Potential Predictors Of Response Research Articles

Anti‑CGRP monoclonal antibodies in resistant migraine: preliminary real-world effectiveness and clinical predictors of response at twoyears.

Monoclonal antibodies targeting calcitonin gene-related peptide (anti-CGRP mAbs) have shown clinical effectiveness and safety in randomized clinical studies. However, long-term studies in clinical practice remain limited. To assess the long-term effectiveness, clinical predictors and safety of three anti-CGRP mAbs (erenumab, galcanezumab, fremanezumab) in resistant migraine patients. A single-center retrospective study was conducted from December 2019 to June 2023 involving 120 resistant migraine patients who received at least a month of anti-CGRP mAbs treatment. Patients completed a headache diary that included monthly acute medication intake (MAM), monthly migraine days (MMD), adverse events as well as completed Patient-Reported Outcome questionnaires (MIDAS [Migraine Disability Assessment] and Headache Impact Test 6 [HIT-6]). The number of patients achieving a ≥ 50% reduction in monthly migraine days was determined and classified as ≥ 50% responders, and baseline parameters and logistic regression between responders and non-responders were analyzed to identify potential predictors of response. Adverse events were registered in every follow-up. Treatment with anti-CGRP mAbs led to reductions in MIDAS, HIT-6, MMD and MAM from baseline to 6-24months. At 6-12months, responders (61% and 57%, respectively) exhibited lower baseline MMD and MAM. Medication overuse was associated with non-responders from 6 to 24months and it was identified as a negative predictor of treatment effectiveness (OR 0.23, 95% CI 0.07-0.74; p = 0.014). Anti-CGRP mAbs prove effectiveness and safety over a 24-month period in a RM population. Patients with no medication overuse and lower basal MMDs and MAM may respond better to anti-CGRP mAbs.

Insights into the Window of Opportunity and Outcome Measures in Patients with Moderate to Severe Hidradenitis Suppurativa Treated with Secukinumab: A Real-World Study.

The concept of a window of opportunity in hidradenitis suppurativa (HS) management suggests that early initiation of biological therapy leads to better outcomes, though its timing remains uncertain. We conducted a retrospective observational multicenter study, including consecutive patients with moderate to severe HS who initiated secukinumab treatment following prior failure with systemic antibiotics or adalimumab. Therapeutic burden was defined as the sum of previous systemic treatment cycles and previous major surgical interventions for HS. Patients were followed up for 24weeks. Main outcomes were safety and effectiveness, assessed through the proportion of patients achieving HS Clinical Response (HiSCR) and a 55% reduction in International HS Severity Score System (IHS4-55). Additionally, potential predictors of response to secukinumab were studied. Analysis was performed on an intention-to-treat basis. A total of 67 patients (33 men, 34 women) were included, with a mean age of 41.55 (11.94) years and a mean baseline IHS4 of 17.88 (11.13). The mean therapeutic burden was 6.06 (3.49). At week24, 10.45% (7/67) of patients experienced adverse events, with three leading to treatment discontinuation. At week24, 41.79% (28/67) of patients achieved HiSCR, and 44.78% (30/67) of patients achieved IHS4-55. HiSCR could not be calculated in 12 patients with a baseline AN count < 3. A lower therapeutic burden was significantly associated with a higher likelihood of achieving HiSCR and IHS4-55 at week24. Secukinumab showed safety and efficacy in real-world patients with HS, and the inverse correlation found between therapeutic burden and treatment response supports the concept of a window of opportunity, offering insights into its timing.

Active infection at the time of CD34+ selected stem cell boost is associated with treatment failure and poor overall survival

AbstractThe use of CD34+ selected stem cell boost (SCB) after allogeneic hematopoietic cell transplant (allo-HCT) has been increasing. Predictors of treatment failure after SCB, both in the context of poor graft function (PGF) or other settings, are not well characterized. We report among the largest single-center retrospective experiences of the use of SCB and evaluate potential predictors of response and outcomes. A total of 58 patients who underwent HCT between 2015 and 2022 and who received SCB, were identified. The indication for SCB was predominantly PGF, defined as the presence of ≥2 cytopenias for at least 2 consecutive weeks beyond day +14 after allo-HCT in the presence of ≤30% bone marrow cellularity and ≥90% donor myeloid chimerism in the absence of morphologic disease. The median dose of infused CD34+ selected SCB products was 3.88 × 106 CD34+ cells per kg (range, 0.99 × 106 to 9.92 × 106). The median 2-year overall survival and nonrelapse mortality after SCB was 47% and 38%, respectively. The cumulative incidences of 6-month grade 3 to 4 acute and 2-year moderate-severe chronic graft-versus-host disease after SCB were 3.4% and 12%, respectively. Overall response (complete response + partial response) was attained in 36 of 58 patients (62%) and in 69% of patients with PGF. On multivariable analysis, an active infection at the time of SCB was the greatest predictor of poor response and survival (P = .013) after SCB. SCB can restore hematopoiesis in the majority of patients, particularly for those with PGF and in whom there is no active infection at the time of infusion.

Clinical effectiveness and predictors of response to topiramate plus lifestyle modification in youth with obesity seen in a weight management clinical setting.

Obesity affects approximately 20% of U.S. youth. Anti-obesity medications (AOMs) are promising lifestyle modification adjuncts for obesity treatment, and topiramate is commonly prescribed in pediatric weight management clinics. It is important to determine "real-world" effectiveness of AOMs and, given shifts towards personalized approaches, characteristics potentially predicting better or worse response. We therefore sought to describe clinical effectiveness from topiramate plus lifestyle modification, and to determine if baseline phenotypic characteristics are associated with better or worse response. We performed a retrospective cohort study (2012-2020) among youth (<18 years old) followed in a U.S. academic-based weight management clinic. Baseline characteristics (i.e., body mass index (BMI), liver function tests, eating-related behaviors) and outcomes (%BMI of 95th percentile (%BMIp95), BMI, percent %BMI change, weight) were determined through review of electronic health records and clinic intake survey data. Among 282 youth prescribed topiramate plus lifestyle modifications (mean baseline age 12.7 years, %BMIp95 144%), %BMIp95 and percent BMI change were statistically significantly reduced at each time point (1.5-, 3-, 6-, and 12-month %BMIp95 reductions: -2.2, -3.9, -6.6, and -9.3 percentage points, respectively; percent BMI reduction: -1.2%, -1.9%, -3.2%, and -3.4%, respectively; all p<0.01). Considering multiple comparisons, no baseline characteristics statistically significantly predicted response at any time point. We found that topiramate plus lifestyle modification reduced %BMIp95 and BMI among youth in a weight management clinical setting, and that no baseline characteristics evaluated were associated with response. These results should be considered preliminary given the observational nature of this study, and prospective studies are needed to further characterize clinical effectiveness and identify and confirm potential predictors of response.

Predictors of real-world response in adults treated with botulinumtoxin-A for upper limb spasticity

Background: To explore predictors of treatment response in adults receiving botulinumtoxin-A (BoNT-A) for upper limb spasticity (ULS) and to describe the association between response and concomitant medication, professional physical therapy, and quality of life (QoL). Methods: This was a secondary analysis of the longitudinal Upper Limb International Spasticity study (ULIS-III) data set. Eligible patients were adults receiving/initiating BoNT-A treatment for ULS in clinical practice. The treatment response was a goal attainment scaling (GAS) T score change of ≥10 points from baseline to follow-up for each cycle. Concomitant medication was recorded. Time spent on professional physical therapy and self-management was recorded using the Upper Limb Focal Spasticity Therapy Recording (ULSTR) schedule. QoL was assessed using the EQ-5D-5L questionnaire. Baseline patient and clinical characteristics were described. Factors predictive of treatment response were explored using stepwise multivariable regression modeling (linear or logistic as appropriate for the outcome) and backward elimination (α=0.1). Results: Overall, 828/981 patients had response data; 71.9% responded to BoNT-A therapy. Potential predictors of response identified were the use of injection guidance techniques (P=0.001), female sex (P=0.031), and abobotulinumtoxin-A therapy (vs. onabotulinumtoxin-A; P&lt;0.001). Compared with nonresponders, responders had marginally lower use of concomitant medication, received marginally more professional physical therapy and (subgroup only) had improved QoL. Age, duration/distribution, severity of impairment, and previous BoNT-A had no predictive value. Conclusions: Future analyses of ULIS-III data will aim to validate these findings and further explore determinants of treatment response and the interplay between care modalities.

DOP22 Predictive biomarkers of therapeutic response in Inflammatory Bowel Disease: a step towards personalized medicine

Abstract Background Inflammatory bowel diseases are complex conditions characterized by heterogeneity at clinical, immunological, molecular, genetic, and microbial levels. The most effective approaches to induce clinical remission and control inflammation in these diseases are biologic and JAK-inhibitor therapies. However, a significant proportion of patients do not respond to treatment. Consequently, the identification of predictive biomarkers of clinical response to the different available therapies could improve the selection of patients who may benefit from the most appropriate treatment. Methods A multiomic study (transcriptomic, proteomic, metabolomic and metagenomic) was performed in 53 patients with active Crohn´s disease (CD) and 50 patients with active ulcerative colitis (UC) before and after 14 weeks of treatment (anti-TNFα, ustekinumab, vedolizumab or tofacitinib). Responders and non-responders patients were categorized based on endoscopic findings. Samples (serum, urine, stool and intestinal biopsies) were used for RNA-seq analysis, liquid chromatography-mass spectrometry, nuclear magnetic resonance, and 16S rRNA gene sequencing. Results Our findings revealed multiple mRNAs, proteins and metabolites associated with the response to different treatments (Table 1). Differential gene expression analyses in intestinal tissue showed that the main differences were detected between responders versus non-responders UC patients to anti-TNF, vedolizumab and tofacitinib. Proteomic analysis found numerous differentially expressed proteins between the study groups. Additionally, ROC curves revealed two proteins with good predictive value to discriminate between CD and UC patients responders versus non-responders to anti-TNF treatment (AUC=0.81 and AUC=0.96, respectively). Metabolomics showed up-regulation of 21 lipoproteins in serum from CD patients responders to ustekinumab compared to non-responders. Metabolic analysis pathways identified enrichment in ketone and butyrate metabolism, mitochondrial electron transport chain, carnitine synthesis, and oxidation of chain fatty acids. Regarding metagenomic results, only differences were found in microbial composition in responders versus non-responders UC patients treated with anti-TNF (Figure 1). Conclusion This study provides early insights into shifts in gene and protein expression in intestinal tissue, alterations in serum and urine metabolites, and changes in gut microbiota as potential predictors of response to biologics and JAK-inhibitor treatment. Further research is needed to validate these results and asses their clinical significance in identifying patients most likely to benefit from each therapeutic approach.

Aggressive pituitary tumors and carcinomas: medical treatment beyond temozolomide.

Aggressive pituitary tumors are a subset of pituitary neoplasms, characterized by unusually fast growth rate, invasiveness and overall resistance to optimized standard treatment. When metastases are present, the term pituitary carcinoma is employed. After failure of standard treatments, current guidelines recommend first-line temozolomide monotherapy. However, a significant number of patients do not respond to temozolomide, or experience disease progression following its discontinuation; in these latter cases, re-challenge with temozolomide is generally advised, although the reported outcomes have been less satisfactory. Although no alternative therapies have been formally recommended after temozolomide failure, growing evidence regarding potential second- or third-line therapeutic strategies has emerged. In the present work, we reviewed the available evidence published up to April 2023 involving the most relevant therapies employed so far, namely immune checkpoint inhibitors, bevacizumab, peptide radionuclide receptor therapy, tyrosine kinase inhibitors and mTOR inhibitors. For each treatment, we report efficacy and safety outcomes, along with data regarding potential predictors of response. Overall, immune checkpoint inhibitors and bevacizumab are showing the most promise as therapeutic options after temozolomide failure. The former showed better responses in pituitary carcinomas. Peptide radionuclide receptor therapy has also showed some efficacy in these tumors, while tyrosine kinase inhibitors and mTOR inhibitors have exhibited so far limited or no efficacy. Further studies, as well as an individualized, patient-tailored approach, are clearly needed. In addition, we report an unpublished case of a silent corticotroph pituitary carcinoma that progressed under dual immunotherapy, and then showed stable disease under a combination of lomustine and bevacizumab.

Baseline demographics and disease characteristics of patients with episodic or chronic cluster headache: data from two phase 3 randomized clinical trials in Europe and North America.

Two phase 3 galcanezumab trials were conducted in Europe and North America to analyze the reduction of weekly cluster headache (CH) attack frequency in populations with episodic and chronic CH. The current study aims to illustrate prospectively recorded baseline clinical data from these trials and to identify possible predictors of response. Patients (aged 18-65 years) met The International Classification of Headache Disorders 3rd edition-beta criteria for CH. Attacks were evaluated using an electronic headache diary for 7-day (episodic) or 14-day (chronic) eligibility assessments before patients were randomized 1:1 to monthly subcutaneous galcanezumab 300 mg or placebo. Data were collected from 106 patients with episodic and 237 with chronic CH. Overall, the mean age [standard deviation] was 45.4 [11.0] years; patients were predominantly White (84.5%), male (75.8%), and European (77.6%). Patients with episodic CH reported 17.5 [10.0] attacks/week; patients with chronic CH reported 18.8 [10.2] attacks/week. The average pain severity score (range 0-4) was 2.5 [0.7] for episodic CH and 2.7 [0.7] for chronic CH. Higher attack frequency was a possible predictor of response to galcanezumab; potential negative predictors of response were greater attack severity and duration. This large dataset of patients with CH provides reliable systematically and prospectively collected information on disease characteristics. The analysis in episodic CH underscores potential predictors of response worth considering for future CH trial design. ClinicalTrials.gov, identifiers: NCT02397473 and NCT02438826.

CTIM-36. IMMUNOHISTOCHEMISTRY EVALUATION ON PRE-TREATMENT TUMOR TISSUE PREDICTS TREATMENT RESPONSE TO MN-166 (IBUDILAST) AND TEMOZOLOMIDE COMBINATION THERAPY IN GLIOBLASTOMA PATIENTS

Abstract STUDY DESIGN MN-166-GBM-1201 is a Phase I/II open-label clinical trial to evaluate MN166 (ibudilast) and temozolomide (TMZ) combination treatment in newly diagnosed and recurrent glioblastoma (GBM) patients. 62 GBM patients (34 newly diagnosed and 28 recurrent) were enrolled in the study. All patients received MN-166 and TMZ combination treatment until disease progression or withdrawal from the study for other reasons. METHODS Pre-treatment tumor tissue at initial surgery from 24 study participants was evaluated to determine potential predictors of response to MN-166, which has been shown to inhibit the interaction between macrophage migration inhibitory factor (MIF) and CD74 with ERK phosphorylation downstream of CD74. We looked at CD11b and CD3 expression to characterize the immune profile within the tumors and Ki67 to determine percentage of proliferating tumor cells, all of which were calculated by a masked researcher. Then, patients were stratified based on progression within the first five months after receiving MN-166 and TMZ. RESULTS Patients who did not progress within 5 months had a significantly lower percentage of CD3+ T cell infiltration than nonresponding patients (p = 0.045), and CD74 expression was lower in patients with no progression (p = 0.16). The other markers demonstrated no differences. MN-166 and TMZ combination therapy was generally safe and well tolerated. CONCLUSION CD3 expression was a good predictor for tumor progression for five months in recurrent GBM patients treated with MN-166 and TMZ. T cell infiltration within GBM tumors has been an active area of research with the success of immune checkpoint blockade (ICB) therapies in other cancers. Moreover, MN-166 has been shown to impact immune suppressive myeloid cells, which are linked to the immune suppressive tumor microenvironment and a resistance mechanism to ICB. Collectively, we postulate that the efficacy of MN-166 for treatment of GBM could be further enhanced by co-treatment with ICBs.

Identification of a bile acid and bile salt metabolism-related lncRNA signature for predicting prognosis and treatment response in hepatocellular carcinoma

Bile acids and salts have been shown to play a role in liver carcinogenesis through DNA damage, inflammation, and tumor proliferation. However, the correlation between bile acid metabolism and hepatocellular carcinoma (HCC) prognosis remains unclear. This study aimed to identify a predictive signature of bile acid and bile salt metabolism-related long non-coding RNAs (lncRNAs) for HCC prognosis and treatment response. The study used HCC RNA-sequencing data and corresponding clinical and prognostic data from The Cancer Genome Atlas. A prognostic model consisting of five bile acid and bile salt metabolism-related lncRNAs was developed and evaluated in a training set, a validation set and an external set. The model demonstrated good performance in predicting HCC prognosis and was shown to be an independent biomarker for prognosis. Additionally, our study revealed a significant association between the signature and immune cell infiltration, as well as its predictive value for therapeutic responses to both immunotherapy and chemotherapy. Furthermore, three LncRNAs (LUCAT1, AL031985.3 and AC015908.3) expression levels in our signature were validated through qRT-PCR in a cohort of 50 pairs of HCC patient tumor samples and corresponding adjacent non-tumor samples, along with 10 samples of normal liver tissue adjacent to benign lesions. These findings suggest that this novel bile acid and bile salt metabolism-related lncRNA signature can independently predict the prognosis of patients with HCC and may be utilized as a potential predictor of response to treatment in this setting.

Landscape of Baseline and Acquired Genomic Alterations in Circulating Tumor DNA with Abemaciclib Alone or with Endocrine Therapy in Advanced Breast Cancer.

To identify potential predictors of response and resistance mechanisms in patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC) treated with the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor abemaciclib ± endocrine therapy (ET), baseline and acquired genomic alterations in circulating tumor DNA (ctDNA) were analyzed and associated with clinical outcomes. MONARCH 3: postmenopausal women with HR+, HER2- ABC and no prior systemic therapy in the advanced setting were randomly assigned to abemaciclib or placebo plus nonsteroidal aromatase inhibitor (NSAI). nextMONARCH: women with HR+, HER2- metastatic breast cancer that progressed on/after prior ET and chemotherapy were randomly assigned to abemaciclib alone (two doses) or plus tamoxifen. Baseline and end-of-treatment plasma samples from patients in MONARCH 3 and nextMONARCH (monotherapy arms) were analyzed to identify somatic genomic alterations. Association between genomic alterations and median progression-free survival (mPFS) was assessed. Most patients had ≥1 genomic alteration detected in baseline ctDNA. In MONARCH 3, abemaciclib+NSAI was associated with improved mPFS versus placebo+NSAI, regardless of baseline alterations. ESR1 alterations were less frequently acquired in the abemaciclib+NSAI arm than placebo+NSAI. Acquired alterations potentially associated with resistance to abemaciclib ± NSAI included RB1 and MYC. In MONARCH 3, certain baseline ctDNA genomic alterations were prognostic for ET but not predictive of abemaciclib response. Further studies are warranted to assess whether ctDNA alterations acquired during abemaciclib treatment differ from other CDK4/6 inhibitors. Findings are hypothesis generating; further exploration is warranted into mechanisms of resistance to abemaciclib and ET. See related commentary by Wander and Bardia, p. 2008.

Potential Predictors of Response to CGRP Monoclonal Antibodies in Chronic Migraine: Real-World Data.

Real-world data (RWD) has identified potential predictors of response to anti-CGRP therapies in patients with chronic migraine (CM). This review aims to synthesize the most remarkable findings published to date regarding this topic. Migraine features such as unilateral pain and positive triptan response and chronic features such as daily headache or medication overuse (MO) emerge as predictors of positive outcomes, potentially linked to elevated baseline serum anti-calcitonin gene-related peptide (anti-CGRP) levels. Demographic and baseline characteristics, encompassing obesity, psychiatric comorbidities, and prior refractoriness to prophylactic treatments, are associated with poor responses in both treatment-naïve patients and after-switch scenarios. Nevertheless, the consistency of these predictors across diverse populations requires further investigation. Recent RWD literature highlights emerging predictors of response of different sources among patients with CM receiving anti-CGRP therapies. Comprehending these predictors and identifying novel biomarkers of response hold the potential to refine treatment strategies for CM patients, enhancing their management and therapeutic outcomes.

Study of platelet kinetics in immune thrombocytopenia to predict splenectomy response.

Despite the efficacy of splenectomy for chronic immune thrombocytopenia (ITP), its considerable failure rate and its possible related complications prove the need for further research into potential predictors of response. The platelet sequestration site determined by 111 In-labelled autologous platelet scintigraphy has been proposed to predict splenectomy outcome, but without standardisation in clinical practice. Here, we conducted a single-centre study by analysing a cohort of splenectomised patients with ITP in whom 111 In-scintigraphy was performed at La Paz University Hospital in Madrid to evaluate the predictive value of the platelet kinetic studies. We also studied other factors that could impact the splenectomy outcome, such as patient and platelet characteristics. A total of 51 patients were splenectomised, and 82.3% responded. The splenic sequestration pattern predicted a higher rate of complete response up to 12 months after splenectomy (p = 0.005), with 90% sensitivity and 77% specificity. Neither age, comorbidities, therapy lines nor previous response to them showed any association with response. Results from the platelet characteristics analysis revealed a significant loss of sialic acid in platelets from the non-responding patients compared with those who maintained a response (p = 0.0017). Our findings highlight the value of splenic sequestration as an independent predictor of splenectomy response.

Circulating cytokine dynamics as potential biomarker of response to anti-PD-1 immunotherapy in BRAFwt MM patients

BackgroundThe biomarkers of immune checkpoint inhibitors (ICIs) efficacy and safety are still urgently needed. As cytokines are easily detected and monitored in circulation, they could be used as potential predictors of response and immune-related adverse events (irAEs) for ICIs therapy. MethodsThe levels of TGF-β, IFN-γ, IL-6, IL-8, IL-10 were measured in sera and plasma by ELISA method of 30 healthy controls (HC) and 32 BRAF wild type (wt) MM patients before and after every 12 weeks of Pembrolizumab, PD-1 inhibitor, until one year or disease progression (DP). ResultsHigher pretherapy levels of circulating TGF-β, IFN-γ, IL-6, and IL-10 were shown in MM patients compared to HC. In patients with disease control, TGF-β and IL-6 first decreased during the therapy, while then they started to successively increase reaching the initial values by the end of the follow up. Furthermore, in this group of patients IFN-γ increased, while IL-8 and IL-10 decreased at final points of the follow up. In patients with DP IL-6 increased at the time of progression, while IL-8 decreased when the best response was achieved. In patients with pseudoprogression IL-6 and IL-10 significantly increased compared to the pretreatment values. Melanoma patients with irAEs had increased baseline values of TGF-β, IFN-γ, IL-6, and IL-10 compared to HC. However, no significant changes in cytokines levels were found in these patients during therapy. ConclusionsInflammatory cytokines monitoring in circulation of BRAFwt MM patients could help in the selection of patients who will have the benefit from Pembrolizumab therapy.

“Trajectories of treatment response in a cognitive-behavioral therapy intervention for depression and adherence in persons with HIV in South Africa”

BackgroundPeople with HIV (PHW) are at greater risk of depression than the general population. Insight into the time-to-treatment-response and predictors of response to psychotherapy may improve implementation in primary care. MethodsWe assessed depression treatment response among 80 participants in a trial of cognitive-behavioral therapy for adherence and depression (CBT-AD) for PWH with MDD and suboptimal antiretroviral therapy (ART) adherence. Participants self-reported depressive symptoms (CESD) at each therapy session. Clinicians assessed participants' depression (HAMD), along with potential predictors of response, every four months for one year. Latent class analyses examined classes of responders for the active and the post-treatment phases. Regression analyses identified predictors of class membership for each phase. ResultsDuring the active treatment phase (CESD) we identified an early response (at session 2 and with continued trajectory of improvement) and a non-response group. There were also two classes during post-treatment (HAM-D): early responders (4-month) and late responders (12-month). Distress aversion was associated with lower likelihood of early response to CBT-AD (aOR = 0.74, 95%CI[0.56–0.90], p = .009), and social support was associated with increased likelihood of early response (aOR = 2.24, 95%CI[1.07–5.46], p = .045). LimitationsSelf-reported depression during the treatment phase may have resulted from social desirability bias. ConclusionsMost participants responded to CBT-AD early during treatment (89 %) and had sustained improvements in depression by 4 months (80 %). Distress aversion was a risk factor for late response, and social support was protective. Future research is needed to assess the optimal dose of CBT-AD in resource limited settings.

592P The role of early change in circulating tumor DNA as a potential predictor of response to chemotherapy in patients with metastatic colorectal cancer

592P The role of early change in circulating tumor DNA as a potential predictor of response to chemotherapy in patients with metastatic colorectal cancer

Successful neoadjuvant chemotherapy plus sintilimab for locally advanced cervical cancer: case series and review of the literature

BackgroundThe locally advanced cervical cancer (LACC) of FIGO stage IB3-IIA2 is characterized by large local mass, poor prognosis and survival rate. Tumor response to neoadjuvant chemotherapy for LACC, utilized as a surrogate endpoint, is urgently needed to improve. Given that the antitumor immune response can be suppressed by programed death-1 axis, the treatment paradigm of neoadjuvant chemotherapy combined with immunotherapy has been explored as one of the prognostic treatments in a variety of solid carcinoma. So far, the application of sintilimab, a domestic immune checkpoint inhibitor, combined with neoadjuvant chemotherapy is still limited in LACC, especially in large lesions.Case descriptionWe present three postmenopausal women diagnosed with FIGO stage IB3-IIA2 cervical squamous cell carcinoma with lesions larger than 5 cm. Demographic, clinical, histopathological, laboratory and imaging data were record. At the completion of the neoadjuvant therapy with paclitaxel plus carboplatin combined with sintilimab, all patients underwent hysterectomy. After neoadjuvant treatment, a pathologic complete response in case 1 and partial responses in case 2 and case 3 were achieved, and neither patient showed any relapse during the follow-up period of 16 to 22 months.ConclusionsThis report provide evidence to support the combination of sintilimab with neoadjuvant chemotherapy in cervical cancer, which has yet to be validated in prospective studies. More clinical data are needed to verify the effectiveness of the combined regimens. This literature review also collected studies involving potential predictors of response to NACT and immunotherapy, which would be helpful in stratifying patients for future trials.

PD-L1 protein expression by Combined Positive Score (CPS) in patients with muscle invasive or advanced urothelial carcinoma: a single institution experience

IntroductionImmune checkpoint inhibitors have revolutionized the treatment of patients with advanced urothelial carcinoma (UC) in the frontline and relapsed settings. Lebanon has one of the highest incidence of UC worldwide, yet no data exists regarding the expression of PD-L1 by Combined Positive Score (CPS) in advanced disease.MethodsWe reviewed all patients treated at our institution for high grade UC, stage pT2 and above, between January 2017 and March 2021. We assessed the expression of PD-L1 by immunohistochemistry using 22C3 clone, and analyzed the association between PD-L1 expression and clinicopathological characteristics. PD-L1 positivity was defined as CPS score ≥ 10.ResultsA total of 101 patients with advanced UC were included, with a median age of 71 years (range, 38 to 96 years); 78% were ever-smokers. Ninety-three of 101 patients (92%) had conventional UC and 43 patients (43%) had positive PD-L1 expression, with 12 patients having CPS of 100. The analysis by molecular subtype showed that patients with maximal CPS of 100 were enriched in “basal” molecular subtype. However, no association was found between PD-L1 expression (positive versus negative) and clinicopathological characteristics.ConclusionThe positivity of PD-L1 expression as assessed by CPS using the 22C3 clone in our population was almost comparable to the results reported in the occidental literature. Therefore, PD-L1 expression, as a potential predictor of response to immunotherapy, concerns the same percentage of the Lebanese UC patients.

Treating depression in an outpatient setting: Predictors of patient response to bouldering psychotherapy, cognitive behavioural therapy or exercise alone.

Bouldering psychotherapy (BPT) for depression has proven effective, but nothing is known about its potential predictors of response. This study should identify predictors of response to BPT, cognitive behavioural therapy (CBT) and an active control (home-based exercise programme; EP) using a literature-based model. In a multicentre randomised controlled trial, 233 outpatients were assigned to BPT, CBT or EP. Response (reduction of at least 46% on the Montgomery-Åsberg Depression Rating Scale [MADRS]) and remission (≤7 MADRS points) were defined as suggested by the literature. Predictors of response were identified twofold: (1) univariate analyses followed by logistic regression analyses in each group with all predictors yielding a univariate p-value <.20 and (2) a backward regression analysis with all potential predictors. Only variables that emerged as predictors in both types of analyses were interpreted. There was a significantly greater proportion of responders (p = .035) in the BPT than in the EP. The chance of response in the BPT was higher for patients with a higher health-related quality of life. In the EP, response was higher for patients with lower interpersonal sensitivity, suffering from their first episode and living with a partner. Response rates in BPT are similar to or even higher than in other outpatient psychotherapy group therapies. BPT and CBT are suitable for a wide range of patients, but patients with higher functionality could start with psychoeducation and exercise.

Immunogenetic polymorphisms predict therapeutic efficacy and survival outcomes in tumor patients receiving PD-1/PD-L1 blockade.

While immune checkpoint inhibitors (ICIs) demonstrate remarkable clinical responses, only a small subset of patients obtains benefits. Genes linked to the tumor immune system are confirmed to be critical for the treatment of ICIs, and their polymorphisms can contribute to ICI efficacy. Here, we examined the potential of immunogenetic variations to predict the efficacy and survival of the PD-1/PD-L1 blockade. Cancerous patients receiving PD-1/PD-L1 blockade were recruited and followed up. Pivotal genes related to tumor-immunity were filtered through a protein-protein interaction network and the degree algorithm in Cytoscape. Finally, 39 genetic variants were genotyped through multiplex genotyping assays. Association analyses between variants and ICI efficacy and progression-free survival (PFS) were performed. Overall, 318 patients were ultimately enrolled. Hence, three immunogenetic variants were identified as predictors of PD-1/PD-L1 blockade response. Mutant alleles from ATG7 rs7625881, CD274 rs2297136, and TLR4 rs1927911 were all at increased risk of tumor progression following ICI therapy (OR: 1.475, 1.641, 1.462, respectively; P value: 0.028, 0.017, 0.027, respectively). Significant immunogenetic variants also attained similar trends in the PD-1 blockade, lung cancer, or lung cancer using PD-1 blockade subgroups. Furthermore, the mutant genotypes of CD274 rs2297136 (GG as the reference: HR: 0.50 (95%CI: 0.29-0.88), P value: 0.015) and TLR4 rs1927911 (AA as the reference: HR: 0.65 (95%CI: 0.47-0.91), P value: 0.012) indicated poorer PFS and were both independent prognostic factors. Immunogenetic polymorphisms, including ATG7 rs7625881, CD274 rs2297136, and TLR4 rs1927911, were first identified as potential predictors of response to PD-1/PD-L1 blockade in tumor patients.