffective viral clearance. Our study highlights the use of the SIV model of AIDS to fill the knowledge gap of the enteric mechanisms of co-infections as risk factors for poor disease outcomes, generation of new viral variants and immune escape in COVID-19.

Retrospective, Registry-based, Cohort Investigation of Clinical Outcomes in Patients with Cutaneous Squamous Cell Carcinoma and Basal Cell Carcinoma in Finland.

Most cases of keratinocyte cancer can be treated effectively with surgery. However, survival is reduced in patients with advanced disease. This retrospective cohort study evaluated overall survival of patients with invasive keratinocyte cancers, and high-risk features for progression of the disease and mortality in Finnish patients in a real-world setting. A total of 43,143 patients with keratinocyte cancer types of basal cell carcinoma and 10,380 with cutaneous squamous cell carcinoma were identified nationwide. More detailed patient records were available for a subset of patients (basal cell carcinoma n = 5,020 and cutaneous squamous cell carcinoma n = 1,482) from a regional database. Fifty percent of patients with advanced cutaneous squamous cell carcinoma died approximately 4.5 years after diagnosis. Multivariable models suggested that risk factors for keratinocyte cancer progression were male sex, presence of comorbidities, immunosuppression, and pre-cancerous lesions, while risk factors for disease-specific mortality were advanced disease stage with immunosuppression, other malignancies, and consecutive surgical excisions. These results suggest that identifying patient and tumour factors associated with poor disease outcome could be important when determining appropriate treatment and follow-up; however, further studies are necessary.

Acute and poor outcome of anti-glomerular basement membrane disease without circulating antibody in a young adolescent

Acute and poor outcome of anti-glomerular basement membrane disease without circulating antibody in a young adolescent

An umbrella review and meta-analysis of the use of renin-angiotensin system drugs and COVID-19 outcomes: what do we know so far?

IntroductionCoronavirus disease 2019 (COVID-19) is caused by the “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2), and commonly presents with fever, loss of smell/taste, and a persistent cough; in severe cases, patients require hospitalisation and external ventilation. Advanced age and pre-existing conditions such as cardiovascular diseases and diabetes have been associated with an increased risk of COVID-19 related mortality.Based on their mechanisms of action and widespread use among patients at high risk of poor disease outcomes, the impact of renin-angiotensin-aldosterone system (RAAS) inhibitors – including angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) – on COVID-19 related outcomes has become a topic of interest, resulting in rapid dissemination of a large number of predominantly retrospective, observational studies since early 2020. Since many of these studies were limited in scope and results were inconclusive, systematic reviews and meta-analyses of published and unpublished findings swiftly followed.AimTo assess the effect of ACEIs and ARBs on COVID-19 related outcomes by summarising the currently available evidence.MethodsUmbrella review of systematic reviews and subsequent meta-analysis. Eligible for inclusion were systematic reviews with meta-analysis focusing on patients with or without COVID-19 exposed to ACEIs and/or ARBs compared to patients not exposed to the medication. Outcomes of interest included risk of infection; hospitalisation; severity; and death. Reviews were identified through a literature search in Medline, EMBASE, Scopus, the Cochrane database of systematic reviews, and medRxiv, from 2019 until 1st of February 2021. Data was extracted using a standardised extraction sheet; the AMSTAR 2 Critical Appraisal Tool for systematic reviews was used for quality assessment. Heterogeneity between studies was evaluated using I2 statistics, and findings of included meta-analyses were summarised using random-effects models. The protocol was registered with PROSPERO (CRD42021233398).ResultsOut of an initial 157 publications, 66 systematic reviews underwent full text screening; after further exclusions based on pre-specified criteria, 47 studies were identified to be relevant. The number of included studies as well as the outcomes of interest varied widely between reviews, with death being the most common.Odds ratio for risk of COVID-19 infection among patients treated with ACEIs/ARBs versus patients not on treatment was 0.99 (95% Confidence Interval (CI) 0.97 – 1.02; 19 studies, I2 = 24.7%); and for hospitalisation among COVID-19 patients treated with ACEIs/ARBs versus not on treatment, 1.23 (95% CI 1.04 – 1.46; 11 studies, I2 = 76.4%); severe disease 0.86 (95% CI 0.78 – 0.95; 28 studies, I2 = 68%); and death, 0.80 (95% CI 0.75 – 0.86; 47 studies, I2 = 51.9%).ConclusionWhile treatment with ACEIs or ARBs does not appear to impact the risk of COVID-19 infection, it appears that patients on treatment have lower risks of severe disease and mortality compared to patients not on ACEIs/ARBS treatment. Findings should be interpreted cautiously as the systematic reviews/meta-analyses included in this study were of variable quality, and there was high heterogeneity among studies for most outcomes. Findings will inform evidenced-based guidelines on the appropriate measures for patients at risk of COVID-19 infection and prescribed RAAS inhibitors.

TREC/KREC Levels and T and B Lymphocyte Subpopulations in COVID-19 Patients at Different Stages of the Disease.

Background: T and B cell-mediated immunity can be assessed using T cell receptor excision circle (TREC) and Kappa-deleting recombination excision circle (KREC) analysis, respectively, and successful implementation of this method requires evaluation of the correlation between the TREC frequencies and T cell subsets as well as KREC levels and B lymphocyte subsets. The aim of the present study was to evaluate the correlation between the TREC/KREC concentrations and T/B lymphocyte subsets at different stages of COVID-19. Methods: We examined 33 patients in the acute stage of COVID-19 (including 8 patients with poor outcomes) and 33 COVID-19 survivors. TREC/KREC concentrations were measured using quantitative real-time PCR. T/B lymphocyte subsets were determined using flow cytometry. Results: Blood TREC and KREC levels were found to be significantly lower in the acute stage of COVID-19 compared to control values. Moreover, a zero blood TREC level was a predictor of a poor disease outcome. Reductions in CD3+CD4+CD45RO−CD62L− and CD3+CD8+CD45RO−CD62L− T cell counts (as well as in the main fractions of B1 and B2 B cells) indicated a favorable outcome in COVID-19 patients in the acute stage of the disease. Decreased CD3+CD4+CD45RO−CD62L+ and CD3+CD8+CD45RO−CD62L+ T cell frequencies and increased CD3+CD8+CD45RO−CD62L− cell counts were found to indicate a poor outcome in patients with acute COVID-19. These patients were also found to have increased B1 cell counts while demonstrating no changes in B2 cell counts. The levels of effector T cell subsets an naïve B cells were normal in COVID-19 survivors. The most pronounced correlations between TREC/KREC levels and T/B cell subsets counts were observed in COVID-19 survivors: there were positive correlations with naïve T and B lymphocytes and negative correlations with central and effector memory T cell subsets. Conclusions: The assessment of correlations between TREC and T cell subsets as well as KREC levels and B cell subset counts in patients with acute COVID-19 and COVID-19 survivors has shown that blood concentrations of TREC and KREC are sensitive indicators of the stage of antigen-independent differentiation of adaptive immunity cells. The results of the TREC and KREC analysis correlated with the stages of COVID-19 and differed depending on the outcome of COVID-19.

A Personalized, Telehealth Music Therapy Intervention for Lonely Older Adults: A Feasibility Study

<h3>Introduction</h3> Music listening interventions, facilitated by a qualified music therapist, have been shown to reduce late-life depression and anxiety but their impact on loneliness has not been well-studied. Risks associated with loneliness in older adults include depression, cognitive decline, poorer disease outcomes and premature mortality. This study evaluated the feasibility of a remotely-delivered, personalized music therapy intervention for older adults living alone during the COVID-19 pandemic, and assessed measures of socioemotional well-being before, during, and after the intervention. <h3>Methods</h3> We recruited community-dwelling cognitively unimpaired older adults who lived alone, endorsed loneliness and were able to use Zoom video conferencing. Individuals with cognitive impairment (TICS < 31), moderate-severe depression (GDS > 10), or hearing impairment were excluded. Eight weekly, individual music therapy sessions were conducted with a board-certified music therapist via Zoom to develop personalized music playlists and to learn specific music listening techniques. Participants listened to playlists for one hour daily, completed a daily journal, and answered online questionnaires at weeks 0 (pre), 4 (mid), and 8 (post). The primary outcome was the PROMIS Social Isolation Scale [PROMS] score. Other questionnaires included the Behavioral Activation for Depression Scale [BADS], Positive Affect and Well-Being Scale [PAWB], Perceived Stress Scale [PSS], Brief Symptom Inventory [BSI], and the Snaith-Hamilton Pleasure Scale [SHAPS]). Qualitative data were collected at week 8 for thematic analysis. <h3>Results</h3> From March to August 2021, 11 participants were enrolled (mean age 74.82 [66-85], 88% women), eight completed the study, and one dropped out, leaving two actively enrolled. Among those who completed, numerical scores for loneliness and all other outcomes changed in an improved direction. Pre- and post-study mean scores and baseline standard deviation for those who completed are reported: PROMS (x¯=20.0, 16.8; sd=5.88), BADS (x¯=36.3, 40.8; sd=10.48), PAWB (x¯=33.5, 37.1; sd=6.61), PSS (x¯=14.5, 11.6; sd=7.89), BSI (x¯=33.3, 23.5; sd=17.1), SHAPS (x¯=47.0, 50.62; sd=6.74). Qualitative interviews were notable for themes of joy and improvements in sleep, health, focus, and physical pain. Participants also reported increased connectedness to culture, country of origin, loved ones, and the music therapist. <h3>Conclusions</h3> Recruitment and participant acceptability of a virtual, personalized music therapy intervention have been positive. Interim data analysis points to a possible improvement in loneliness and other outcome measures, though limited by low statistical power. Music therapy appears to be a novel and feasible approach to address loneliness and emotional wellbeing in at-risk community-dwelling older adults.

Genomic instability detected from the saliva of Head and Neck Squamous Cell Carcinoma patients: Association with clinical implications

ObjectivesGenomic instability in cancers is often associated with poor disease outcomes. In Head and Neck Squamous Cell Carcinoma (HNSCC), saliva being the contact fluid contains cancers cells shed from the primary tumour. This study detected genomic instability from cancer cells shed in saliva and correlated the same with clinical implications. DesignGenomic instability in HNSCC patients (n = 81) was analysed and compared with control subjects (n = 30). Alu sequences were amplified from the DNA of the cells shed in saliva and from the blood (Germline DNA) using Alu-PCR. Band variations between amplified products of salivary cells' DNA and germline DNA were compared. 'Instability Score' was calculated by counting the band variation(s). The 'Instability Score' was further used as a measure of genomic instability. ResultsHigher instability was detected in patients as compared to the controls (p < 0.0001). After treatment, there was a significant decrease (p < 0.0001) in the Instability score and patients with higher instability scores responded better to radiotherapy. The patient group consuming both tobacco and alcohol had a higher instability score in comparison to the tobacco group (p = 0.0056). Also, Instability scores are inversely correlated with nodal metastasis (p = 0.0075). A high Instability score before treatment resulted in a better prognosis in HNSCC patients (HR: 1.8, 95%CI: 1.024–3.164, p = 0.0306). ConclusionOur data suggest that genomic instability estimated from the tumour cells shed in the saliva of HNSCC patients by amplifying Alu sequence (Alu-PCR) is associated with radiotherapy response.

Longitudinal Impact of Sputum Inflammatory Phenotypes on Small Airway Dysfunction and Disease Outcomes in Asthma

Little is known about the relationship between airway inflammatory phenotypes and some important asthma features such as small airway dysfunction (SAD). To describe the longitudinal impact of airway inflammatory phenotypes on SAD and asthma outcomes. We measured eosinophil and neutrophil counts in induced sputum at baseline and 1 year later to stratify 197 adult patients with asthma into 4 inflammatory phenotypes. We conducted a comprehensive assessment of lung function using spirometry, body plethysmography, impulse oscillometry, and inert gas single and multiple breath washouts. We compared lung function, asthma severity, exacerbation frequency, and symptom control between the phenotypes. We studied the longitudinal impact of persistent sputum inflammatory phenotypes and the change of sputum cell counts on lung function. Patients were stratified into eosinophilic (23%, n=45), neutrophilic (33%, n= 62), mixed granulocytic (22%, n= 43), and paucigranulocytic (24%, n= 47) phenotypes. Patients with eosinophilic and mixed granulocytic asthma had higher rates of airflow obstruction and severe exacerbation as well as poorer symptom control than patients with paucigranulocytic asthma. All SAD measures were worse in patients with eosinophilic and mixed asthma than in those with paucigranulocytic asthma (all P values <.05). Eosinophilic asthma also indicated worse distal airflow obstruction, increased ventilation inhomogeneity (all P values <.05), and higher tendency for severe exacerbation (P= .07) than neutrophilic asthma. Longitudinally, persistent mixed granulocytic asthma was associated with the worst follow-up measures of SAD compared with persistent neutrophilic, persistent paucigranulocytic, or nonpersistent asthma phenotypes. In patients with stable forced expiratory volume in 1 second (FEV1), the mean increase in small airway resistance (R5-20) was greater in patients with persistent mixed granulocytic asthma (+103%) than in patients with persistent neutrophilic (+26%), P= .040, or persistent paucigranulocytic asthma (-41%), P= .028. Multivariate models adjusted for confounders and treatment with inhaled or oral corticosteroids or antieosinophilic biologics indicated that the change of sputum eosinophil rather than neutrophil counts is an independent predictor for the longitudinal change in FEV1, forced expiratory flow at 25% to 75% of forced vital capacity, specific effective airway resistance, residual lung volume, and lung clearance index. In asthma, airway eosinophilic inflammation is the main driver of lung function impairment and poor disease outcomes, which might also be aggravated by the coexistence of airway neutrophilia to confer a severe mixed granulocytic asthma phenotype. Persistent airway eosinophilia might be associated with dynamic SAD even in patients with stable FEV1.

Integrated Analysis of Transcriptomic and Genomic Data Reveals Blood Biomarkers With Diagnostic and Prognostic Potential in Non-small Cell Lung Cancer.

Background: Lung cancer is the second most common cancer and the main leading cause of cancer-associated death worldwide. Non-small cell lung cancer (NSCLC) accounts for about 85% of lung cancer diagnoses and more than 50% of all lung cancer cases are diagnosed at an advanced stage; hence have poor prognosis. Therefore, it is important to diagnose NSCLC patients reliably and as early as possible in order to reduce the risk of mortality. Methods: We identified blood-based gene markers for early NSCLC by performing a multi-omics approach utilizing integrated analysis of global gene expression and copy number alterations of NSCLC patients using array-based techniques. We also validated the diagnostic and the prognostic potential of the gene signature using independent datasets with detailed clinical information. Results: We identified 12 genes that are significantly expressed in NSCLC patients’ blood, at the earliest stages of the disease, and associated with a poor disease outcome. We then validated 12-gene signature’s diagnostic and prognostic value using independent datasets of gene expression profiling of over 1000 NSCLC patients. Indeed, 12-gene signature predicted disease outcome independently of other clinical factors in multivariate regression analysis (HR = 2.64, 95% CI = 1.72–4.07; p = 1.3 × 10−8). Significantly altered functions, pathways, and gene networks revealed alterations in several key genes and cancer-related pathways that may have importance for NSCLC transformation, including FAM83A, ZNF696, UBE2C, RECK, TIMM50, GEMIN7, and XPO5. Conclusion: Our findings suggest that integrated genomic and network analyses may provide a reliable approach to identify genes that are associated with NSCLC, and lead to improved diagnosis detecting the disease in early stages in patients’ blood instead of using invasive techniques and also have prognostic potential for discriminating high-risk patients from the low-risk ones.

Haematological parameters in COVID-19 disease

Background: The coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and was declared as a pandemic by World Health Organization. Various haematological parameters alteration has been documented in SARS-CoV-2 infection. However, there is a need for research to evaluate the pattern of the haematological parameters of COVID-19 patients. Aims: The main aim of this study was to determine demographic characteristics, to study various haematological parameters and their relation with the outcome of the disease. Materials and Methods: A total of 150 patients who tested positive for COVID-19 were included in the study. A prospective study was done in the Department of Pathology, GCS Medical College, Hospital and Research Centre, Ahmedabad, for the period of 15 days (01 August 2020–15 August 2020). Patients were categorised according to severity, oxygen (O2) requirement and their the outcome. Haematological parameters and clinical data were obtained. Median values of age and haematological parameters were compared between these groups. Results: Patients who needed oxygen support had higher median age, absolute neutrophil count and platelet-to-lymphocyte ratio. Patients in the intensive care unit (ICU) had higher age, leucocytosis with absolute lymphopoenia and a high neutrophil-to-lymphocyte ratio. The parameters found to be associated with a poor outcome were higher median age with low haemoglobin, low mean corpuscular volume and absolute lymphopoenia. Conclusions: Males and older people are more prone to COVID-19 infection. Parameters such as high total leucocyte count, high absolute neutrophil count, low absolute lymphocyte count and high neutrophil-to-lymphocyte ratio may be considered cardinal laboratory findings with prognostic potential for the requirement of O2, ICU admission and poor outcome of COVID-19 disease.

Managed care opportunities and approaches to select treatment for sight preservation.

Anti-vascular endothelial growth factor therapies have become the mainstay of treatment for both diabetic macular edema and neovascular age-related macular degeneration. This treatment is imperative for vision preservation including visual acuity. However, treatment burdens include high costs, frequent injections, continued visual loss, and loss of ability to perform day-to-day functions. Although clinical trial data have provided insights to treatment options and protocols, real-world patient experiences and adherence to therapies do not often mimic clinical trials as patients cannot fully adhere to their treatment schedule, leading to poor disease outcomes. Payers may consider various strategies such as step therapies, fee schedule management, and driving utilization through specialty pharmacies to contain costs. However, it is important to recognize not all patients will respond to a one-size-fits-all approach to treatment, warranting a more personalized approach.

Low tricuspid annular plane systolic excursion is associated with a poor outcome in patients with COVID-19: A systematic review and meta-analysis.

Background: This systematic review and meta-analysis aimed to assess whether tricuspid annular plane systolic excursion (TAPSE) could be used as a prognostic tool in patients with coronavirus disease 19 (COVID-19).Methods:Studies on the relationship between TAPSE and COVID-19 since February 2021. Standardized mean difference (SMD) and 95% confidence intervals were used to assess the effect size. The potential for publication bias was assessed using a contour-enhanced funnel plot and Egger test. A meta-regression was performed to assess if the difference in TAPSE between survivors and nonsurvivors was affected by age, sex, hypertension or diabetes.Results:Sixteen studies comprising 1579 patients were included in this meta-analysis. TAPSE was lower in nonsurvivors (SMD −3.24 (−4.23, −2.26), P < .00001; I2 = 71%), and a subgroup analysis indicated that TAPSE was also lower in critically ill patients (SMD −3.85 (−5.31, −2.38,), P < .00001; I2 = 46%). Heterogeneity was also significantly reduced, I2 < 50%. Pooled results showed that patients who developed right ventricular dysfunction had lower TAPSE (SMD −5.87 (−7.81, −3.92), P = .004; I2 = 82%). There was no statistically significant difference in the TAPSE of patients who sustained a cardiac injury vs those who did not (SMD −1.36 (−3.98, 1.26), P = .31; I2 = 88%). No significant publication bias was detected (P = .8147) but the heterogeneity of the included studies was significant. A meta-regression showed that heterogeneity was significantly greater when the incidence of hypertension was <50% (I2 = 91%) and that of diabetes was <30% (I2 = 85%).Conclusion:Low TAPSE levels are associated with poor COVID-19 disease outcomes. TAPSE levels are modulated by disease severity, and their prognostic utility may be skewed by pre-existing patient comorbidities.Trial retrospectively registered (February 12, 2021):PROSPERO CRD42021236731

Perianal Crohn Disease Is More Common in Children and Is Associated With Complicated Disease Course Despite Higher Utilization of Biologics: A Population-based Study From The epidemiology group of the Israeli IBD Research Nucleus (epiIIRN).

Both perianal and pediatric-onset Crohn disease (CD) disease are associated with complicated disease course and higher drug utilization. we aimed to explore the differences between pediatric and adult-onset perianal CD and their disease course. We included all patients with newly diagnosed CD from 2005 to 2019 at two Israeli Health Maintenance Organizations, covering 78% of the population. A combination of ICD-9 codes, radiology and procedures was used to define fistulizing perianal CD (PCD) and its severity according to the association with simple and complex perianal disease. A total of 12,905 patients were included (2186 [17%] pediatric-onset, 10,719 [83%] adults), with a median follow-up of 7.8 years. PCD was diagnosed in 1530 (12%) patients, with higher incidence in children (308 [14%] children vs 1222 adults [11%]; P < 0.001). Children had higher incidence of severe PCD (141/308 [47%] vs 433/1222 [35%]; P < 0.001). At 5 years, children with PCD were more likely than adults to be treated with biologics (212 [69%] vs 515 [42%]; odds ratio [OR] 2.6 [95% confidence interval (CI) 1.6-4.0]; P < 0.001) and immunomodulators (238 [74%] vs 643 [53%]; OR 2.8 [95% CI 2.1-3.6]; P < 0.001). PCD in children was still associated with poorer disease outcomes as shown for surgeries (36 [12%] vs 93 [8%]; P = 0.02) and steroid-dependency (52 [17%] vs 156 [13%]; P < 0.001). Multivariable modeling indicated that the severity of PCD is a stronger predictor of disease course than age. PCD is more common in pediatric-onset CD and is associated with higher drug utilization and worse disease outcomes, in large due to higher rate of severe PCD in children.

CD70 is a promising CAR-T cell target in patients with advanced renal cell carcinoma.

384 Background: Renal cell carcinoma (RCC) comprises a heterogeneous group of tumors of different histological subtypes. Each subtype is characterized by distinct immunohistochemical and molecular features and different biology. Currently, patients with advanced RCC have poor disease outcomes despite recent breakthroughs in immunotherapy. Chimeric antigen receptor (CAR)-T cell therapy has produced remarkably effective and durable clinical responses in hematological malignancies. However, there have been very limited success of CAR-T cell therapy in solid tumors. CD70 and its signaling partner CD27 are cell surface molecules that have emerged as novel targets for immune modulation approach. CD70 is also a promising target for CAR-T cell therapy, as it is overexpressed on multiple types of solid tumors including RCC and not expressed in most normal tissue. Studies have shown clear cell RCC (CCRCC) commonly expresses CD70. To date, no studies has evaluated CD70 expression in metastatic RCC in comparison with primary RCC. Methods: Four Tissue Microarrays (TMAs) were constructed using 395 tumors from 374 patients with RCC, 4 to 8 cores per tumor. There were 359 primary tumors, 36 metastatic tumors, and 344 matched normal. The primary RCC included 309 CCRCC including 11 with sarcomatoid differentiation, 38 papillary RCC (pRCC) including 1 with sarcomatoid differentiation, 8 chromophobe RCC (ChRCC), and 4 collecting duct RCC (CDC). The metastatic RCC were composed of 31 CCRCC including 3 with sarcomatoid differentiation and 5 PRCC. CD70 expression was evaluated using immunohistochemistry (IHC) and Definiens image analysis. CD70 expression was measured using the percentage of CD70-positive tumor cells. A CD70-positive tumor was defined as CD70 immunopercentage ≥ cutoff value in at least one core. Results: CD70 staining was detected in tumor cells in primary and metastatic RCC, with minimal staining in normal renal parenchyma. When the positive cutoff was defined as ≥1% of tumor cells demonstrating CD70 staining, the positive rate in CCRCC, pRCC, ChRCC, CDC, and SarRCC was 98%, 32%, 0%, 11%, and 46%, respectively. When the positive cutoff was defined as ≥ 25% of tumor cells stained positive for CD70, the positive rate in CCRCC, pRCC, ChRCC, CDC, and SarRCC was 41%, 10%, 0%, 0%, and 23%, respectively. Finally, when the positive cutoff was defined as ≥50%, the positive rate in CCRCC, pRCC, ChRCC, CDC, and SarRCC was 22%, 2%, 0%, 0%, and 8%, respectively. Metastatic RCC showed a higher % of tumor cells expressing CD70 compared to primary RCC for patients with CCRCC (mean 15% vs 9%) or SarRCC (12% vs 9%). Conclusions: Clear cell and sarcomatoid RCC are the RCC subtypes that demonstrate the highest CD70 expression. CD70 expression is further increased in metastatic lesions compared to the primary tumors. Anti-CD70 CAR-T cell therapy may benefit a significant fraction of patients with advanced CCRCC and sarcomatoid RCC.

Nerve Dependence in Colorectal Cancer.

Cancerous invasion of nerves has been reported in a list of malignant tumors as a high-risk pathological feature and marker of poor disease outcome especially in neurotrophic cancers (such as in pancreas and prostate), indicating that although once neglected, nerves could have played a pivotal role in tumorigenesis and cancer progression. In colorectal cancer, perineural invasion, a specific form of tumor-nerve interaction referring to the identification of tumor cells in proximity to the nerve, has been recognized as a strong and independent prognosis predictor; denervation of autonomic nerves and enteric nerves have shown that the existence of these nerves in the gut are accompanied by promoted cancer proliferation, further supporting that nerve is a potential accomplice to shield and nurture tumor cells. However, the precise role of nerve in CRC and the pattern of interaction between CRC cells and nerve has not been unveiled yet. Here we aim to review some basic knowledge of the importance of nerves in CRC and attempt to depict a mechanistic view of tumor-nerve interaction during CRC development.

Co-occurrence CDK4/6 amplification serves as biomarkers of de novo EGFR TKI resistance in sensitizing EGFR mutation non-small cell lung cancer

Despite the development of predictive biomarkers to shape treatment paradigms and outcomes, de novo EGFR TKI resistance advanced non-small cell lung cancer (NSCLC) remains an issue of concern. We explored clinical factors in 332 advanced NSCLC who received EGFR TKI and molecular characteristics through 65 whole exome sequencing of various EGFR TKI responses including; de novo (progression within 3 months), intermediate response (IRs) and long-term response (LTRs) (durability > 2 years). Uncommon EGFR mutation subtypes were significantly variable enriched in de novo resistance. The remaining sensitizing EGFR mutation subtypes (exon 19 del and L858R) accounted for 75% of de novo resistance. Genomic landscape analysis was conducted, focusing in 10 frequent oncogenic signaling pathways with functional contributions; cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGF-β, p53 and β-catenin/Wnt signaling. Cell cycle pathway was the only significant alteration pathway among groups with the FDR p-value of 6 × 10–4. We found only significant q-values of < 0.05 in 7 gene alterations; CDK6, CCNE1, CDK4, CCND3, MET, FGFR4 and HRAS which enrich in de novo resistance [range 36–73%] compared to IRs/LTRs [range 4–22%]. Amplification of CDK4/6 was significant in de novo resistance, contrary to IRs and LTRs (91%, 27.9% and 0%, respectively). The presence of co-occurrence CDK4/6 amplification correlated with poor disease outcome with HR of progression-free survival of 3.63 [95% CI 1.80–7.31, p-value < 0.001]. The presence of CDK4/6 amplification in pretreatment specimen serves as a predictive biomarker for de novo resistance in sensitizing EGFR mutation.

PREDICTORS OF CLINICAL OUTCOMES IN INDIAN PATIENTS WITH ACUTE ENCEPHALOPATHY: A PROSPECTIVE OBSERVATIONAL STUDY FROM A TERTIARY CARE CENTER IN INDIA

Objective: Objective of the study was to evaluate the predictors of poor disease outcome at discharge and at 1 month in patients with acute encephalopathy. Methods: This prospective, observational, single center study included adult patients meeting the diagnostic criteria for acute confusion state and admitted in the intensive care unit of a tertiary care hospital. A modified Rankin Scale (mRS) score of &lt;3 was considered as “good outcome,” while mRS ≥3 was considered as an indicator of “poor outcome.” Results: Among the total population of 219, 52.5% (n=115) were male, the mean age was 41.58 (±18.10) years and mean disease duration was 14.30 (±10.05) days (range: 1–30 days). Lethargy was the most common history at presentation (84.93%), while sleep abnormalities were least common (4.57%), and tuberculous meningitis was the most common etiology (21%). Diminution of vision, diplopia, dysarthria, cranial nerve symptoms, abdominal pain, difficulty in breathing, seizures, high-risk behavior, loss of appetite and the diagnosis of posterior reversible encephalopathy, retroviral disease, stroke and tuberculous meningitis were significant predictors of “poor outcome” at discharge (p&lt;0.05). A diagnosis of tuberculous meningitis, history of headache, diminution of vision, diplopia, dysarthria, seizures, sensory deficits and loss of appetite and neuroimaging findings of atrophy, intracranial bleeding, demyelination, and space-occupying lesion were found to be significant predictors of “poor outcome” at 1 month post-discharge in this population (p&lt;0.05). Conclusion: In patients with acute encephalopathy, tuberculous etiology, the presence of focal brainstem deficits and specific neuroimaging findings indicate poor outcomes at discharge as well as at 1 month follow-up.

Role of the PI3K/Akt signaling pathway in liver ischemia reperfusion injury: a narrative review.

To explore the role of phosphatidylinositol-3-kinase/protein kinase B and alpha serine/threonine protein kinase PI3K/PKB (also known as PI3K/Akt) signaling pathway in liver ischemia reperfusion injury. The PI3K/Akt signaling pathway is one of the major signal transduction pathways that regulates numerous cellular activities in vivo. The main functions of this pathway include induction of stem cell differentiation and metastasis, promotion of cell proliferation, inhibition of apoptosis, and regulation of tissue inflammation, tumor growth, and invasion. Liver ischemia reperfusion injury is an inevitable clinical problem that can occur during liver transplantation, liver resection, and various circulatory shock events, and it is one of the primary reasons for postoperative liver dysfunction, and poor disease outcome and patient prognosis. In recent years, it has been found that PI3K/Akt signaling pathway is closely related to liver ischemia reperfusion injury. In this review, a large number of relevant literatures were collected to explain the biological basis of PI3K/Akt signaling pathway and its role in liver ischemia reperfusion injury. The review was based on a PubMed search using the terms "liver ischemia reperfusion injury", "PI3K/Akt signaling pathway", and "PI3K/Akt signaling pathway AND liver ischemia reperfusion injury", so as to understand the complex interaction between them. Activated PI3K/Akt signaling pathway can exert anti-inflammatory, antioxidant stress, anti-apoptosis and autophagy regulation effects through downstream related targeted pathways and proteins, thus alleviating liver ischemia-reperfusion injury. Therefore, the regulation of PI3K/Akt signaling pathway is expected to become an effective targeted pathway for clinical prevention and alleviation of liver ischemia reperfusion injury.

P388 Asking teenagers and young adults with IBD; “what matters to you?”. A qualitative survey during the COVID-19 pandemic

BackgroundGood paediatric to adult transition of IBD care is important to prevent disengagement and poor disease outcomes [1]. The aim of this study was to qualitatively measure what is important to patients before they attended a new transitional service. There may be a dichotomy between the treating healthcare workers’ priorities and teenagers’ priorities that form a barrier to effective communication. Unprepared services can result in negative consequences for those involved [2] and a greater understanding of what matters to teenagers and young adults may improve the clinicians’ ability to facilitate the transition process.MethodsWe asked, 75 teenagers and young adults, aged between, 14 and, 21, who attended a new transitional service at a tertiary IBD unit in the North of England, to complete a survey prior to their clinic review. This ‘what matters to you’ survey included, 12 suggestions they could circle, with no limitations on how many many they selected, but a suggestion to choose up to, 3 topics. The survey was conducted during the COVID-19 pandemic and UK national lockdown, between September, 2020 and September, 2021.Results ConclusionInflammatory bowel disease is a condition with potentially a high morbidity from physical symptoms, and it is important not to forget this as a focus of a consultation. Medical therapies and their effects on the patient were important to, 48% of responders, and the transition process should include further education on treatment options with discussions of compliance. The impact on education and schooling feature as a significant topic and should be discussed during transition. Minimising the impact on education and employment should be considered when developing transitional services. Mental health wellbeing and body image were highly significant to a smaller number of patients and remain an important consideration. Interestingly not a single responder including the COVID-19 outbreak as a concern despite universally being on biological therapy or immunomodulators. It is important to note that whilst no patients reported ‘smoking, drugs and alcohol’ as important, risk-taking behaviours are increased in this patient population [3], they need to be sensitively discussed to become apparent and may be under-represented with the methodology used.