Non-responder Group Research Articles

Lung Ultrasound Evaluation of Aeration Changes in Response to Prone Positioning in Acute Respiratory Distress Syndrome (ARDS) Patients Requiring Venovenous Extracorporeal Membrane Oxygenation: An Observational Study.

Prone positioning (PP) has been proven to be a beneficial approach in enhancing survival outcomes for patients with severe acute respiratory distress syndrome (ARDS) who need venovenous extracorporeal membrane oxygenation (V-V ECMO) support. The study utilized bedside lung ultrasound (LUS) to evaluate changes in lung aeration caused by PP in ARDS patients receiving V-V ECMO. This retrospective single-center study involved adult ARDS patients requiring V-V ECMO. The assessment of LUS involved examining specific dorsal lung regions, encompassing 16 areas, during three pre-defined time points: baseline (10 minutes prior), three-hour PP positioning, and 10-minute post-supine repositioning, all within the initial three days. Based on the oxygenation response to PP, patients were categorized into responder and non-responder groups. The primary outcome was LUS score changes during the initial three-day period. Secondary outcomes examined the impact of PP on the partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) (P/F) ratio, V-V ECMO weaning success, length of ICU stay, and hospital survival. Among the enrolled patients (27 in total), 16 were responders and 11 were non-responders. In the responder group, the global LUS score underwent a significant reduction from 26.38 ± 4.965 at baseline to 20.75 ± 3.337 (p < 0.001) after the first PP session, which further decreased to 15.94 ± 2.816 (p< 0.001) after three days. However, no significant differences were observed among PP non-responders. The oxygenation reaction yielded comparable results. There was a significant correlation between the duration of daily PP and the reduction in global LUS score among PP responders (r = -0.855, p < 0.001). In cases where the global LUS score decreased by > 7.5 after three days of PP, the area under the receiver operating characteristic curve (AUROC) for predicting ECMO weaning success was 0.815, while it was 0.761 for predicting hospital survival. LUS has the potential to predict the response to PP and evaluate the prognosis of ARDS patients with V-V ECMO, althoughmore studies are demanded in the future.

Impact of HIF prolyl hydroxylase inhibitors in heart failure patients with renal anemia

ObjectiveHypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors are a new class of anti-anemia agents. We retrospectively evaluated the safety and efficacy of HIF-PH inhibitors in patients with heart failure (HF) complicated by anemia associated with chronic kidney disase. HIF-PH inhibitor treatment was initiated in 32 patients with chronic HF complicated by renal anemia and were followed up for 3 months.ResultsHematocrit and hemoglobin levels markedly improved 3 months after HIF-PH inhibitor treatment. However, levels of NT-proBNP, which is an indicator of HF, did not decrease considerably. Based on the rate of change in NT-proBNP, we divided the patients into “responder” and “non-responder” groups. The results showed that considerably more patients had a ferritin level of less than 100 ng/mL in the non-responder group at baseline. There were substantially more patients with TSAT of less than 20% in the non-responder group at 1 month after HIF-PH inhibitor treatment. The cut-off values to maximize the predictive power of ferritin level at baseline and TSAT value at 1 month after treatment were 41.8 ng/ml and 20.75. HIF-PH inhibitor treatment can be expected to be effective for improving both anemia and HF if ferritin≥41.8 ng/ml at baseline or TSAT≥20.75 at 1 month after treatment.

Neutrophil to lymphocyte ratio and systemic immune-inflammatory index as markers of response to autologous hematopoietic stem cell transplantation in persons with multiple sclerosis.

Biomarkers that help to evaluate the immune system and could be useful in multiple sclerosis (MS) are the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and systemic immune-inflammatory index (SII). The objective of this work is to evaluate the significance of the SII index, PLR, and NLR before and after transplantation in individuals with MS who underwent autologous hematopoietic stem cell transplant (aHSCT) at a single institution. Patients with MS who received an aHSCT between 2017 and 2022 were included in the study. NLR, PLR, and SII index were calculated prior to the transplant and 100 days after, and evaluation of the expanded disability status scale (EDSS) was done before the transplant and 12 months after. The cohort was divided into two groups: aHSCT responders (R) and nonresponders (NR). Fifty-eight individuals were examined: 37 patients in the responders group R group and 21 in NR group. There was no statistically significant difference in the SII, NLR, and PLR prior to the transplant, however at 100 days post-HSCT, NLR in the R group was 1.8 versus 3.1 in the NR group (p = 0.003), PLR was 194 versus 295, respectively (p = 0.024), meanwhile SII index was 489.5 versus 729.3 (p < 0.001). High NLR and SII index values after the aHSCT were associated with a worsening in the EDSS score. However, since this is the first ever study that compared NLR and SII index with the aHSCT response in persons with MS, further studies must be performed to corroborate this information.

Value of diffusion kurtosis MR imaging and conventional diffusion weighed imaging for evaluating response to first-line chemotherapy in unresectable pancreatic cancer

ObjectiveTo investigate the diagnostic value of diffusion kurtosis magnetic resonance imaging (DKI) and conventional diffusion-weighted imaging (DWI) for evaluating the response to first-line chemotherapy in unresectable pancreatic cancer.Materials and methodsWe retrospectively analyzed 21 patients with clinically and pathologically confirmed unresected pancreatic cancer who received palliative chemotherapy. Three-tesla MRI examinations containing DWI sequences with b values of 0, 100, 700, 1400, and 2100 s/mm2 were performed before and after chemotherapy. Parameters included the apparent diffusion coefficient (ADC), mean diffusion coefficient (MD), and mean diffusional kurtosis (MK). The performances of the DWI and DKI parameters in distinguishing the response to chemotherapy were evaluated by the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. Overall survival (OS) was calculated from the date of first treatment to the date of death or the latest follow-up date.ResultsThe ADCchange and MDchange were significantly higher in the responding group (PR group) than in the nonresponding group (non-PR group) (ADCchange: 0.21 ± 0.05 vs. 0.11 ± 0.09, P = 0.02; MDchange: 0.37 ± 0.24 vs. 0.10 ± 0.12, P = 0.002). No statistical significance was shown when comparing ADCpre, ADCpost, MKpre, MKpost, MKchange, MDpre, and MDpost between the PR and non-PR groups. The ROC curve analysis indicated that MDchange (AUC = 0.898, cutoff value = 0.7143) performed better than ADCchange (AUC = 0.806, cutoff value = 0.1369) in predicting the response to chemotherapy.ConclusionThe ADCchange and MDchange demonstrated strong potential for evaluating the response to chemotherapy in unresectable pancreatic cancer. The MDchange showed higher specificity in the classification of PR and non-PR than the ADCchange. Other parameters, including ADCpre, ADCpost, MKpre, MKpost, MKchange, MDpre, and MDpost, are not suitable for response evaluation. The combined model SUMchange demonstrated superior performance compared to the individual DWI and DKI models. Further experiments are needed to evaluate the potential of DWI and DKI parameters in predicting the prognosis of patients with unresectable pancreatic cancer.

Taurohyocholic acid acts as a potential predictor of the efficacy of tyrosine kinase inhibitors combined with programmed cell death-1 inhibitors in hepatocellular carcinoma.

Background and aims: Tyrosine kinase inhibitors (TKIs) combined with programmed cell death protein-1 (PD-1) have significantly improved survival in patients with unresectable hepatocellular carcinoma (uHCC), but effective biomarkers to predict treatment efficacy are lacking. Peripheral blood bile acids (BAs) are associated with tumor response to therapy, but their roles in HCC remain unclear. Methods: This retrospective study included HCC patients who received first-line TKIs combined with PD-1 inhibitors treatment (combination therapy) in our clinical center from November 2020 to June 2022. The aim of this study was to analyze the changes in plasma BA profiles before and after treatment in both the responding group (Res group) and the non-responding group (Non-Res group). We aimed to explore the potential role of BAs in predicting the response to combination therapy in HCC patients. Results: Fifty-six patients with HCC who underwent combination therapy were included in this study, with 28 designated as responders (Res group) and 28 as non-responders (Non-Res group). There were differences in plasma BA concentrations between the two groups before systemic therapy. Plasma taurohyocholic acid (THCA) levels in the Res group were significantly lower than those in the Non-Res group. Patients with low levels of THCA exhibited superior median progression-free survival (7.6 vs. 4.9months, p = 0.027) and median overall survival (23.7 vs. 11.6months, p = 0.006) compared to those of patients with high levels of THCA. Conclusion: Peripheral blood BA metabolism is significantly correlated with combination therapy response and survival in patients with HCC. Our findings emphasize the potential of plasma BAs as biomarkers for predicting combination therapy outcomes and offering novel therapeutic targets for modulating responses to systemic cancer therapy.

Mutation of PTEN: Loss and Likelihood of Being a Non-responder to Trastuzumab in a Sample of Iraqi Her2+ Breast Cancer Patients.

PTEN controls upstream PI3K relatives, such as AKT. PTEN gene mutations have been documented to affect outcomes in main or distant malignancies, including breast cancer (BC). PTEN gene deletions are common in a variety of humancancers. A key factor in the response to this kind of therapy is genetic diversity. The purpose of this research is to determine whether a PTEN loss mutation influences a patient's propensity to not respond to trastuzumab (TRS) in cases of Her2+ BC. Diwaniya Teaching Hospital's oncology ward provided 60 patients with Her2+ BC who had been on TRS for at least 12 months for this study. Patients were split in half using the RECIST criteria for evaluating responses to therapy in solid tumors: responders and non-responders. A PTEN polyclonal primary antibody was used for the detection of PTEN in breast tissue in the current study. This research employs a rating system based on eight specimens (26.67%) among non-responsive women who demonstrated PTEN loss compared with one specimen (3.33%) among responsive women. Statistically, PTEN loss varied significantly between the responsive and non-responsive groups. Loss of PTEN was also not linked to shifts in creatine kinase-myocardial band (CK-MB), troponin T (TnT), or any other biomarker, or troponin I (Tn1) at baseline or after 12 months of TRS therapy. These results give us important information about how PTEN deletion mutations might work as a predictor for TRS response in women with Her2+ BC.

Occurrence of Existing BCR-ABL Baseline Mutations and Associated Haplotype (NmR) Among CML Patients with Diverse IM Response: A Hospital-based Study from North-East India.

Highly polymorphic BCR-ABL kinase domains have been reported to harbor more than a hundred mutations, and among these, 40-60% have been identified as influencers of imatinib mesylate (IM) resistance. The emergence of IM resistance poses a significant challenge in the management of Chronic Myeloid Leukemia (CML). M351T (rs121913457), E255K (rs387906517), and Y253H (rs121913461) are of particular clinical significance due to their association with high-level imatinib resistance. This study was conducted to investigate the potential role of three significant SNPs in CML progression due to IM resistance. During the study period from 2018 to 2022 (48months), the blood samples from 219 Reverse transcriptase-PCR-confirmed CML patients following RNA extraction and cDNA preparation were subjected to M351T, E255K, and Y253H mutation analysis by PCR-RFLP. After agarose gel visualization, the samples were subjected to Sanger sequencing to confirm the nucleotide change at the polymorphic loci. The wild-type genotype of all three ABL1 SNPs under investigation exhibits a significant reduction in frequency among IM non-responders compared to the responder group. The CGT haplotype frequency exhibits a significant difference between IM responder (4.2%) and non-responder (11.8%) (p = 0.002 < 0.05). Further, CGC haplotype was observed solely among the imatinib non-responder patients with a frequency percentage of 3.3% (p = 0.004), whereas the said genotype was absent among the responder group. A reduced overall survival rate was observed with deviation from wild-type genotype (M351T loci (T > C) with 1.217 times, E255K (G > A) with 1.485 and Y253H (T > C) with 1.399 times increase in hazard ratio) thereby enhancing mortality risk due to disease progression. The significant increase in the frequency of M351T, E255K, and Y253H loci among the IM non-responder group indicated their probable association with the development of IM resistance among CML patients. A haplotype frequency distribution pattern analysis of ABL1 loci further identified the CGC haplotype as an independent predictor for IM resistance. As such the study highlights the importance of patient characteristics, genotype distribution, and haplotype frequency distribution in predicting the response to IM treatment and clinical outcomes of CML patients.

Long-term functional outcomes in polytrauma: a fundamentally new approach is needed in prediction

PurposeModern trauma care has reduced mortality but poor long-term outcomes with low follow-up rates are common with limited recommendations for improvements. The aim of this study was to describe the impact of severe injury on the health-related quality of life, specifically characterise the non-responder population and to identify modifiable predictors of poorer outcomes.MethodsFive-year (2012–2016) prospective cohort study was performed at a level 1 trauma centre. Baseline Short-Form Health Survey (SF36) was collected at admission, and at 6 and 12 months postinjury together with demographics, injury mechanism and severity, psychosocial wellbeing, and return to work capacity.ResultsOf the 306 consecutive patients [age 52 ± 17 years, male 72%, ISS 21 (17, 29), mortality 5%], 195 (64%) completed questionnaires at baseline, and at 12 months. Preinjury physical health scores were above the general population (53.1 vs. 50.3, p < 0.001) and mental health component was consistent with the population norms (51.7 vs. 52.9, p = 0.065). One year following injury, both physical health (13.2, 95% CI 14.8, 11.6) and mental health scores (6.0, 95% CI 8.1, 3.8) were significantly below age- and sex-adjusted preinjury baselines. Non-responders had similar ISS but with a lower admission GCS, and were more likely to be younger, and without comorbidities, employment, or university education.ConclusionContrary to their better than population norm preinjury health status, polytrauma patients remain functionally impaired at least 1 year after injury. The identified high risk for non-responding group needs more focused efforts for follow-up. A fundamentally different approach is required in polytrauma research which identify modifiable predictors of poor long-term outcomes.

Longitudinal plasma proteomic analysis identifies biomarkers and combinational targets for anti-PD1-resistant cancer patients

The response rate of anti-PD1 therapy is limited, and the influence of anti-PD1 therapy on cancer patients is unclear. To address these challenges, we conducted a longitudinal analysis of plasma proteomic changes with anti-PD1 therapy in non-small cell lung cancer (NSCLC), alveolar soft part sarcoma (ASPS), and lymphoma patients. We included 339 plasma samples before and after anti-PD1 therapy from 193 patients with NSCLC, ASPS, or lymphoma. The plasma proteins were detected using data-independent acquisition-mass spectrometry and customable antibody microarrays. Differential proteomic characteristics in responders (R) and non-responders (NR) before and after anti-PD1 therapy were elucidated. A total of 1019 proteins were detected using our in-depth proteomics platform and distributed across 10–12 orders of abundance. By comparing the differential plasma proteome expression between R and NR groups, 50, 206, and 268 proteins were identified in NSCLC, ASPS, and lymphoma patients, respectively. Th17, IL-17, and JAK-STAT signal pathways were identified upregulated in NR group, while cellular senescence and transcriptional misregulation pathways were activated in R group. Longitudinal proteomics analysis revealed the IL-17 signaling pathway was downregulated after treatment. Consistently, many proteins were identified as potential combinatorial therapeutic targets (e.g., IL-17A and CD22). Five noninvasive biomarkers (FLT4, SFTPB, GNPTG, F5, and IL-17A) were further validated in an independent lymphoma cohort (n = 39), and another three noninvasive biomarkers (KIT, CCL3, and TNFSF1) were validated in NSCLC cohort (n = 76). Our results provide molecular insights into the anti-PD1 therapy in cancer patients and identify new therapeutic strategies for anti-PD1-resistant patients.

Machine Learning Predicts Oxaliplatin Benefit in Early Colon Cancer.

A combination of fluorouracil, leucovorin, and oxaliplatin (FOLFOX) is the standard for adjuvant therapy of resected early-stage colon cancer (CC). Oxaliplatin leads to lasting and disabling neurotoxicity. Reserving the regimen for patients who benefit from oxaliplatin would maximize efficacy and minimize unnecessary adverse side effects. We trained a new machine learning model, referred to as the colon oxaliplatin signature (COLOXIS) model, for predicting response to oxaliplatin-containing regimens. We examined whether COLOXIS was predictive of oxaliplatin benefits in the CC adjuvant setting among 1,065 patients treated with 5-fluorouracil plus leucovorin (FULV; n = 421) or FULV + oxaliplatin (FOLFOX; n = 644) from NSABP C-07 and C-08 phase III trials. The COLOXIS model dichotomizes patients into COLOXIS+ (oxaliplatin responder) and COLOXIS- (nonresponder) groups. Eight-year recurrence-free survival was used to evaluate oxaliplatin benefits within each of the groups, and the predictive value of the COLOXIS model was assessed using the P value associated with the interaction term (int P) between the model prediction and the treatment effect. Among 1,065 patients, 526 were predicted as COLOXIS+ and 539 as COLOXIS-. The COLOXIS+ prediction was associated with prognosis for FULV-treated patients (hazard ratio [HR], 1.52 [95% CI, 1.07 to 2.15]; P = .017). The model was predictive of oxaliplatin benefits: COLOXIS+ patients benefited from oxaliplatin (HR, 0.65 [95% CI, 0.48 to 0.89]; P = .0065; int P = .03), but COLOXIS- patients did not (COLOXIS- HR, 1.08 [95% CI, 0.77 to 1.52]; P = .65). The COLOXIS model is predictive of oxaliplatin benefits in the CC adjuvant setting. The results provide evidence supporting a change in CC adjuvant therapy: reserve oxaliplatin only for COLOXIS+ patients, but further investigation is warranted.

Alexithymia and depression may predict treatment failure in patients undergoing Gamma Knife radiosurgery for trigeminal neuralgia: the potential contribution of colored pain drawings.

Gamma Knife radiosurgery (GKRS) effectively achieves high rates of pain control in trigeminal neuralgia (TN); however, psychological factors can also impact how individuals perceive pain and respond to treatment. The authors aimed to measure the effects of alexithymia and depression on GKRS outcomes, as well as the potential role of colored pain drawings (CPDs) in identifying patients who require additional psychological support. Seventy-three medically intractable, typical patients with TN were included. Participants completed a visual analog scale (VAS), the Toronto Alexithymia Scale (TAS-20), and the Turkish version of the Beck Depression Inventory-II (BDI-II). Participants used colored pens to draw their pain patterns on standardized face charts and CPDs were categorized as expected or unexpected. Based on the Barrow Neurological Institute pain scale, patients were categorized as responders or nonresponders. Most patients (63%) were female, and the median age was 60 (range 27-88) years. Of 73 patients, 56 (76.7%) were responders and 17 (23.3%) were nonresponders. Forty-nine patients (67.1%) had expected CPDs, whereas 24 (32.9%) had unexpected CPDs. Responder and nonresponder groups had similar ages, genders, education, comorbidities, and initial VAS scores. Both groups preferred the colors red and black to describe intense pain (79.2% vs 67.3%, p = 0.411). Significantly better pain relief was observed in patients with expected CPDs than in those with unexpected CPDs (87.8% vs 54.2%, p = 0.003). The unexpected CPD group had significantly more alexithymia (58.3% vs 32.7%, p = 0.045). The mean BDI-II score of the cohort was 26 (range 15-37) and was significantly higher in the unexpected group (28.3 vs 24.8, p = 0.028). Unexpected CPD (OR 12.540) and higher TAS-20 score (OR 3.22) increased treatment failure risk. The outcomes of TN treatment can be influenced by psychological factors, and patients with TN with higher total TAS-20 and BDI-II scores, along with unexpected CPDs, had an increased likelihood of treatment failure. CPDs can be accessed quickly and may allow the physician to screen out most patients with unfavorable psychometrics and proceed with the necessary treatment with appropriate psychological support.

Renal arterial resistive index as a prognostic marker in lupus nephritis patients

IntroductionLupus nephritis (LN) is known to be one of the most serious complications of SLE and it is a major predictor of poor prognosis. Despite the improvement in understanding the pathophysiology of lupus nephritis and greater improvement in diagnostic approaches, lupus nephritis patients have poorer outcomes. ObjectivesStudy the relation between renal resistive index (RRI) and renal function and histopathological parameters in lupus nephritis (LN) patients. Also to investigate the usefulness of RRI in predicting response to treatment. Patients and methodsThis study included 126 patients who were split into two groups (group 1: 101 LN patients and group 2: 25 SLE patients without renal affection); and 100 healthy controls (group 3). The RRI was measured for all participants through a colored Doppler ultrasound examination. LN patients underwent renal biopsy and received their therapy and were followed up for 6 months. ResultsThe RRI was significantly greater in the LN group (mean±SD; 0.64±0.07) than in SLE patients without nephritis (0.5884±0.04) (P<0.0001). The RRI was greater in LN class IV (P<0.0001). RRI significantly correlated with the chronicity index (r=0.704, P<0.0001), activity index (r=0.310, P=0.002), and serum creatinine (r=0.607, P<0.0001) and negatively correlated with eGFR (r=−0.719, P<0.0001). Almost eighty-five percent (84.8%) of LN patients responded to induction therapy. RRI was significantly greater in the nonresponder group (mean±SD, 0.73±0.02) than that in the responder group (0.63±.07) (P<0.0001). All non-responders to induction therapy while only 29.8% of responders had an RRI of ˃0.7. RRI, according to regression analysis was a significant predictor of response to treatment in LN patients. ConclusionRRI was significantly greater in the LN group and significantly correlated with kidney function and histopathological parameters. RRI can predict response to induction therapy in LN patients.

Hemodynamic Response to Exercise Training in Heart Failure With Reduced Ejection Fraction Patients.

Supervised exercise training decreases total and cardiac mortality and increases quality of life of heart failure with reduced ejection fraction (HFrEF) patients. However, response to training is variable from one patient to another and factors responsible for a positive response to training remain unclear. The aims of the study were to compare cardiac hemodynamic changes after an exercise training program in responders (R) versus non-responders (NR) HFrEF patients, and to compare different discriminators used to assess response to training. Seventy-six HFrEF patients (86% males, 57 ± 12 years) completed an exercise training program for 4 weeks. Patients underwent cardiopulmonary exercise testing (CPET) on a cycle ergometer before and after training. Cardiac hemodynamics were measured by impedance cardiography during CPET. The R and NR groups were classified using the median change in peak oxygen uptake (V̇O2peak). There were statistically significant differences in V̇O2peak (+35% vs. -1%, P < 0.0001) and in peaks of ventilation (+30% vs. +2%, P < 0.0001), cardiac output (COpeak) (+25% vs. +4%, P < 0.01), systolic blood pressure (+12% vs. +2%, P < 0.05), diastolic blood pressure (+9% vs. +4%, P < 0.05) and heart rate (+8% vs. +1%, P < 0.01) between R and NR after the training program. V̇O2peak was the best discriminator between R and NR (receiver operating characteristic (ROC) area under the curve (AUC) = 0.83, P < 0.0001), followed by COpeak (ROC AUC = 0.77, P < 0.0001). V̇O2peak is the best discriminator between HFrEF R and NR patients after the training program. Responders showed improvements in peak hemodynamic parameters. These results pave the way for other studies to determine how the individualization of exercise training programs and peak hemodynamic parameters potentially linked to a better positive response status.

Application of artificial intelligence (AI) features of nuclear morphology from BLASST-1 (Bladder Cancer Signal Seeking Trial) of nivolumab, gemcitabine, and cisplatin in patients with MIBC undergoing cystectomy.

674 Background: BLASST-1 is a multi-center phase II trial evaluating neoadjuvant nivolumab (N) with gemcitabine-cisplatin (GC) for patients (pts) with MIBC undergoing radical cystectomy (RC) (NCT03294304). 41 pts with MIBC (cT2-T4a, N≤1, M0) were enrolled between Feb 2018 and June 2019; (cT2N0 90%, cT3N0 7%, cT4N1 3%). Pts received C (70mg/m2) IV on D1, G (1000mg/m2) on D1, D8, and N (360 mg) IV on D8 every 21 days for 4 cycles followed by RC within 8 wks. The primary endpoint was pathologic downstaging (PaR; ≤pT1N0). Safety, Relapse-free survival (RFS), Progression-free survival (PFS) and biomarker analyses were secondary endpoints. PaR rate was 65.8%, the pCR (≤pT is N0) rate was 49% and there were no safety concerns or delays to RC. Morphometric characteristics of the cell nucleus can be used to assess bladder cancer grading and gain insights into cellular functionalities. In this study, we sought to evaluate the ability of the AI model to identify non-responders to neoadjuvant chemo-immunotherapy. in the BLASST-1 cohort based on computerized image features of nuclear morphology and architecture on pre-treatment transurethral resection of bladder tumor (TURBT) tissues. Methods: Of the 41 pts, we had H&amp;E images available for 34 pts, of which 23 had PaR and 11 did not have PaR and these were classified as responder (R) and non-responder (NR) groups. A machine learning model (U-net) was developed and invoked for tumor segmentation on the H&amp;E images from the BLASST-1 cohort. A second machine learning model (HoVer-Net) was employed to segment and classify individual nuclei. A total of 408 features relating to the textural and spatial arrangement of individual cancer nuclei were extracted. The 17 most significant features, identified through the least absolute shrinkage and selection operator, were used to train a Cox regression model to predict the risk of death using 361 MIBC pts from the Cancer Genome Atlas (TCGA). This Cox model was then applied to assign a risk score to pts in BLASST-1, using a threshold learned from TCGA pts, the individual pts in BLASST-1 were assigned as either low-risk or high-risk. Results: The top identified prognostic features described the textural appearance of individual nuclei with more texture. This model accurately predicted PaR in BLASST-1, with an area under a receiver operating characteristic curve of 0.83. Overall, the pts with the same nuclear angle direction within the tumor tissue had a high chance of response to the neoadjuvant chemo-IO combination in the BLASST-1 trial. Conclusions: A computerized AI model relying on nuclear morphologic and architecture features demonstrated prognostic capability in MIBC within the TCGA dataset and predictive capability for the PaR in the BLASST-1 trial. These findings support further validation studies.

Depression of dynamic cerebral autoregulation during neural activation: The role of responders and non-responders

Neurovascular coupling (NVC) interaction with dynamic cerebral autoregulation (dCA) remains unclear. We investigated the effect of task complexity and duration on the interaction with dCA. Sixteen healthy participants (31.6 ± 11.6 years) performed verbal fluency (naming-words (NW)) and serial subtraction (SS) paradigms, of varying complexity, at durations of 05, 30 and 60 s. The autoregulation index (ARI), was estimated from the bilateral middle cerebral artery blood velocity (MCAv) step response, calculated by transfer function analysis (TFA), for each paradigm during unstimulated (2 min) and neuroactivated (1 min) segments. Intraclass correlation (ICC) and coefficient of variation (CV) determined reproducibility for two visits and objective criteria were applied to classify responders (R) and non-responders (NoR) to task-induced MCAv increase. ICC values demonstrated fair reproducibility in all tasks. ARI decreased in right (RH) and left (LH) hemispheres, irrespective of paradigm complexity and duration (p < 0.0001). Bilateral ARI estimates were significantly decreased during NW for the R group only (p < 0.0001) but were reduced in both R (p < 0.0001) and NoR (p = 0.03) groups for SS tasks compared with baseline. The reproducible attenuation of dCA efficiency due to paradigm-induced NVC response, its interaction, and different behaviour in R and NoR, warrant further research in different physiological and clinical conditions.

Multiomic molecular characterization of the response to combination immunotherapy in MSS/pMMR metastatic colorectal cancer

BackgroundImmune checkpoint inhibitor (ICI) combinations represent an emerging treatment strategies in cancer. However, their efficacy in microsatellite stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer (CRC) is variable. Here, a...

The gut microbiome predicts response to UDCA/CDCA treatment in gallstone patients: comparison of responders and non-responders

The treatment of gallbladder (GB) stones depends on condition severity. Ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) are commonly used to treat GB stones, but the factors affecting response rates have not been fully identified. Therefore, we investigated the relationship between response to UDCA/CDCA treatment and changes in the gut microbiomes of patients with GB stones with the intention of identifying gut microbiomes that predict susceptibility to UDCA/CDCA treatment and treatment response. In this preliminary, prospective study, 13 patients with GB stones were treated with UDCA/CDCA for 6 months. Patients were classified into responder and non-responder groups based on treatment outcomes. Gut microbiomes were analyzed by 16S rDNA sequencing. Taxonomic compositions and abundances of bacterial communities were analyzed before and after UDCA/CDCA treatment. Alpha and beta diversities were used to assess similarities between organismal compositions. In addition, PICRUSt2 analysis was conducted to identify gut microbial functional pathways. Thirteen patients completed the treatment; 8 (62%) were assigned to the responder group and the remainder to the non-responder group. Low abundances of the Erysipelotrichi lineage were significantly associated with favorable response to UDCA/CDCA treatment, whereas high abundances of Firmicutes phylum indicated no or poor response. Our results suggest that a low abundance of the Erysipelotrichi lineage is significantly associated with a favorable response to UDCA/CDCA and that a high abundance of Firmicutes phylum is indicative of no or poor response. These findings suggest that some gut microbiomes are susceptible to UDCA/CDCA treatment and could be used to predict treatment response in patients with GB stones.

High Ferritin Is Not Needed in Hemodialysis Patients: A Retrospective Study of Total Body Iron and Oral Iron Replacement Therapy.

In vivo iron levels can be adjusted through intestinal iron absorption to be maintained at a suitable level; however, optimal iron levels in hemodialysis (HD) patients are unclear. In this study, we investigated total body iron (TBI), calculated as the sum of red blood cell (RBC) iron and iron stores, during courses of low-dose oral iron replacement therapy, and evaluated in vivo iron sufficiency and its indicators in HD patients. We analyzed data on 105 courses of low-dose iron replacement therapy administered to 83 patients on maintenance HD over 7 months. We evaluated changes in TBI, RBC iron, and iron stores from the initiation of treatment to month 7 in two groups of patients, namely, iron-therapy responders and non-responders. TBI showed significant increases until month 4 and plateaued thereafter in iron-therapy responders, and tended to increase and then reached a similar plateau in non-responders (month 7: 1900 ± 447 vs. 1900 ± 408 mg). Steady-state TBI was strongly correlated with body surface area (y = 1628.6x - 791.91, R2 = 0.88, p < 0.001). We observed constant TBI during oral iron replacement therapy suggesting the activation of a "mucosal block". The results suggest that body surface area has utility for estimating the required TBI with regression equations.

Identification of the key genes and mechanisms associated with transcatheter arterial chemoembolisation refractoriness in hepatocellular carcinoma.

Transcatheter arterial embolisation (TACE) is the primary treatment for intermediate-stage hepatocellular carcinoma (HCC) patients while some HCC cases have shown resistance to TACE. To investigate the key genes and potential mechanisms correlated with TACE refractoriness in HCC. The microarray datasets of TACE-treated HCC tissues, HCC and non-HCC tissues were collected by searching multiple public databases. The respective differentially expressed genes (DEGs) were attained via limma R package. Weighted gene co-expression network analysis was employed for identifying the significant modules related to TACE non-response. TACE refractoriness-related genes were obtained by intersecting up-regulated TACE-associated and HCC-associated DEGs together with the genes in significant modules related to TACE non-response. The key genes expression in the above two pairs of samples was compared respectively via Wilcoxon tests and standard mean differences model. The prognostic value of the key genes was evaluated by Kaplan-Meier curve. Multivariate analysis was utilised to investigate the independent prognostic factor in key genes. Single-cell RNA (scRNA) sequencing analysis was conducted to explore the cell types in HCC. TACE refractoriness-related genes activity was calculated via AUCell packages. The CellChat R package was used for the investigation of the cell-cell communication between the identified cell types. HCC tissues of TACE non-responders (n = 66) and TACE responders (n = 81), HCC (n = 3941) and non-HCC (n = 3443) tissues were obtained. The five key genes, DLG associated protein 5 (DLGAP5), Kinesin family member 20A (KIF20A), Assembly factor for spindle microtubules (ASPM), Kinesin family member 11 (KIF11) and TPX2 microtubule nucleation factor (TPX2) in TACE refractoriness-related genes, were identified. The five key genes were all up-regulated in the TACE non-responders group and the HCC group. High expression of the five key genes predicted poor prognosis in HCC. Among the key genes, TPX2 was an independent prognostic factor. Four cell types, hepatocytes, embryonic stem cells, T cells and B cells, were identified in the HCC tissues. The TACE refractoriness-related genes expressed primarily in hepatocytes and embryonic stem cells. Hepatocytes, as the providers of ligands, had the strongest interaction with embryonic stem cells that provided receptors. Five key genes (DLGAP5, KIF20A, ASPM, KIF11 and TPX2) were identified as promoting refractory TACE. Hepatocytes and embryonic stem cells were likely to boost TACE refractoriness.

Predictors of a Favorable Response to Erector Spinae Plane Block for Lumbosacral Radiculopathy

BACKGROUND: The erector spinae plane block (ESPB), which was introduced to manage the thoracic pain, is a technical easy and less invasive ultrasound-guided technique. Although the ESPB is used widely in various clinical situations, no studies have evaluated the association between the clinical outcomes of the ESPB and the numerical changes of the perfusion index (PI). OBJECTIVES: The purpose of this study is to investigate the association between the clinical response following ESPB and other possible factors including the changes of PI. STUDY DESIGN: Prospective, nonrandomized, and an open-label study. SETTING: The pain clinic of a tertiary university hospital. METHODS: This study included 91 patients of low back pain with degenerative spinal disease who received L4 ESPB using 20 mL of 0.2% ropivacaine. For the predication of clinical outcome, the PI was measured for 30 min at the blocked side subsequent to the ESPB. Various demographic data were also analyzed to predict the clinical outcomes. RESULTS: The PI of the responder group was higher value than that of the nonresponder group until 30 min but did not show any statistically significant differences. Multivariate logistic regression analysis revealed that the duration of pain (odds ratio [OR], 0.95; 95% CI, 0.90-1.00; P = 0.043), the right side injection (OR, 3.87; 95% CI, 1.42-10.55; P = 0.008), and the PI ratio of 1.5–3 at 10 min (OR, 3.79; 95% CI, 1.36-10.57; P = 0.011), were independent factors associated with successful outcomes. Limitation: The responder and the nonresponders were categorized using only changes of the numeric rating scale. The categorization based on the changes of functional disability or quality of life was not used. CONCLUSION: The right side injection, duration of pain less than 3 months, PI ratio of 1.5–3 at 10 min following the ESPB were associated with successful clinical outcomes. KEY WORDS: Erector spinae plane block, perfusion index, numeric rating scale, low back pain