Poor Treatment Outcomes In Patients Research Articles

C-Myc inhibition and p21 modulation contribute to unsymmetrical bisacridines-induced apoptosis and senescence in pancreatic cancer cells.

Pancreatic cancer (PC) is one of the most aggressive cancers and is the seventh leading cause of cancer-related death worldwide. PC is characterized by rapid progression and resistance to conventional treatments. Mutations in KRAS, CDKN2A, TP53, SMAD4/DPC4, and MYC are major genetic alterations associated with poor treatment outcomes in patients with PC. Therefore, optimizing PC therapy is a tremendous challenge. Unsymmetrical bisacridines (UAs), synthesized by our group, are new promising compounds that have exhibited high cytotoxicity and antitumor activity against several solid tumors, including pancreatic cancer. The cellular effects induced by UAs in PC cells were evaluated by MTT assay (cell growth inhibition), flow cytometry, and fluorescence and light microscopy (cell cycle distribution, apoptosis, and senescence detection). Analysis of the effects of UAs on the levels of proteins (c-Myc, p53, SMAD4, p21, and p16) was performed by Western blotting. Apoptosis was the main triggered mechanism of death after UAs treatment, and induction of the SMAD4 protein can facilitate this process. c-Myc, which is one of the molecular targets of UAs, can participate in the induction of cell death in a p53-independent manner. Moreover, UAs can also induce accelerated senescence through the upregulation of p21. Notably, senescent cells can die via apoptosis after prolonged exposure to UAs. UAs have emerged as potent anticancer agents that induce apoptosis by inhibiting c-Myc protein and triggering cellular senescence in a dose-dependent manner by increasing p21 levels. Thus, UAs exhibit desirable features as promising candidates for future pancreatic anticancer therapies.

Risk factors for diagnosis and treatment delay among patients with multidrug-resistant tuberculosis in Hunan Province, China.

Multidrug-resistant tuberculosis (MDR-TB) is a global health threat associated with high morbidity and mortality rates. Diagnosis and treatment delays are associated with poor treatment outcomes in patients with MDR-TB. However, the risk factors associated with these delays are not robustly investigated, particularly in high TB burden countries such as China. Therefore, this study aimed to measure the length of diagnosis and treatment delays and identify their risk factors among patients with MDR-TB in Hunan province. A retrospective cohort study was conducted using MDR-TB data from Hunan province between 2013 and 2018. The main outcomes of the study were diagnosis and treatment delay, defined as more than 14days from the date of symptom to diagnosis confirmation (i.e., diagnosis delay) and from diagnosis to treatment commencement (i.e., treatment delay). A multivariable logistic regression model was fitted, and an adjusted odds ratio (AOR) with a 95% confidence interval (CI) was used to identify factors associated with diagnosis and treatment delay. In total, 1,248 MDR-TB patients were included in this study. The median length of diagnosis delays was 27days, and treatment delays were one day. The proportion of MDR-TB patients who experienced diagnosis and treatment delay was 62.82% (95% CI: 60.09-65.46) and 30.77% (95% CI: 28.27-33.39), respectively. The odds of experiencing MDR-TB diagnosis delay among patients coming through referral and tracing was reduced by 41% (AOR = 0.59, 95% CI: 0.45-0.76) relative to patients identified through consultations due to symptoms. The odds of experiencing diagnosis delay among ≥ 65years were 65% (AOR = 0.35, 0.14-0.91) lower than under-15 children. The odds of developing treatment delay among foreign nationalities and people from other provinces were double(AOR = 2.00, 95% CI: 1.31-3.06)compared to the local populations. Similarly, the odds of experiencing treatment delay among severely ill patients were nearly 2.5 timeshigher (AOR = 2.49, 95% CI: 1.41-4.42)compared to patients who were not severely ill.On the other hand, previously treated TB cases had nearly 40% (AOR = 0.59, 95% CI: 0.42-0.85) lower odds of developing treatment delay compared with new MDR-TB cases. Similarly, other ethnic minority groups had nearly 40% (AOR = 0.57, 95% CI: 0.34-0.96) lower odds of experiencing treatment delay than the Han majority. Many MDR-TB patients experience long diagnosis and treatment delays in Hunan province. Strengthening active case detection can significantly reduce diagnosis delays among MDR-TB patients. Moreover, giving attention to patients who are new to MDR-TB treatment, are severely ill, or are from areas outside Hunan province will potentially reduce the burden of treatment delay among MDR-TB patients.

Combination of pembrolizumab and lenvatinib in second-line therapy for MSS/pMMR advanced endometrial cancer: literature review and a case report

Despite the existing standard treatments for endometrial cancer, the prognosis for these patients remained poor until recently. None of currently available cytostatics ensured long-term disease control and long-term survival of patients receiving standard platinum-based therapy. Poor treatment outcomes in patients with advanced endometrial cancer necessitated changes in therapeutic approaches and development of more effective treatment regimens. Better understanding of carcinogenesis mechanisms, emergence of a new molecular classification of endometrial cancer, and implementation of tailored treatment approaches based on tumor types led to a significant breakthrough in the treatment of advanced endometrial cancer. Currently, the most effective second-line therapy for endometrial cancer with high level microsatellite instability (MSI-h) or deficient mismatch repair system (dMMR) (25 % of cases), and no indications for surgery is pembrolizumab monotherapy. Most of cancers (about 75 %) are represented by microsatellite-stable and mismatch repair proficient tumors (MSS/рMMR). Patients with such tumors demonstrating disease progression after systemic therapy should receive a combinations of the immune checkpoint inhibitor pembrolizumab and the multi-targeted tyrosine kinase inhibitor lenvatinib. In this article, we review relevant literature and report a case of successful treatment of MSS/pMMR advanced endometrial cancer with a combination of pembrolizumab and lenvatinib as a second-line therapy (after disease progression in response to platinum-containing first-line chemotherapy), which ensured long-term disease control.

Impact of Lifestyle Change Intervention on Tuberculosis Treatment Outcome in Tuberculosis Patients with Diabetes Mellitus Comorbidity in South West Nigeria

It is well documented in the literature that there is poor treatment outcome in patients with Tuberculosis and Diabetes (TBDM) comorbidity due to the observed interference of drugs for Tuberculosis (TB) treatment on anti-diabetic drugs and elevated glucose level reduces the efficacy of anti- tuberculosis drugs leading to poor TB treatment outcome, and that insulin therapy is not affected by this drug interaction. Importantly, access to Insulin is a challenge due to its prohibitive out-of-pocket cost. The only alternative sustainable treatment for TBDM patients in resource-limited communities is lifestyle-based intervention. This study evaluated the impact of lifestyle intervention on TB treatment outcomes in patients with TBDM comorbidity. This study is a quasi-experimental intervention involving two cohorts of 25 TBDM patients each, as control and experimental cohorts. Their enrolment was from Tuberculosis patients from health facilities in Lagos and Oyo states. The questionnaires were administered before the commencement of the Intervention and at 8 weeks. The sputum Acid Fast Bacillus (AFB) was checked, and chest x-ray (CXR) done before Intervention and Sputum AFB at 8 weeks. The Control group showed no difference in the means of the sputum AFB 95%CI: 0.12(- 0.12 – 0.36; p>0.05), which was an indication of poor treatment outcome. The difference in the means of the sputum AFB in the intervention group was statistically significant 95%CI: -0.8(-0.9 - -0.6; p<0.05). The intervention with educational and behavioral lifestyle modifications significantly improved the outcome of treatment of TB in TBDM comorbidity. Keywords: Behavioral change, Tuberculosis, Diabetes, comorbidity, Treatment outcome.

The Role of Food Addiction and Lifetime Substance Use on Eating Disorder Treatment Outcomes.

Food addiction (FA) and substance use (SU) in eating disorders (ED) have been associated with a more dysfunctional clinical and psychopathological profile. However, their impact on treatment outcomes has been poorly explored. Therefore, this transdiagnostic study is aimed at examining whether the presence of FA and/or SU is associated with treatment outcomes in patients with different ED types. The results were not able to reveal significant differences in treatment outcomes between patients with and without FA and/or SU; however, the effect sizes suggest higher dropout rates in the group with both FA and SU. The predictive models of treatment outcomes showed different features associated with each group. High persistence (i.e., tendency to perseverance and inflexibility) was the personality trait most associated with poor treatment outcomes in patients without addictions. High harm avoidance and younger age at ED onset were the variables most related to poor outcomes in patients with FA or SU. Finally, in the group with both addictive behaviors (FA and SU), the younger patients presented the poorest outcomes. In conclusion, our results suggest that, regardless of presenting addictive behaviors, patients with ED may similarly benefit from treatment. However, it may be important to consider the differential predictors of each group that might guide certain treatment targets.

Lower risk of depression after smoking cessation and alcohol abstinence in patients with gastric cancer who underwent gastrectomy: A population-based, nationwide cohort study.

Although depression is associated with poor treatment outcomes in patients with cancer, little is known about whether lifestyle modifications could help prevent depression. The authors aimed to identify the effect of lifestyle modifications, including smoking cessation, alcohol abstinence, and starting regular physical activity, on new-onset depression in patients with gastric cancer who underwent surgery. By using the Korean National Health Insurance Service database, patients with gastric cancer who underwent surgery between 2010 and 2017 were identified. Self-reported lifestyle behaviors within 2 years before and after surgery were analyzed using the health examination database. Patients were classified according to changes in lifestyle behaviors, and their risk of new-onset depression was compared. Among 18,902 patients, 2302 (12.19%) developed depression (26.00 per 1000 person-years). Smoking cessation (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.66-0.91) and alcohol abstinence (HR, 0.79; 95% CI, 0.69-0.90) were associated with reduced risk of depression development compared with persistent smoking and persistent drinking, respectively. Starting regular physical activity was not associated with risk of depression. When lifestyle behaviors after gastrectomy were scored from 0 to 3 points (1 point each for not smoking, not drinking, and being physically active), the risk of depression tended to decrease as lifestyle scores increased from 0 points (reference) to 1 point (HR, 0.69; 95% CI, 0.55-0.83), 2 points (HR, 0.60; 95% CI, 0.50-0.76), and 3 points (HR, 0.55; 95% CI, 0.45-0.68). Smoking cessation and alcohol abstinence are associated with reduced risk of developing depression in patients with gastric cancer who undergo surgery.

Unfavorable treatment outcomes among patients with drug-resistant TB in Uganda.

BACKGROUND: Drug-resistant TB (DR-TB) remains a significant public health burden and a threat to the progress made in TB control and prevention in sub-Saharan Africa.OBJECTIVE: To determine the risk-predictors of poor treatment outcomes in patients with DR-TB in Uganda.METHODS: We retrospectively reviewed medical records of adult Ugandans who had been treated for DR-TB at Mbarara Regional Referral Hospital (MRRH) in Uganda.RESULTS: Of the 385 files reviewed, 332 (86.2%) met the study inclusion criteria. Of these, 226 (68.1%) were men and 193 (58.1%) were HIV-positive. A total of 73 participants (22.7%) had unfavorable treatment outcomes (treatment failure, loss to follow-up or death). History of cigarette smoking (OR 5.10, 95% CI 2.4-11.4; P < 0.001), age >60 years (OR 6.32, 95% CI 2.2-18.6; P < 0.001), anemia (OR 2.38, 95% CI 1.1-5.3; P = 0.02) and thrombocytopenia (OR 3.60, 95% CI 1.6-8.1; P < 0.001) were independent predictors of unfavorable treatment outcomes.CONCLUSION: There is a high prevalence of unfavorable treatment outcomes among patients with DR-TB. Further research is required to design a prognostic model for DR-TB patients in a resource-limited setting.

Low p16 Cytoplasmic Staining Predicts Poor Treatment Outcome in Patients with p16-Negative Locally Advanced Head and Neck Squamous Cell Carcinoma Receiving TPF Induction Chemotherapy.

Human papillomavirus (HPV) has been proven to be associated with head and neck squamous cell carcinoma (HNSCC), and diffuse p16 unclear staining is usually considered as HPV-positive. The aim of the current study was to investigate the role of p16 cytoplasmic staining in HNSCC prognosis. A total of 195 HNSCC patients who received docetaxel, cisplatin, and 5-fluouracil (TPF) induction chemotherapy followed by chemoradiotherapy were enrolled. The status of p16 cytoplasmic staining was determined using immunohistochemistry. The median follow-up was 26.0 months for the whole study population and 90.3 months for 51 living survivors. p16 cytoplasmic staining was low in 108 patients and high in 87 patients. Low expression of p16 cytoplasmic staining and primary tumor location in the oral cavity were both independent factors indicating a worse response rate to TPF induction chemotherapy in the univariate and multivariate analyses. The logistic regression model also showed that low expression of p16 cytoplasmic staining and clinical N2-3 status were independent prognostic factors for worse progression-free survival and overall survival. Our study showed that p16 cytoplasmic staining could predict the treatment response to TPF induction chemotherapy and is an independent prognostic factor of survival in HNSCC.

Hsa-miR-195-5p Inhibits Autophagy and Gemcitabine Resistance of Lung Adenocarcinoma Cells via E2F7/CEP55.

Lung adenocarcinoma (LUAD) is a common malignancy. Many studies have shown that LUAD is resistant to gemcitabine chemotherapy, resulting in poor treatment outcomes in patients. We designed this study to reveal influences of hsa-miR-195-5p/E2F7/CEP55 axis on gemcitabine resistance and autophagy of LUAD cells. The expression data of LUAD-related mRNAs were downloaded from TCGA-LUAD database for differential expression analysis. The bioinformatics databases (hTFtarget, starBase and TargetScan) were used to predict the upstream and downstream regulatory molecules of E2F7. Then the binding relationships between E2F7 and regulatory molecules were verified by ChIP and dual-luciferase reporter assay. qRT-PCR and western blot were used to detect the mRNA and protein levels of has-miR-195-5p, E2F7, and CEP55. CCK-8 assay was used to analyze the half-maximal inhibitory concentration (IC50) and cell proliferation ability of LUAD cells after gemcitabine treatment. Apoptosis was detected by flow cytometry. Apoptosis/autophagy markers and LC3 aggregation were detected by western blot and immunofluorescence, respectively. Finally, the mouse transplantation model was constructed to verify the regulation mechanism in vivo. In LUAD cells and tissues, E2F7 and CEP55 were highly expressed, while has-miR-195-5p was relatively less expressed. The ChIP or dual-luciferase assays demonstrated the binding relationships of E2F7 to the CEP55 promoter region and has-miR-195-5p to the 3'-UTR of E2F7. Cell experiments demonstrated that overexpression of hsa-miR-195-5p stimulated LUAD cell apoptosis and inhibited autophagy and gemcitabine resistance, while further overexpression E2F7/CEP55 could reverse the impact by hsa-miR-195-5p overexpression. In vivo experiments identified that hsa-miR-195-5p/E2F7/CEP55 axis constrained the growth of LUAD tumor. Hsa-miR-195-5p promoted apoptosis, repressed proliferation, and autophagy via E2F7/CEP55 and reduced gemcitabine resistance in LUAD, indicating that hsa-miR-195-5p/E2F7/CEP55 may be a novel target for LUAD.

Chip-Derived Vs De Novo Treatment-Related Myeloid Neoplasms after Autologous Stem Cell Transplant for Lymphoid Disorders

Autologous stem cell transplant (ASCT) involves high intensity conditioning regimens with significant cytotoxicity. Therapy-related myeloid neoplasms (tMN) represent a serious complication characterized by high-risk features and poor treatment outcomes in patients potentially cured from their primary neoplastic disorders. While the 2016 WHO classification broadly divides tMN into MDS or AML, yet their heterogeneity warrants a more distinctive characterization based on specific prior exposures and subsequently-developed unique features, as emphasized by the updated 2022 WHO revision. We previously analyzed the genomics of tMN including features suggestive of their derivation from either CHIP or de novo driver mutations1. Specifically for tMN pathobiology, ASCT may be very instructive due to the high dose therapy and repopulation of the hematopoiesis out of a limited number of transplanted hematopoietic stem cells. Post-ASCT tMN may be unique and possibly related to antecedent CHIP, CHIP induced by the procedure, or driver lesions. We took advantage of a large volume of ASCT performed at our institution along with excellent clinical annotations and long follow up to study the dynamics of tMN in this setting. We accrued a total of 1507 patients undergone ASCT, of whom 35 (2.3%) developed tMN at a median follow up time of 5.4 years following the procedure. The clinical and molecular phenotype of these index cases were then compared to a cohort of tMN patients (n=263) without prior history of ASCT. Of note, both groups had similar MDS/AML proportions. Compared to the rest of the ASCT cohort, patients developing tMN were older at the time of the transplant procedure (66 vs 46% ≥60 years, P=.02) and had a higher male preponderance (91 vs 59%, P<.0001). Post-ASCT tMN was more common following non-Hodgkin's lymphoma (NHL) than multiple myeloma (MM) (2.5 vs 1.1%, P=.0002) but similar between NHL and Hodgkin's disease (2.5 vs 1.5%, P=0.13). We then studied whether graft size and mobilization regimens could increase the risk of tMN. The incidence of this complications was higher with a mobilization involving GCSF (G), Etoposide (E) and Plerixafor (P) (GEP) rather than G, G+E or G+P (P=.0001), as well as when a CD34+ dose ≤3.5 x106 (4.1 vs 1.9%, P=.03) was infused. No difference was noted with respect to time to engraftment following ASCT. Multivariate analysis confirmed the independent influence of age ≥60 (HR 2.4, 95% CI 1.1-5.6), male sex (HR 7.1, 2.5-29.9), diagnosis (prior NHL vs MM; HR 3.3, 1.5-8.2) and mobilization scheme (GEP vs G+P; HR 4.7, 1.3-13.7). The caveat was the lack of significant effect of the graft size on tMN risk. When compared to non-transplanted cases, tMN following ASCT still showed a male preponderance (91 vs 51%, P<.0001) and exhibited a higher prevalence of high-risk (IPSS-R>3.5) MDS (79 vs 57%, P=.05). Furthermore, tMN arising post-ASCT appeared to follow a more aggressive course with a significantly shorter latency duration following the procedure (median 2.6 vs 6.5 years, P<.0001) and shorter overall survival (median 16 vs 58 months, P<.0001; Fig1). Cytogenetic profiling revealed higher frequencies of complex karyotype (49 vs 31%, P=.05), del(5q)/5- (26 vs 20%, P=.5), del(7q)/7- (46 vs 27.5%, P=.03), and del(17p)/17- (27 vs 6%, P=.0025) in the ASCT-exposed as opposed to non-transplanted cases. Subsequent analysis of isolated cytogenetic aberrations showed that isolated del(7q)/7- was significantly enriched in post-ASCT tMN (20 vs 6%, P=.0129). Mutational analysis revealed similar patterns with the exception of TP53, which was significantly more frequent in the ASCT-exposed group (41 vs 13%, P=.0028), mostly displaying a multi-hit configuration (32 vs 11%, P=.0178). We have previously shown that ancestral hits in DNMT3A, TET2, ASXL1 and JAK2 (CHIP-mutations) indicate derivation of disease from CHIP vsU2AF1, RUNX1 and STAG2 highlighted de novo cases, thereby prompting us to investigate whether CHIP may have been the originator of tMN post ASCT2. However, the frequencies of CHIP- and de novo -mutations were similar across the post-ASCT tMN and the non-ASCT tMN groups. Interestingly, within the post-ASCT tMN, patients who had CHIP-derived tMN had lower survival compared to the rest of the group (median 9 vs 25 months, P=.0079). Sequencing experiments on serial specimens are ongoing to determine whether CHIP- derived mutations were present prior to ASCT constituting a risk for tMN. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy of Immune Checkpoint Inhibitor With or Without Chemotherapy for Nonsquamous NSCLC With Malignant Pleural Effusion: A Retrospective Multicenter Cohort Study

IntroductionMalignant pleural effusion (MPE) is associated with poor treatment outcome in patients with NSCLC receiving immune checkpoint inhibitors (ICIs). ICIs and chemotherapy (ICI/Chemo) combination therapy is currently the standard therapy for NSCLC, and some ICI/Chemo regimens for nonsquamous (non-Sq) NSCLC contain bevacizumab (BEV), which is effective for controlling MPE and may enhance immune response. This study aimed to determine the optimal first-line treatment for this clinical population. MethodsWe retrospectively enrolled consecutive patients with non-Sq NSCLC with MPE who received ICI/Chemo or pembrolizumab monotherapy. Treatment outcomes were analyzed in patients with programmed death-ligand 1 (PD-L1) tumor proportion score more than or equal to 50% who were administered ICI/Chemo or pembrolizumab monotherapy (PD-L1 high cohort) and in patients with any PD-L1 status, treated with ICI/Chemo with or without BEV (ICI/Chemo cohort). We used propensity score matching (PSM) to reduce bias. ResultsPD-L1 high and ICI/Chemo cohorts included 143 and 139 patients, respectively. In PD-L1 high cohort, 37 patients received ICI/Chemo. With PSM, the median progression-free survival was significantly longer in the ICI/Chemo group than in the pembrolizumab group (11.1 versus 3.9 mo, respectively, p = 0.0409). In the ICI/Chemo cohort, 23 patients received BEV. With PSM, no significant difference occurred in median progression-free survival between BEV and non-BEV groups (6.1 versus 7.4 mo, p = 0.9610). ConclusionICI/Chemo seemed more effective than pembrolizumab monotherapy for patients with non-Sq NSCLC with MPE. Nevertheless, the synergistic effect of BEV with ICI/Chemo may be limited. Further studies are needed to clarify the key factor in the tumor-induced immunosuppression environment in these patients.

Clinical characteristics of patients with CRSwNP with intensely high eosinophil level.

BackgroundHigh tissue and blood eosinophils are linked to poor treatment outcome in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). However, the difference between the patients with different level of blood or tissue eosinophilia in relation to disease control is still lacking.ObjectivesThis study aimed to characterize patients with CRSwNP with intensely high eosinophil level.MethodsA retrospective study of CRSwNP patients underwent endoscopic sinus surgery was conducted. The patients were subdivided with various cut‐off values of blood and tissue eosinophils. Tissue eosinophils of ≥50% and 10%–20% were defined as intensely high tissue eosinophils (IH‐tissue‐eos) and high tissue eosinophils (H‐tissue‐eos), respectively. Blood eosinophils of ≥0.6 × 109/L and 0.2 × 109/L–0.3 × 109/L were defined as intensely high blood eosinophils (IH‐blood‐eos) and high blood eosinophils (H‐blood‐eos). Clinical characteristics, Lund‐Mackay score (LMS), and disease control status were compared between subgroups.ResultsA total of 302 patients were enrolled. There was a trend toward a higher rate of uncontrolled disease when the patients subdivided by blood eosinophil cut‐off values ranged from 0.1 × 109/L to 0.6 × 109/L. The controlled patients accounted for 27%, 36%, 22%, and 31%, and the uncontrolled patients 46%, 32%, 52%, and 31% of patients in IH‐tissue‐eos, H‐tissue‐eos, IH‐blood‐eos, and H‐blood‐eos subgroup, respectively. The percentages of patients in the three categories of control were not significantly different between IH‐tissue‐eos and H‐tissue‐eos subgroups. By contrast, the IH‐blood‐eos subgroup had higher percentages of current smoker and asthma, preoperative LMS and tissue eosinophil percentage, and showed a trend toward a higher rate of uncontrolled subjects compare with the H‐blood‐eos subgroup.ConclusionCRSwNP patients with IH‐blood‐eos (≥0.6 × 109/L) may be possibly associated with a poorer disease control than those with levels near the threshold of blood eosinophilia (0.2 × 109/L–0.3 × 109/L). Further larger, preferably prospective studies are needed to confirm this relationship.Level of Evidence: 4.

Flow Cytometric Analysis of Microbial Diversity in Patients with Aggressive Lymphoma Disease Undergoing Chemoimmunotherapy

IntroductionMicrobial dysbiosis is associated with increased infectious complications and poorer treatment outcomes in patients with hematologic malignancies (Galloway-Pena et al., 2016, Peled et al., 2020). While the effective reconstitution of microbial diversity by autologous fecal microbiota transfer appears within clinical reach (Malard et al, 2021), diagnosis of dysbiosis typically relies on comparatively slow and laborious molecular techniques. We validated a fast and reliable method to assess and track microbial diversity based on flow cytometric analysis (FCM) of single cell phenotypical traits in stool samples of patients undergoing therapy for aggressive lymphoma disease.MethodsStool samples of 12 patients with B-cell neoplasms and 1 patient with a T-cell neoplasm were collected at the time of diagnosis, directly before each cycle of chemoimmunotherapy administration (CHOP backbone +/- anti-CD20 therapy) and every 3 months during follow-up (2-11 samples per patient totaling n = 77 samples). Microbiome analyses were performed by sequencing the V3/V4 16S rRNA region and by FCM of light scatter properties and DNA content (DAPI staining). Phenotypic and taxonomic alpha diversity (inverse Simpson index, D2) was determined from the flow cytometric profiles and sequencing data, respectively, using the PhenoFlow R package (Props et al., 2016). Longitudinal trends in alpha diversity were evaluated with the SplinectomeR R package (Shields-Cutler et al., 2018).ResultsCorrelation analysis and ordinary least squares regression confirmed a statistically significant association between FCM-based phenotypic and sequencing-based taxonomic alpha diversity in “real-world” patient fecal samples (Pearson's correlation r p = 0.56, r 2 = 0.32, p < 0.001) (Figure 1). Despite the distinct and complex data types generated by the two methods, these results demonstrate that phenotypic diversity measurements obtained from FCM can serve as proxies for taxonomic diversity measurements obtained from 16S rRNA sequencing.Next, we analyzed the dynamics of microbial alpha diversity in our cohort over the course of therapy and follow-up using a spline-based approach optimized for longitudinal data. We demonstrated a statistically significant non-linear trend of alpha diversity with a decrease during the period of chemotherapy administration followed by reconstitution during the immunotherapy and follow-up period (Figure 2) using both FCM and 16S rRNA sequencing (p = 0.001). Notably, the samples collected during the treatment phase were obtained 2-3 weeks after the last administration of chemoimmunotherapy, depicting a progressive and sustained dysbiosis in patients during the months of chemotherapy.ConclusionsWe demonstrated a clear correlation between microbial alpha diversity as determined by 16S rRNA sequencing and by our flow cytometric-based approach. Using FCM analysis, we found a marked decline in diversity during chemotherapy administration. These results are in line with the dysbiosis pattern observed by 16S rRNA sequencing and with previous studies (Rashidi et al., 2019). Our findings thus demonstrate that FCM could provide a fast, first-line point-of-care monitoring of microbial diversity dynamics. [Display omitted] DisclosuresJenq: Merck: Consultancy; Karius: Consultancy; Microbiome DX: Consultancy; Seres: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Kaleido: Membership on an entity's Board of Directors or advisory committees; MaaT Pharma: Membership on an entity's Board of Directors or advisory committees; Prolacta: Membership on an entity's Board of Directors or advisory committees; LISCure: Membership on an entity's Board of Directors or advisory committees. Bullinger: Daiichi Sankyo: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Gilead: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Hexal: Consultancy; Novartis: Consultancy, Honoraria; Bayer: Research Funding; Pfizer: Consultancy, Honoraria; Seattle Genetics: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Menarini: Consultancy; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Astellas: Honoraria. Na: Octapharma: Honoraria, Research Funding; Shire/Takeda: Honoraria, Research Funding; Bristol Myers Squibb: Research Funding.

Multiphasic Prehabilitation Across the Cancer Continuum: A Narrative Review and Conceptual Framework.

The field of cancer survivorship has significantly advanced person-centered care throughout the cancer continuum. Within cancer survivorship, the last decade has seen remarkable growth in the investigation of prehabilitation comprising pre-treatment interventions to prevent or attenuate the burden of oncologic therapies. While the majority of evidence remains in the surgical setting, prehabilitation is being adapted to target modifiable risk factors that predict poor treatment outcomes in patients receiving other systemic and localized anti-tumor treatments. Here, we propose a multiphasic approach for prehabilitation across the cancer continuum, as a conceptual framework, to encompass the variability in cancer treatment experiences while adopting the most inclusive definition of the cancer survivor.

Sarcopenia predicts a poor treatment outcome in patients with head and neck squamous cell carcinoma receiving concurrent chemoradiotherapy.

Sarcopenia, defined as a decrease in the skeletal muscle mass and its function, is associated with a poor clinical outcome in several malignancies. We aimed to examine whether sarcopenia can be a predictor of incompletion of concurrent chemoradiotherapy (CCRT) and survival for head and neck cancer (HNC) patients. Forty-one male HNC patients who received CCRT were enrolled in the study. Cross-sectional muscle areas at the third lumbar vertebral level were normalized by the squared height of the patients and were termed the lumbar skeletal muscle index (LSMI, cm2/m2), a marker of sarcopenia. Patients were divided into high (30/41, 73%) and low (11/41, 27%) LSMI groups. The LSMI cut-off value was set at 39.7 cm2/m2 based on a receiver operating characteristic curve for incompletion of CCRT. The groups were compared for survival rate by the Kaplan-Meier method. Factors predicting incompletion of CCRT were investigated among several variables. Multivariate analysis showed that a pre-treatment low LSMI (P = 0.033) and age over 70years (P = 0.023) were the only significant predictors for incompletion of CCRT. The 2-year disease-specific survival (DSS) rate was significantly lower in the low LSMI group (61%) than in the high LSMI group (97%, P = 0.012), whereas there were no differences in the DSS rate between the low and high body mass index groups. The prevalence of sarcopenia in HNC patients receiving CCRT was 27%. Its presence before treatment was a significant predictor of incomplete CCRT and poor DSS rate in HNC patients.

Associated factors of poor treatment outcomes in patients with giant cell arteritis: clinical implication of large vessel lesions

BackgroundRelapses frequently occur in giant cell arteritis (GCA), and long-term glucocorticoid therapy is required. The identification of associated factors with poor treatment outcomes is important to decide the treatment algorithm of GCA.MethodsWe enrolled 139 newly diagnosed GCA patients treated with glucocorticoids between 2007 and 2014 in a retrospective, multi-center registry. Patients were diagnosed with temporal artery biopsy, 1990 American College of Rheumatology classification criteria, or large vessel lesions (LVLs) detected by imaging based on the modified classification criteria. Poor treatment outcomes (non-achievement of clinical remission by week 24 or relapse during 52 weeks) were evaluated. Clinical remission was defined as the absence of clinical signs and symptoms in cranial and large vessel areas, polymyalgia rheumatica (PMR), and elevation of C-reactive protein (CRP) levels. A patient was determined to have a relapse if he/she had either one of the signs and symptoms that newly appeared or worsened after achieving clinical remission. Re-elevation of CRP without clinical manifestations was considered as a relapse if other causes such as infection were excluded and the treatment was intensified. Associated factors with poor treatment outcomes were analyzed by using the Cox proportional hazard model.ResultsCranial lesions, PMR, and LVLs were detected in 77.7%, 41.7%, and 52.5% of the enrolled patients, respectively. Treatment outcomes were evaluated in 119 newly diagnosed patients who were observed for 24 weeks or longer. The mean initial dose of prednisolone was 0.76 mg/kg/day, and 29.4% received any concomitant immunosuppressive drugs at baseline. Overall, 41 (34.5%) of the 119 patients had poor treatment outcomes; 13 did not achieve clinical remission by week 24, and 28 had a relapse after achieving clinical remission. Cumulative rates of the events of poor treatment outcomes in patients with and without LVLs were 47.5% and 17.7%, respectively. A multivariable model showed the presence of LVLs at baseline was significantly associated with poor treatment outcomes (adjusted hazard ratio [HR] 3.54, 95% CI 1.52–8.24, p = 0.003). Cranial lesions and PMR did not increase the risk of poor treatment outcomes.ConclusionThe initial treatment intensity in the treatment algorithm of GCA could be determined based upon the presence or absence of LVLs detected by imaging at baseline.

Development of a risk score for prediction of poor treatment outcomes among patients with multidrug-resistant tuberculosis.

Treatment outcomes among patients treated for multidrug-resistant tuberculosis (MDR-TB) are often sub-optimal. Therefore, the early prediction of poor treatment outcomes may be useful in patient care, especially for clinicians when they have the ability to make treatment decisions or offer counselling or additional support to patients. The aim of this study was to develop a simple clinical risk score to predict poor treatment outcomes in patients with MDR-TB, using routinely collected data from two large countries in geographically distinct regions. We used MDR-TB data collected from Hunan Chest Hospital, China and Gondar University Hospital, Ethiopia. The data were divided into derivation (n = 343; 60%) and validation groups (n = 227; 40%). A poor treatment outcome was defined as treatment failure, lost to follow up or death. A risk score for poor treatment outcomes was derived using a Cox proportional hazard model in the derivation group. The model was then validated in the validation group. The overall rate of poor treatment outcome was 39.5% (n = 225); 37.9% (n = 86) in the derivation group and 40.5% (n = 139) in the validation group. Three variables were identified as predictors of poor treatment outcomes, and each was assigned a number of points proportional to its regression coefficient. These predictors and their points were: 1) history of taking second-line TB treatment (2 points), 2) resistance to any fluoroquinolones (3 points), and 3) smear did not convert from positive to negative at two months (4 points). We summed these points to calculate the risk score for each patient; three risk groups were defined: low risk (0 to 2 points), medium risk (3 to 5 points), and high risk (6 to 9 points). In the derivation group, poor treatment outcomes were reported for these three groups as 14%, 27%, and 71%, respectively. The area under the receiver operating characteristic curve for the point system in the derivation group was 0.69 (95% CI 0.60 to 0.77) and was similar to that in the validation group (0.67; 95% CI 0.56 to 0.78; p = 0.82). History of second-line TB treatment, resistance to any fluoroquinolones, and smear non-conversion at two months can be used to estimate the risk of poor treatment outcome in patients with MDR-TB with a moderate degree of accuracy (AUROC = 0.69).

Next generation sequencing identifies baseline viral mutants associated with treatment response to pegylated interferon in HBeAg-positive chronic hepatitis B.

Current data of hepatitis B virus (HBV) variants associated with treatment outcome identified by next generation sequencing (NGS) are limited. This study was aimed at determining the role of baseline sequence variations in the enhancer II (EnhII), basal core promotor (BCP) and pre-core (PC) regions of HBV genotype C in patients treated with pegylated interferon (PEG-IFN). Patients with HBeAg-positive chronic hepatitis B (CHB) treated with 48-week PEG-IFN were enrolled. Combined response (CR) at week 96 was defined by HBeAg seroconversion plus HBV DNA < 2000IU/mL and HBsAg < 1000IU/mL. Pre-treatment viral mutations were characterized by Sanger sequencing and NGS (Miseq Illumina platform). Among 47 patients (32 male, mean age 32.4years), CR was achieved in 12 (25.5%) individuals. Overall, NGS was superior to Sanger sequencing in detecting mutations (61.7% vs. 38.3%, P < 0.001). Based on NGS, the prevalence of T1753V (T1753C/A/G) and A1762T/G1764A variants were significantly lower in responders compared to non-responders (8.3% vs. 51.4%, P = 0.009 and 33.3% vs. 68.6%, P = 0.032, respectively). No significant difference between groups was found regarding C1653T and G1896A mutants. The absence of T1753V and A1762T/G1764A mutations were factors associated with CR (OR 11.65, 95%CI 1.36-100.16, P = 0.025, and OR 4.36, 95%CI 1.08-17.63, P = 0.039, respectively). The existence of pre-treatment T1753V, A1762T/G1764A mutations and their combination yielded negative predictive values of 94.7%, 85.7% and 93.8%, respectively. The presence of HBV mutants in the BCP region determined by NGS at baseline was associated with poor treatment outcome in patients with HBeAg-positive CHB receiving PEG-IFN.

Refractoriness to transarterial chemoembolization in patients with recurrent hepatocellular carcinoma after curative resection.

Background/AimsIt is important to identify patients who are refractory to transarterial chemoembolization (TACE), which is performed for the treatment of hepatocellular carcinoma (HCC). We investigated the predictors of poor treatment outcomes in patients with recurrent HCC treated who were treated with TACE after curative resection.Methods428 patients with recurrent HCC after curative resection who were treated with TACE were enrolled.ResultsThe median age of the study population was 59.2 years. On multivariate analysis, ≥2 TACE procedures within 6 months (hazard ratio [HR] = 1.898), and the des-gamma carboxyprothrombin level (HR = 1.000) independently predicted the progression to Barcelona Clinic Liver Cancer (BCLC) stage C in patients with BCLC stage 0-B HCC (both P<0.05). In addition, ≥2 and ≥3 TACE procedures within 6 months independently predicted mortality in the entire study population (HR = 1.863 and 1.620, respectively). The probability of progression to BCLC stage C in patients with BCLC stage 0-B HCC and the mortality rate in the entire study population were significantly higher in patients treated with ≥2 TACE within 6 months than in those who underwent fewer procedures (P = 0.002 and P<0.001, respectively).ConclusionsMore than 2 TACE procedures within 6 months might be associated with the refractoriness to TACE in patients with recurrent HCC after curative resection.

ADOLESCENT OBESITY IS ASSOCIATED WITH MORE SEVERE PRESENTATIONS OF OSTEOCHONDRITIS DISSECANS OF THE KNEE

Background Body mass index (BMI) above the normal range has been associated with poorer treatment outcomes in patients with osteochondritis dissecans (OCD) of the knee. Patients with BMIs over 25kg/m2 show an increased risk of postoperative arthritis, and BMI has also been shown to be independently predictive of osteochondral allograft transplantations failure in knee OCD. However, these data have largely focused on post-treatment outcomes relating BMI and OCD. Considering the increase in childhood obesity in the U.S., there is a dearth of research regarding how BMI affects OCD at presentation. This is an especially important question given the effect that various load-bearing forces have on the articular surface. Humeral capitellum lesions in young athletes, for example, have been shown to be more anterior in baseball players than gymnasts, owing to different vectors of force distribution. In this paper, we asked whether any differences in knee OCD lesions, in terms of either severity or location, were associated with changes in patient BMI. We hypothesized that patients with higher BMI percentiles would have femoral condylar OCD lesions that were more severe at initial presentation and were located more posteriorly on the condyle. Methods A retrospective review was performed for patients 10- to 18-years old treated for OCD of the knee at a tertiary-care hospital from 2006-2017. Exclusion criteria consisted of location of OCD other than the femoral condyle and lack of BMI data within three months of presentation. BMI percentile was analyzed as a continuous variable and used to stratify patients into groups per CDC guidelines: underweight, normal, overweight, and obese. Markers of severity included lesion size, cystic changes, subchondral fluid, subchondral edema, and the need for surgical treatment and fixation. Age and laterality were also assessed. Angle of lesion incidence was determined by applying a best fit circle to the distal condyles and measuring the average angle in reference to a line parallel to the femoral axis drawn through the center of the circle. Analysis was performed using t-test and linear regression analysis. Results Of 339 patients initially identified with knee OCD, 263 (78%) patients were excluded: 145 (43%) for age &gt;19 years, 31 (9%) for age &lt;10 years, and 86 (25%) for absence of BMI data. For the 77 (23%) patients meeting all inclusion criteria, age at presentation was mean 14.2 (range 10.1-18.8 years). BMI percentile categories were as follows: underweight (n=2, 2.6%), normal (n=50, 64.9%), overweight (n=13, 16.9%), obese (n=12, 15.6%). Linear regression analyses of the cumulative running averages for each variable (Fig.1) demonstrated a moderate correlation between BMI percentile and need for surgical treatment (R2=0.732, p&lt;0.0001). A similar correlation was seen with fluid under lesion (R2=0.716, p&lt;0.0001) and with subchondral edema (R2=0.63, p&lt;0.0001). Cystic changes were graphically observed to decrease steadily from the 50th to 100th BMI percentiles, though no correlation was observed (R2=0.026). Even with the negative correlation seen with cystic changes, a strong correlation was seen between BMI percentile and patients with at least one sign of lesion instability (R2=0.872, p&lt;0.0001). An inflection point was graphically identified at the 80th BMI percentile for several markers of severity, and subsequent analysis confirmed that patients higher than the 80th percentile were significantly more likely to need surgical fixation (RR: 1.826, 95% CI: 1.03-3.24), to have subchondral edema (RR: 2.523, 95% CI: 1.34-4.76), to have medial condylar lesions (RR: 1.292, 95% CI: 1.014-1.647), and to have lesions located more anterior (Fig. 2) on the condyle (mean=13.41±14.47° for &gt;80th percentile vs 22.52±16.99° for &lt;80th percentile, p&lt;0.05). Discussion and Conclusions In this sample, increasing BMI percentile was strongly correlated with the severity of lesion at initial presentation and with the need for surgery. Cystic changes were the only markers of lesion noted to decrease as BMI percentile increased. Given that cystic changes are a sign of a chronic OCD lesion, overweight and obese patients may present earlier in the disease course. Contrary to our original hypothesis, increasing BMI percentile is actually associated with femoral condylar lesions that are more anterior, rather than more posterior. This finding may be due to a preference for repetitive loading of the knee in the standing position. To our knowledge, this is the first study to show a relationship between BMI and severity or location of femoral condylar OCD at presentation. These results have important implications for the prevention and early detection of OCD in pediatric patients, and they show a role for future biomechanical and population-based studies of body mass on OCD of the femoral condyles. [Figure: see text]