Therapeutic Response In Patients Research Articles

JAK2 as Predictor of Therapeutic Response in Patients with Chronic Myeloid Leukemia Treated with Imatinib

Background. Chronic myeloid leukemia (CML) or chronic granulocytic leukemia is a myeloproliferative neoplasm indicated by the presence of the Philadelphia (Ph+) chromosome. First-line tyrosine kinase inhibitor, imatinib, is the gold standard for treatment. However, there has been known unresponsiveness to treatment, especially due to the involvement of other genes, such as the Janus kinase 2 (JAK2) gene. This study aimed to evaluate the relationships between JAK2 levels and complete hematological response (CHR), as well as early molecular response (EMR) after 3 months of imatinib treatment in patients with chronic phase CML. Methods. Patients with Ph+ CML in the chronic phase (n = 40; mean age, 40 ± 11 years) were recruited to complete assessments consisting of clinical examination and blood test, including evaluation of complete blood counts and the JAK2 levels, at baseline and following 3 months of therapy with imatinib (at an oral dose of 400 mg per day). Subjects were divided into two groups according to the presence of CHR and EMR. Results. JAK2 gene levels, phosphorylated, and total JAK2 proteins at baseline were significantly lower in the group with the presence of CHR and EMR. In addition, baseline JAK2 levels, including JAK2 gene expression, phosphorylated, and total JAK2 proteins, were negatively correlated with the presence of CHR and EMR. Conclusions. Based on these findings, JAK2 levels may be a potential indicator for evaluating treatment response on imatinib due to its role in the pathophysiology of CML.

Validation of Prognostic and Predictive Models for Therapeutic Response in Patients Treated with [177Lu]Lu-PSMA-617 Versus Cabazitaxel for Metastatic Castration-resistant Prostate Cancer (TheraP): A Post Hoc Analysis from a Randomised, Open-label, Phase 2 Trial

BackgroundPrognostic models have been developed using data from a multicentre noncomparative study to forecast the likelihood of a 50% reduction in prostate-specific antigen (PSA50), longer prostate-specific antigen (PSA) progression-free survival (PFS), and longer overall survival (OS) in patients with metastatic castration-resistant prostate cancer receiving [177Lu]Lu-PSMA radioligand therapy. The predictive utility of the models to identify patients likely to benefit most from [177Lu]Lu-PSMA compared with standard chemotherapy has not been established. ObjectiveTo determine the predictive value of the models using data from the randomised, open-label, phase 2, TheraP trial (primary objective) and to evaluate the clinical net benefit of the PSA50 model (secondary objective). Design, setting, and participantsAll 200 patients were randomised in the TheraP trial to receive [177Lu]Lu-PSMA-617 (n = 99) or cabazitaxel (n = 101) between February 2018 and September 2019. Outcome measurements and statistical analysisPredictive performance was investigated by testing whether the association between the modelled outcome classifications (favourable vs unfavourable outcome) was different for patients randomised to [177Lu]Lu-PSMA versus cabazitaxel. The clinical benefit of the PSA50 model was evaluated using a decision curve analysis. Results and limitationsThe probability of PSA50 in patients classified as having a favourable outcome was greater in the [177Lu]Lu-PSMA-617 group than in the cabazitaxel group (odds ratio 6.36 [95% confidence interval {CI} 1.69–30.80] vs 0.96 [95% CI 0.32–3.05]; p = 0.038 for treatment-by-model interaction). The PSA50 rate in patients with a favourable outcome for [177Lu]Lu-PSMA-617 versus cabazitaxel was 62/88 (70%) versus 31/85 (36%). The decision curve analysis indicated that the use of the PSA50 model had a clinical net benefit when the probability of a PSA response was ≥30%. The predictive performance of the models for PSA PFS and OS was not established (treatment-by-model interaction: p = 0.36 and p = 0.41, respectively). ConclusionsA previously developed outcome classification model for PSA50 was demonstrated to be both predictive and prognostic for the outcome after [177Lu]Lu-PSMA-617 versus cabazitaxel, while the PSA PFS and OS models had purely prognostic value. The models may aid clinicians in defining strategies for patients with metastatic castration-resistant prostate cancer who failed first-line chemotherapy and are eligible for [177Lu]Lu-PSMA-617 and cabazitaxel. Patient summaryIn this report, we validated previously developed statistical models that can predict a response to Lu-PSMA radioligand therapy in patients with advanced prostate cancer. We found that the statistical models can predict patient survival, and aid in determining whether Lu-PSMA therapy or cabazitaxel yields a higher probability to achieve a serum prostate-specific antigen response.

Loss of GABARAP mediates resistance to immunogenic chemotherapy in multiple myeloma

Immunogenic cell death (ICD) is a form of cell death by which cancer treatments can induce a clinically relevant anti-tumor immune response in a broad range of cancers. In multiple myeloma (MM), the proteasome inhibitor bortezomib is an ICD inducer and creates durable therapeutic responses in patients. However, eventual relapse and resistance to bortezomib appear inevitable. Here, by integrating patient transcriptomic data with an analysis of calreticulin (CRT) protein interactors, we found that GABARAP is a key player whose loss prevented tumor cell death from being perceived as immunogenic after bortezomib treatment. GABARAP is located on chromosome 17p, which is commonly deleted in high-risk MM patients. GABARAP deletion impaired the exposure of the eat-me signal CRT on the surface of dying MM cells in vitro and in vivo, thus reducing tumor cell phagocytosis by dendritic cells and the subsequent anti-tumor T cell response. Low GABARAP was independently associated with shorter MM patient survival and reduced tumor immune infiltration. Mechanistically, we found that GABARAP deletion blocked ICD signaling by decreasing autophagy and altering Golgi apparatus morphology, with consequent defects in the downstream vesicular transport of CRT. Conversely, upregulating autophagy using rapamycin restored Golgi morphology, CRT exposure and ICD signaling in GABARAPKO cells undergoing bortezomib treatment. Therefore, coupling an ICD inducer, like bortezomib, with an autophagy inducer, like rapamycin, may improve patient outcomes in MM, where low GABARAP in the form of del(17p) is common and leads to worse outcomes.

Decreasing the steroid rapidly may help to improve the clinical outcomes of patients with intestinal steroid-refractory acute graft-versus-host disease receiving basiliximab treatment.

Intestinal steroid refractory acute graft-versus-host disease (SR-aGVHD) is the major cause of mortality in allogeneic hematopoietic stem cell transplantation (allo-HSCT). This retrospective cohort study aimed to identify the relationship between different steroid decreasing velocity and therapeutic response in patients with intestinal SR-aGVHD receiving basiliximab treatment, and also aimed to propose a reasonable steroid decreasing regimen for these patients. The median time for steroid dose decreasing to the 50% of initial dose and decreasing to the low-dose steroid for patients achieving ORR was 5 days and 12 days, respectively, which was both shorter than patients without achieving ORR. The ORR, NRM and survival in rapid and medium steroid decreasing group were all better than slow group. The cumulative incidence of ORR at any time was 90.4%, 78.1% and 62.3%, respectively, in rapid, medium, and slow group. The cumulative incidence of NRM at 1 year after basiliximab treatment was 18.7% (95% CI 11.3%-26.1%), 22.8% (95% CI 14.2%-31.4%) and 32.8% (95% CI 24.1%-41.5%), respectively, in rapid, medium, and slow group. The probability of OS at 1 year after basiliximab treatment was 76.9% (95% CI 68.9%-84.9%), 72.7% (95% CI 63.7%-81.7%), and 62.3% (95% CI 53.5%-71.1%), respectively, in rapid, medium, and slow group. Hence, it was helpful to decrease steroid to the 50% of initial dose ≤ 5 days and to the low-dose steroid ≤ 12 days after basiliximab treatment for intestinal SR-aGVHD patients, which may also be the reasonable steroid decrease protocol for these patients.

Abstract 2406: Circulating tumor DNA as a potential indicator of treatment response in patients with surgically unresectable PDAC

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly heterogeneous and extremely aggressive neoplasm. Most patients with PDAC present with symptomatic, surgically unresectable disease at initial diagnosis. Systemic chemotherapy is the standard care for patients diagnosed with unresectable PDAC, despite the dismal survival rate due to disease recurrence. In this context, liquid biopsy based ctDNA monitoring may aid to improve detection accuracy and allow real time disease prognosis. Here we aimed to investigate the utility of ctDNA in longitudinal tumor monitoring to assess treatment response and to predict disease recurrence. We performed targeted NGS sequencing to investigate over 900 mutations (SNVs) and 12 copy number variations (CNVs) in 53 genes, using the Ion S5 Oncomine PanCancer gene panel in 40 PDAC patients with unresectable disease. Serial plasma samples were obtained from patients in the course of 24 months, including samples collected before the first intervention (baseline) as well as within 2 months after initiation of chemotherapy. Patients were followed for a period of up to 2-years from diagnosis through treatment, to death or final follow-up. Genomic DNA from paired plasma-buffy coat samples were sequenced to exclude clonal hematopoiesis. Overall detection of ctDNA alterations in baseline samples was 55% (22/40) with increasingly higher detection rates and mutation loads in advanced disease (88% in stage IV patients). Alterations including SNVs and CNVs were preferentially distributed among 9 genes; mutations in TP53 (45%), KRAS (38%) and SMAD4 (5%) were most commonly identified. To asses response to chemotherapy, the presence of residual ctDNA after clinical intervention was evaluated by comparing total ctDNA MAF (mutant allele frequency) detected in plasma at diagnosis and within 2 months of chemotherapy. 71% (17/24) of patients who reached progressive disease (PD) had detectable baseline mutations and 79% (19/24) had persistent residual mutations at 2 months of treatment. Conversely, 94% (15/16) of non-PD patients had no detectable ctDNA or had a significant reduction in total MAF after 2 months of chemotherapy. Absence of residual ctDNA after 2 months of chemotherapy was associated with a better OS (p=0.031; HR = 3.48). On the other hand, residual ctDNA after 2 months of chemotherapy was associated with a shorter PFS (p=0.042; HR = 3.28). Our study demonstrates that monitoring ctDNA levels derived from plasma provides valuable insights into the therapeutic response in patients with unresectable PDAC, even in the absence of matched tumor genotyping. We found a significant correlation between increased ctDNA levels following the initiation of treatment and poorer survival outcomes. Citation Format: Fabio Pittella Silva, Yasutoshi Kimura, Masayo Motoya, Toru Nakamura, Takeshi Murakami, Kazunori Watanabe, Siew-Kee Low, Yusuke Nakamura. Circulating tumor DNA as a potential indicator of treatment response in patients with surgically unresectable PDAC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2406.

Constructing lactylation-related genes prognostic model to effectively predict the disease-free survival and treatment responsiveness in prostate cancer based on machine learning.

Background: Prostate cancer (PCa) is one of the most common malignancies in men with a poor prognosis. It is therefore of great clinical importance to find reliable prognostic indicators for PCa. Many studies have revealed the pivotal role of protein lactylation in tumor development and progression. This research aims to analyze the effect of lactylation-related genes on PCa prognosis. Methods: By downloading mRNA-Seq data of TCGA PCa, we obtained the differential genes related to lactylation in PCa. Five machine learning algorithms were used to screen for lactylation-related key genes for PCa, then the five overlapping key genes were used to construct a survival prognostic model by lasso cox regression analysis. Furthermore, the relationships between the model and related pathways, tumor mutation and immune cell subpopulations, and drug sensitivity were explored. Moreover, two risk groups were established according to the risk score calculated by the five lactylation-related genes (LRGs). Subsequently, a nomogram scoring system was established to predict disease-free survival (DFS) of patients by combining clinicopathological features and lactylation-related risk scores. In addition, the mRNA expression levels of five genes were verified in PCa cell lines by qPCR. Results: We identified 5 key LRGs (ALDOA, DDX39A, H2AX, KIF2C, RACGAP1) and constructed the LRGs prognostic model. The AUC values for 1 -, 3 -, and 5-year DFS in the TCGA dataset were 0.762, 0.745, and 0.709, respectively. The risk score was found a better predictor of DFS than traditional clinicopathological features in PCa. A nomogram that combined the risk score with clinical variables accurately predicted the outcome of the patients. The PCa patients in the high-risk group have a higher proportion of regulatory T cells and M2 macrophage, a higher tumor mutation burden, and a worse prognosis than those in the low-risk group. The high-risk group had a lower IC50 for certain chemotherapeutic drugs, such as Docetaxel, and Paclitaxel than the low-risk group. Furthermore, five key LRGs were found to be highly expressed in castration-resistant PCa cells. Conclusion: The lactylation-related genes prognostic model can effectively predict the DFS and therapeutic responses in patients with PCa.

ARRDC3 regulates the targeted therapy sensitivity of clear cell renal cell carcinoma by promoting AXL degradation

ABSTRACT AXL plays crucial roles in the tumorigenesis, progression, and drug resistance of neoplasms; however, the mechanisms associated with AXL overexpression in tumors remain largely unknown. In this study, to investigate these molecular mechanisms, wildtype and mutant proteins of arrestin domain-containing protein 3 (ARRDC3) and AXL were expressed, and co-immunoprecipitation analyses were performed. ARRDC3-deficient cells generated using the CRISPR-Cas9 system were treated with different concentrations of the tyrosine kinase inhibitor sunitinib and subjected to cell biological, molecular, and pharmacological experiments. Furthermore, immunohistochemistry was used to analyze the correlation between ARRDC3 and AXL protein expressions in renal cancer tissue specimens. The experimental results demonstrated that ARRDC3 interacts with AXL to promote AXL ubiquitination and degradation, followed by the negative regulation of downstream signaling mechanisms, including the phosphorylation of protein kinase B and extracellular signal-regulated kinase. Notably, ARRDC3 deficiency decreased the sunitinib sensitivity of clear cell renal cell carcinoma (ccRCC) cells in a manner dependent on the regulation of AXL stability. Overall, our results suggest that ARRDC3 is a negative regulator of AXL and can serve as a novel predictor of sunitinib therapeutic response in patients with ccRCC.

Using Electronic Health Record Data to Determine the Safety of Aqueous Humor Liquid Biopsies for Molecular Analyses

PurposeKnowing the surgical safety of anterior chamber liquid biopsies will support the increased use of proteomics and other molecular analyses to better understand disease mechanisms and therapeutic responses in patients and clinical trials. Manual review of operative notes from different surgeons and procedures in electronic health records (EHR) is cumbersome, but free-text software tools could facilitate efficient searches. DesignRetrospective case series. Participants1,418 aqueous humor (AH) liquid biopsies from patients undergoing intraocular surgery. MethodsFree-text EHR searches were performed using the Stanford Research Repository (STARR) cohort discovery tool to identify complications associated with anterior chamber paracentesis and subsequent endophthalmitis. Complications of the surgery unrelated to the biopsy were not reviewed. Main Outcome MeasuresBiopsy associated intraoperative complications and endophthalmitis. Results1,418 AH liquid biopsies were performed by 17 experienced surgeons. EHR free-text searches were 100% error-free for surgical complications, >99% for endophthalmitis (<1% false positive), and >93.6% for anesthesia type, requiring manual review for only a limited number of cases. More than 85% of cases were performed under local anesthesia without ocular muscle akinesia. Although the most common indication was cataract (50.1%), other diagnoses included glaucoma, diabetic retinopathy, uveitis, age-related macular degeneration, endophthalmitis, retinitis pigmentosa, and uveal melanoma. A 50-100μL sample was collected in all cases using either a 30-gauge needle or a blunt cannula via a paracentesis. The median follow-up was more than seven months. There was only one minor complication (0.07%) identified: a case of a small tear in Descemet’s membrane without long-term sequelae. No other complications occurred, including other corneal injuries, lens or iris trauma, hyphema, or suprachoroidal hemorrhage. There was no case of postoperative endophthalmitis. ConclusionsAnterior chamber liquid biopsy during intraocular surgery is a safe procedure and may be considered for large-scale collection of AH samples for molecular analyses. Free-text EHR searches are an efficient approach to reviewing intraoperative procedures.

Comparing Three Different Anti–Programmed Death-Ligand 1 Antibodies in Immunohistochemical Evaluation of Combined Chemoimmunotherapy Response in Patients With NSCLC: A Prospective Study

IntroductionMultiple programmed death-ligand 1 (PD-L1) immunohistochemistry assays performed using different antibodies including DAKO 22C3, DAKO 28-8, and Ventana SP142 PD-L1—predictive markers for response to various immune checkpoint inhibitors in NSCLC—have been approved in several countries. The differences in multiple PD-L1 immunohistochemistry assay results in predicting the therapeutic response to combined chemoimmunotherapy in patients with NSCLC remain unclear. MethodsIn this multicenter prospective observational study, we monitored 70 patients with advanced NSCLC treated with combined chemoimmunotherapy at 10 institutions in Japan. The expression of PD-L1 in pretreatment tumors was evaluated using the 22C3, 28-8, and SP142 assays in all patients. ResultsThe PD-L1 level in tumor cells determined using the 22C3 assay was the highest among the three assays performed with different antibodies. According to the 22C3 assay results, the PD-L1 tumor proportion score greater than or equal to 50% group had a significantly longer progression-free survival period than the PD-L1 tumor proportion score less than 50% group. Nevertheless, the other assays did not reveal remarkable differences in the objective response rate or progression-free survival. ConclusionsIn our study, PD-L1 expression determined using the 22C3 assay was more correlated with the therapeutic response of patients with NSCLC treated with combined chemoimmunotherapy than that determined using the 28-8 and SP142 assays. Therefore, the 22C3 assay may be useful for clinical decision-making for patients with NSCLC treated with combined chemoimmunotherapy. Trial registration number: UMIN 000043958.

Short-term serial circulating tumor DNA assessment predicts therapeutic efficacy for patients with advanced pancreatic cancer

PurposeWe investigated the potential clinical utility of short-term serial KRAS-mutated circulating cell-free tumor DNA (ctDNA) assessment for predicting therapeutic response in patients undergoing first-line chemotherapy for advanced pancreatic cancer.MethodsWe collected 144 blood samples from 18 patients with locally advanced or metastatic cancer that were undergoing initial first-line chemotherapy of gemcitabine plus nab-paclitaxel (GEM plus nab-PTX). Analysis of KRAS-mutated ctDNA was quantified by digital droplet polymerase chain reaction (ddPCR) as mutant allele frequency (MAF). This study investigated pretreatment KRAS-mutated ctDNA status and ctDNA kinetics every few days (days 1, 3, 5 and 7) after initiation of chemotherapy and their potential as predictive indicators.ResultsOf the 18 enrolled patients, an increase in KRAS-mutated ctDNA MAF values from day 0–7 after initiation of chemotherapy was significantly associated with disease progression (P < 0.001). Meanwhile, positive pretreatment ctDNA status (MAF ≥ 0.02%) (P = 0.585) and carbohydrate antigen 19-9 (CA19-9) values above the median (P = 0.266) were not associated with disease progression. In univariate analysis, this short-term increase in ctDNA MAF values (day 0–7) was found to be associated with significantly shorter progression free survival (PFS) (hazard ration [HR], 24.234; range, (2.761–212.686); P = 0.0002).ConclusionThis short-term ctDNA kinetics assessment may provide predictive information to reflect real-time therapeutic response and lead to effective refinement of regimen in patients with advanced pancreatic cancer undergoing systemic chemotherapy.

P965 Ulcerative proctitis treated with biologics: is it too hard to treat?

Abstract Background Patients with ulcerative proctitis are widely considered a challenging population because the reported reduced response rate to conventional medical treatment. On the other hand, data on the role of biological therapies in this specific cohort are currently scarce Methods We retrospectively evaluated all patients with proctitis (defined as the mucosal inflammation of only the rectum with ulcerative colitis confirmed by histology) treated with biologics (infliximab, adalimumab, vedolizumab -VDZ-, ustekinumab -UST) and tofacitinib (TOFA) at four referral centers in the last 5 years. All patients were treated with concomitant topical mesalamine. We included in this study only patients who underwent colonoscopy at baseline and after 52 weeks of treatment, in order to evaluate therapeutic response in terms of mucosal healing (defined as a Mayo Endoscopic Score -MES- &amp;lt;2), besides that clinical remission (defined as a Partial Mayo Score -PMS- &amp;lt;2 without oral or topical corticosteroid therapy). We collect clinical and demographic data, as well as fecal calprotectin (FC) and C-Reactive Protein (CRP) levels at baseline and after the induction of therapy Results Among 64 patients enrolled (age 50.8±16.5 years, 29 [45.3%] women), 33 (51.6%) were treated with anti-TNF), 15 with VDZ, 13 with UST, and 3 with TOFA. Globally, 51 (79.7%) patients achieved clinical remission and 37 (57.8%) patients achieved endoscopic remission at 52 weeks. There were no group differences in age, sex, BMI, disease duration, PMS, MES, drug, or baseline CRP levels between patients achieving or not either clinical or endoscopic remission. Baseline calprotectin levels were lower in patients who achieved endoscopic remission (median [IQ range] 297 [158, 475] versus 442 [230, 1545] µg/mL, p=0.036), but not in those who achieved clinical remission. After the induction phase, lower calprotectin levels were observed in patients achieving clinical (46 [15, 166] versus 553 [72, 1649] µg/mL, p=0.001) and endoscopic remission (38 [15, 112] versus 328 [52, 2171] µg/mL, p=0.0002), compared with non-responders. The effects of post-induction calprotectin levels on clinical remission (β= -0.001, p=0.020) and endoscopic remission (β= -0.007, p=0.006) remained significant in multivariable models adjusted for age, sex, BMI, disease duration, and biological treatment. A cut point of 200 µg/mL post-induction was identified to predict endoscopic remission (sensitivity 92%, specificity 64%, ROC AUC 0.781) Conclusion High rates of clinical and endoscopic remission with biological therapies could be achieved in patients with ulcerative proctitis. Fecal calprotectin levels after the induction of biological therapies seem to predict the therapeutic response in patients with ulcerative proctitis

P1031 Intestinal ultrasound for monitoring therapeutic response in patients with ulcerative colitis treated with upadacytynib

Abstract Background Intestinal ultrasound (IUS) is a noninvasive method to assess disease activity in inflammatory bowel disease (IBD) although there are still limited data of usefulness of IUS in ulcerative colitis (UC) compared to Crohn’s disease (CD). The aim of the study was to evaluate usefulness of intestinal ultrasound in comparison to endoscopy in assessment of the efficacy of upadacytynib (UPA) in induction of remission in patients with UC. Methods This was a prospective, two-centers study in which we enrolled 27 patients with a flare of UC (total Mayo score&amp;gt;7) treated with UPA (8 weeks of induction period). IUS, calprotectin level and laboratory tests were conducted in week 0, 4 and 8. Milano ultrasound criteria (MUC) were used to assess the IUS disease activity. Results Among 27 patients 34% achieved clinical remission and 40,6% endoscopic remission already in week 4. After 8 weeks of treatment with UPA clinical remission in 53,1% and endoscopic remission in 56,2% of UC patients were achieved. In IUS the most affected parts of the colon were rectum and sigmoid colon. 100% of the patients had an increased bowel wall thickness (BWT)&amp;gt;3mm in the sigmoid colon and rectum at baseline. In the first 4 weeks of the study, the percentage of patients with an increased BWT in the sigmoid colon and rectum decreased significantly and remained low at week 8. 78% of patients with normalized BWT had endoscopic remission vs 22% without endoscopic remission (p&amp;lt;0.001). There was 74% correlation between MUC and total Mayo score (p=0,013). Conclusion Upadacitinib has demonstrated a positive efficacy during induction of remission in UC patients, shown as improvement in IUS parameters as well as in endoscopy improvement. Our data showed a strong correlation between normalization of BWT and endoscopic remission in patients with UC treated with upadacytynib. IUS seems to be a useful and non-invasive method for monitoring disease course and for assessing treatment response in UC patients.

Integrating single-cell and bulk transcriptomic analyses to develop a cancer-associated fibroblast-derived biomarker for predicting prognosis and therapeutic response in breast cancer.

Cancer-associated fibroblasts (CAFs) contribute to the progression and treatment of breast cancer (BRCA); however, risk signatures and molecular targets based on CAFs are limited. This study aims to identify novel CAF-related biomarkers to develop a risk signature for predicting the prognosis and therapeutic response of patients with BRCA. CAF-related genes (CAFRGs) and a risk signature based on these genes were comprehensively analyzed using publicly available bulk and single-cell transcriptomic datasets. Modular genes identified from bulk sequencing data were intersected with CAF marker genes identified from single-cell analysis to obtain reliable CAFRGs. Signature CAFRGs were screened via Cox regression and least absolute shrinkage and selection operator (LASSO) analyses. Multiple patient cohorts were used to validate the prognosis and therapeutic responsiveness of high-risk patients stratified based on the CAFRG-based signature. In addition, the relationship between the CAFRG-based signature and clinicopathological factors, tumor immune landscape, functional pathways, chemotherapy sensitivity and immunotherapy sensitivity was examined. External datasets were used and sample experiments were performed to examine the expression pattern of MFAP4, a key CAFRG, in BRCA. Integrated analyses of single-cell and bulk transcriptomic data as well as prognostic screening revealed a total of 43 prognostic CAFRGs; of which, 14 genes (TLN2, SGCE, SDC1, SAV1, RUNX1, PDLIM4, OSMR, NT5E, MFAP4, IGFBP6, CTSO, COL12A1, CCDC8 and C1S) were identified as signature CAFRGs. The CAFRG-based risk signature exhibited favorable efficiency and accuracy in predicting survival outcomes and clinicopathological progression in multiple BRCA cohorts. Functional enrichment analysis suggested the involvement of the immune system, and the immune infiltration landscape significantly differed between the risk groups. Patients with high CAF-related risk scores (CAFRSs) exhibited tumor immunosuppression, enhanced cancer hallmarks and hyposensitivity to chemotherapy and immunotherapy. Five compounds were identified as promising therapeutic agents for high-CAFRS BRCA. External datasets and sample experiments validated the downregulation of MFAP4 and its strong correlation with CAFs in BRCA. A novel CAF-derived gene signature with favorable predictive performance was developed in this study. This signature may be used to assess prognosis and guide individualized treatment for patients with BRCA.

No Correlation between Anti-drug Antibodies and Therapeutic Response in Tunisian Patients with Chronic Inflammatory Diseases Treated by TNF Blockers.

Tumor necrosis factor alpha (TNF alpha) blockers such as infliximab (IFX) and adalimumab (ADA) had significantly changed the course of inflammatory diseases such as rheumatoid arthritis (RA), spondyloarthritis (SpA) and Crohn's disease (CD). However, about 30% of patients do not respond to these treatments. This lack of response may be due to the formation of antibodies against these drugs (anti-drug antibodies: ADAbs). The aim of this study was to determine the prevalence of ADAbs against IFX and ADA, and the trough serum concentration of IFX and ADA in RA, SpA or CD patients and to assess their impact on the therapeutic response. A cross sectional, multi-centric study was conducted, including patients with RA, SpA or CD treated with IFX or ADA as a first biotherapy for at least 6 months. ADAbs and trough levels were measured by an Enzyme Linked Immunosorbent assay (ELISA). 197 patients were included (57 RA, 73 SpA and 67 CD). ADAbs were positive in 40% of cases for IFX and 25% for ADA. They were positive in 40% of SpA, 35% of RA, and 21% of CD. The presence of ADAbs was inversely correlated to the trough levels of IFX and ADA during RA (p = 0.01 and p < 0.0001), SpA (p < 0.01 and p < 0.0001) and CD (p = 0.001 and p = 0.04). For all pathologies, the presence of ADAbs was not correlated with disease activity. Concomitant methotrexate significantly reduced immunogenicity. In our study, the presence of ADAb and low trough levels seem to not affect the therapeutic response in patients on TNF alpha antagonists. Other tracks more than immunogenicity should be investigated to explain the loss of response to these biotherapies.

Crosstalk of cuproptosis-related subtypes, establishment of a prognostic signature, and immune infiltration characteristics in gastric cancer

BackgroundCuproptosis is a novel form of cellular demise that occurs through a unique pathway involving lipoylated proteins in the tricarboxylic acid (TCA) cycle and is closely linked to mitochondrial metabolism. Nevertheless, the comprehensive elucidation of the impact of carcinogenesis-associated genes (CRGs) on prognosis, tumor microenvironment (TME), and therapeutic response in patients with gastric cancer (GC) remains unclear. MethodsIn total, 1374 GC samples were gathered from three Gene Expression Omnibus (GEO) datasets and The Cancer Genome Atlas database. The samples were then stratified into different subtypes through unsupervised clustering of the 13 CRG profiles. The CRG_score was developed to quantify CRG patterns of individual tumors. Subsequently, we investigated the associations among the various groups and clinicopathological features, immune infiltration features, TME mutation status, and response to immunotherapy. ResultsThe GC samples were divided into two clusters based on their distinct clinicopathological features, prognosis, and immune characteristics. Using LASSO and Cox regression analyses, 9 genes were identified for constructing a prognostic signature related to cuproptosis. The novel signature displayed outstanding durability and prognostic capability for the overall lifespan of individuals. Additionally, the expression levels of signature genes in GC tissues and adjacent normal tissues were tested by qRT-PCR. Moreover, we developed a remarkably dependable nomogram to enhance the practicality of the CRG_score in clinical settings. High tumor mutation burden, increased microsatellite instability-high, immune activation, along with good survival probability and increased immunoreactivity to immune checkpoint inhibitors, were distinguishing features of low CRG_scores. ConclusionsThe findings of this study revealed the possible impacts of CRGs on the TME, clinical and pathological characteristics, and outlook of patients with GC. This signature was strongly linked to the immune response against GC and has the potential to serve as a valuable tool for predicting patient prognosis.

Clinical Outcomes of Crizotinib Readministration in Patients with Nonsmall Cell Lung Cancer with Anaplastic Lymphoma Kinase Rearrangement: Case Report and Review of Literature

AbstractRecent studies have demonstrated promising outcomes of the first-line anaplastic lymphoma kinase-tyrosine kinase inhibitor (ALK-TKI) “crizotinib” in patients with locally advanced and metastatic lung cancers with high expression of the fusion protein “EML4-ALK.” High drug resistance, however, restricts the therapeutic advantages of ALK-TKIs in patients with nonsmall cell lung cancer (NSCLC). The contemporary literature documents limited treatment approaches for patients with NSCLC relapse or nonresponsiveness to second-/third-generation ALK-TKIs. We hereby provide a descriptive analysis of five NSCLC cases treated with crizotinib, ceritinib, and alectinib for a median duration of 54 months. The outcomes indicate a profound therapeutic response in patients receiving 4th and subsequent line of treatment with crizotinib. The crizotinib retreatment actively reduced patient resistance to the ALK-TKIs by reversing the mesenchymal epithelial transition amplification. The results from this case series also emphasize the possible role of next-generation sequencing in determining therapeutic resistance and transforming the treatment paradigm for NSCLC. Partial response was observed in the patients after 6 months of crizotinib readministration. This is possibly the first case series reporting crizotinib rechallenge in patients of ALK positive NSCLC who failed on subsequent ALK-TKIs and multiple lines of chemotherapies.

Inhibition of ERO1a and IDO1 improves dendritic cell infiltration into pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and treatment resistant cancers. Due to its desmoplastic and hypoxic nature along with an abundance of myeloid cell infiltration and scarce T cell infiltration, PDAC is considered a cold tumor. Here we sought to investigate myeloid cell infiltration and composition in PDAC spheroids by targeting the hypoxia-associated pathways endoplasmic reticulum oxidoreductase 1 alpha (ERO1a) and indoleamine 2,3-dioxygenase 1 (IDO1). Using MiaPaCa2 spheroids with hypoxic core, we assessed the roles of ERO1a and IDO1 inhibition in modulating monocyte infiltration and differentiation, followed by characterizing immunomodulatory factors secreted using LC-MS/MS. Inhibition of ERO1a and IDO1 significantly improved monocyte infiltration and differentiation into dendritic cells. LC-MS/MS analysis of the PDAC spheroid secretome identified downregulation of hypoxia and PDAC pathways, and upregulation of antigen presentation pathways upon inhibition of ERO1a and IDO1. Furthermore, immunomodulatory factors involved in immune infiltration and migration including interleukin-8, lymphocyte cytosolic protein 1, and transgelin-2, were upregulated upon inhibition of ERO1a and IDO1. Collectively, our results show that inhibition of ERO1a and IDO1 modulates the tumor microenvironment associated with improved monocyte infiltration and differentiation into dendritic cells to potentially influence therapeutic responses in patients with PDAC.

Predicting therapeutic responses in head and neck squamous cell carcinoma from TP53 mutation detected by cell-free DNA.

Head and neck squamous cell carcinoma (HNSCC) is an epithelial malignant tumor originating from the oral cavity, oropharynx, nasal cavity, sinuses, nasopharynx, hypopharynx, or larynx. Mutations in TP53 are the most common of all somatic genomic changes in HNSCC, and TP53 mutations are associated with the response to immunotherapy and chemotherapy. Tumor-derived circulating cell-free DNA (cfDNA) is a minimally invasive method to determining genetic alterations in cancer. This study aimed to explore the therapeutic responses of patients with HNSCC with TP53 mutation and the accuracy of cfDNA for detecting TP53 mutation. Information on TP53 mutations, patient survival time, and clinical data in HNSCC were downloaded from The Cancer Genome Atlas database. The difference in immune infiltration between the TP53-mutant group and the wild-type group was compared. We applied the single-sample gene set enrichment analysis method on the transcriptome of HNSCC samples to assess the distribution of immune cell types between the two groups. The chemotherapy response was constructed using the R software package, "pRRophetic". Gene set enrichment analysis was performed based on the TP53 mutation. The next-generation sequencing was executed on cfDNA from nine patients with HNSCC to detect genetic alterations. Tumor biopsy (n=9) was sequenced using the same technique. TP53 was the most frequently mutated gene in HNSCC. The TP53 mutation was related to immune cells and the expression of immune-associated genes. The TP53 mutation group showed lower response to immunotherapy but high sensitivity to some chemotherapies compared with the wild-type group. TP53 was the most frequently mutated gene (6/9; 66.67%) in cfDNA. Only 27.27% of TP53 mutations in tumor tissue were detected outside of cfDNA. TP53 mutation could be used as a specific predictor of treatment response in patients with HNSCC. Using cfDNA to detect the TP53 mutations in patients with HSNCC is a feasible method. The results suggested that the therapeutic response in patients could be predicted by detecting TP53 mutations in cfDNA, and large-scale and prospective studies are needed to validate this hypothesis.

Molecular subtyping based on immune cell marker genes predicts prognosis and therapeutic response in patients with lung adenocarcinoma

ObjectiveLung adenocarcinoma (LA) is one of the most common malignancies and is responsible for the greatest number of tumor-related deaths. Our research aimed to explore the molecular subtype signatures of LA to clarify the correlation among the immune microenvironment, clinical outcomes, and therapeutic response.MethodsThe LA immune cell marker genes (LICMGs) identified by single-cell RNA sequencing (scRNA-seq) analysis were used to discriminate the molecular subtypes and homologous immune and metabolic traits of GSE72094 LA cases. In addition, the model-building genes were identified from 1441 LICMGs by Cox-regression analysis, and a LA immune difference score (LIDscore) was developed to quantify individual differences in each patient, thereby predicting prognosis and susceptibility to immunotherapy and chemotherapy of LA patients.ResultsPatients of the GSE72094 cohort were divided into two distinct molecular subtypes based on LICMGs: immune activating subtype (Cluster-C1) and metabolically activating subtype (cluster-C2). The two molecular subtypes have distinct characteristics regarding prognosis, clinicopathology, genomics, immune microenvironment, and response to immunotherapy. Among the LICMGs, LGR4, GOLM1, CYP24A1, SFTPB, COL1A1, HLA-DQA1, MS4A7, PPARG, and IL7R were enrolled to construct a LIDscore model. Low-LIDscore patients had a higher survival rate due to abundant immune cell infiltration, activated immunity, and lower genetic variation, but probably the higher levels of Treg cells in the immune microenvironment lead to immune cell dysfunction and promote tumor immune escape, thus decreasing the responsiveness to immunotherapy compared with that of the high-LIDscore patients. Overall, high-LIDscore patients had a higher responsiveness to immunotherapy and a higher sensitivity to chemotherapy than the low-LIDscore group.ConclusionsMolecular subtypes based on LICMGs provided a promising strategy for predicting patient prognosis, biological characteristics, and immune microenvironment features. In addition, they helped identify the patients most likely to benefit from immunotherapy and chemotherapy.

ADC Values for Detecting Bowel Inflammation and Biologic Therapy Response in Patients With Crohn Disease: A Post Hoc Prospective Trial Analysis.

BACKGROUND. New biologic agents for Crohn disease (CD) create a need for noninvasive disease markers. DWI may assess bowel inflammation without contrast agents. OBJECTIVE. The purpose of this study was to evaluate ADC values for identifying bowel inflammation and therapeutic response in patients with CD treated with biologic therapy. METHODS. This study entailed post hoc analysis of prospective trial data. Analysis included 89 patients (median age, 37 years; 49 women, 40 men) with CD treated by biologic therapy who underwent MR enterography (MRE) at baseline and 46 weeks after therapy, from March 2013 to April 2021; 43 patients underwent ileocolonoscopy at both time points. Analysis was conducted at the level of small-bowel and colorectal segments (586 segments analyzed). MR index of activity (MaRIA) score and presence of endoscopic ulcers were determined at both time points. One observer measured bowel wall ADC. Diagnostic performance was evaluated. Dichotomous ADC assessments used a threshold of 1301 × 10-6 mm2/s based on initial ROC analysis; dichotomous MaRIA score assessments used a threshold of 11 (moderate to severe inflammation). A second observer repeated ADC measurements in 15 patients. RESULTS. At baseline, ADC had AUC of 0.92, sensitivity of 78.6%, specificity of 91.4%, and accuracy of 88.2% for detecting segments with MaRIA score 11 or greater. At baseline, AUC for detecting endoscopic ulcers was 0.96 for MaRIA score versus 0.87 for ADC (p < .001); sensitivity, specificity, and accuracy were 70.8%, 90.2%, and 85.1% for ADC and 86.2%, 96.2%, and 93.6% for MaRIA score. At follow-up, ADC had AUC of 0.87, sensitivity of 75.4%, specificity of 83.6%, and accuracy of 80.0% for detecting improvement in MaRIA score to less than 11. At follow-up, AUC for detecting endoscopic ulcer healing was 0.94 for MaRIA score versus 0.84 for ADC (p = .01); sensitivity, specificity, and accuracy were 70.7%, 95.8%, and 84.4% for ADC and 90.2%, 100.0%, and 95.6% for MaRIA score. Interobserver agreement for ADC, based on intraclass correlation coefficient, was 0.70 at baseline and 0.65 at follow-up. CONCLUSION. The findings do not support use of ADC rather than MaRIA scores for detecting biologic therapy response. CLINICAL IMPACT. ADC may have an adjunct role in assessing bowel inflammation in CD, but showed limited performance for detecting biologic therapy response.