Assessment Of Clinical Response Research Articles

Neoadjuvant chemoradiation for down staging of locally-advanced rectal cancer, and assessment of clinical response with digital rectal examination, magnetic resonance imaging and colonoscopy

Background: In this era of total neoadjuvant treatment (TNT) followed by rectal preservation non-operative management (NOM) or wait and watch (WW) approach for non-metastatic locally-advanced rectal cancer (LARC), reliable and reproducible response evaluation to neoadjuvant therapies forms the cornerstone. Through this study, we try to evaluate clinical response of locally-advanced rectal cancer to neoadjuvant chemoradiation (CRT) in terms of downstaging and total mesorectal excision (TME), and the accuracy of digital rectal examination (DRE), magnetic resonance imaging (MRI) and colonoscopy in the assessment of clinical response to neoadjuvant CRT. Methods: Histologically proven locally advanced rectal adenocarcinoma patients, after pretreatment evaluation, were considered for neoadjuvant chemoradiation, i.e., intensity-modulated radiation therapy (IMRT) with 5-fluorouracil (5-FU) and leucovorin-based concurrent chemotherapy. Patients were evaluated 6-8 weeks after completion of CRT and clinical response assessed by means of DRE, colonoscopy and MRI of pelvis. Following surgery, pathological response was assessed on the final histopathological examination (HPE). Results: Twenty-two patients were accrued for this protocol, of which, 15 (68.2%) were male and 7 (31.8%) were female. Downstaging and TME was achieved in 90.9% of the patients. The sensitivity of DRE, colonoscopy and MRI to detect a complete response was 66.67% and specificity was 94.74%. There were no severe toxicities or deaths reported. Conclusions: Neoadjuvant concurrent chemoradiotherapy with bolus 5-FU and leucovorin is an accepted modality of treatment for locoregionally-advanced rectal cancer, which offers higher rates of downstaging and TME. Digital rectal examination, colonoscopy and MRI together can be reliably used to assess response following neoadjuvant CRT.

Deciding treatment end point in necrotizing otitis externa: validation of a standardized clinical response assessment strategy with positron emission tomography findings.

Primary: To explore criteria for treatment endpoint in NOE. Secondary: To study correlation of inflammatory markers, Erythrocyte sedimentation Rate (ESR) and C-reactive protein (CRP) with disease status. Prospective cohort study conducted in a tertiary care hospital over two years (2021-2023) consisted 28 patients with NOE. Treatment culmination point was decided based on symptoms control and correlated with PET-scan findings. Clinical response was analysed with respect to the serum inflammatory markers and PET Scan findings. There was fair degree of agreement between clinical resolution and resolution of findings on PET scan (kappa coefficient - 0.76 [95% CI; 0.40,1.00]). Inflammatory markers showed statistically significant decline with clinical resolution but failed to return to normal. Decision to terminate treatment of NOE can be reliably made on clinical grounds in patients remaining asymptomatic for three weeks. Resolution of inflammation on PET scan is in congruity with the clinical remission .

B-342 Teclistamab interference in serum protein electrophoresis and serum immunofixation electrophoresis in patients with recurrent or relapsed multiple myeloma

Abstract Background Serum protein electrophoresis (SPEP) and serum immunofixation electrophoresis (IFE) analyses are mainstays in the initial diagnosis, risk stratification, and evaluating treatment response in patients with multiple myeloma (MM) in accordance with the International Myeloma Working Group criteria. Published reports have demonstrated that therapeutic monoclonal antibodies (mAbs) used to treat MM (e.g. anti-CD38 IgG-kappa) are detectable by SPEP and IFE, which may interfere with accurate evaluation of complete response. Recently, Teclistamab (Tecvayli®; Janssen Biotech, Horsham Township, PA), a humanized bispecific IgG-lambda mAb targeting B-cell maturation antigen (BCMA) and CD3 on T cells was approved for treating patients with penta-refractory MM. In contrast with other IgG-kappa therapeutic mAbs, the degree to which Teclistamab may interfere with detection and quantification of monoclonal proteins is unknown. Therefore, we sought to assess the interference of Teclistamab therapy on routine SPEP and IFE analysis. Methods Patients treated with Teclistamab were identified by retrospective review of electronic medical records. Teclistamab (90 mg/mL) was spiked into a remnant patient sample with IgG lambda MM at a final concentration of 10 μg/mL, which corresponds to ½Cmax values in patients infused with Teclistamab. SPEP and IFE were performed using the Helena SPIFE Touch instrument. Computer-assisted densitometry was used to quantify monoclonal proteins in the gamma region of SPEP gels. Results In several patients with refractory MM treated with Teclistamab, IFE analysis revealed IgG lambda or lambda light chain monoclonal proteins, which were inconsistent with previously-identified monoclonal proteins (e.g. IgG kappa). In one patient diagnosed with IgG lambda MM, spiking 10 μg/mL Teclistamab increased M-spike abundance by approximately 0.15 g/dL when quantified by SPEP. Conclusions In patients with relapsed or refractory MM, treatment with Teclistamab may confound accurate clinical assessment of complete response by SPEP and IFE methods. Increased awareness of this preanalytical interference is necessary to guide clinical decision making.

Defining Echocardiographic Degrees of Right Heart Size and Function in Pulmonary Vascular Disease From the PVDOMICS Study

BACKGROUND: Defining qualitative grades of echocardiographic metrics of right heart chamber size and function is critical for screening, clinical assessment, and measurement of therapeutic response in individuals with pulmonary vascular disease (PVD). In a population enriched for PVD, we sought to establish qualitative grades and prognostic value of right heart chamber size and function. METHODS: We investigated 1053 study participants in PVDOMICS (Redefining Pulmonary Hypertension Through the PVD Phenomics Program) to determine clinical and echocardiographic differences associated with increasing pulmonary vascular resistance severity. Right heart chamber size and function were qualitatively assessed using a percentile-based approach above the median values to create a clinical grading system for right heart adaptation. The relationship between echocardiographic categories and all-cause mortality was examined using survival analyses adjusted for potential confounders. RESULTS: A stepwise increase in adverse right heart remodeling was observed with a concomitant decrease in functional parameters by pulmonary vascular resistance strata ( P <0.001 for all). Mild, moderate, and severe categories of right heart chamber size and dysfunction were defined using a percentile-based approach across the spectrum of PVD. During a median follow-up of 2.07 years (interquartile range, 1.23–3.01 years), 130 participants died (11.4%). Progressive pulmonary vascular resistance increase and 2DE evidence of right heart dysfunction inclusive of fractional area change, and right ventricular global longitudinal strain were independently associated with increased all-cause mortality risk in multivariate analysis adjusted for age, disease duration, and male sex. CONCLUSIONS: In this well-characterized sample of adults with diverse etiologies and varying PVD severity, we define categories of abnormal right heart chamber size and function. Further, we demonstrate a stepwise relationship between these categories of abnormal morphology and function and all-cause mortality. Defining grades of right ventricular dysfunction in individuals with known PVD has important clinical implications for monitoring disease progression and response to therapies.

Assessment of clinical and pathological response to neoadjuvant chemotherapy in breast cancer according to molecular subtypes

Background. Breast cancer (BC) is the commonest tumor in women. It is the leading malignancy in world, and representing an emerging oncologic issue in all countries. In Iraq, BC cases reached 7246 in 2021by Iraqi Cancer Registry reports. Objectives. The study conducted for assessment the clinical and pathological responses to neoadjuvant chemotherapy in BC among molecular subtypes and for description the clinico-pathologic features, and patterns of BC according to molecular subtypes. Methods. A prospective study of 60 females with breast cancer histologically confirmed were enrolled. All women received neoadjuvant chemotherapy. Then all patients underwent definitive surgery including MRM+AC or BCS+AC. The patients’ demographic, the pathologic and molecular subtypes date of the primary tumor were recorded. Results. The mostly distributed age group was belong to group 46-55 yrs in 22, 36.7%. The mean age was 49.7±10.8 yrs. The IDC represented the most common histopathological types of BC. The most of cases seen in upper-outer quadrant (UOQ). The results post-chemotherapy as followed: ypTx stage reported in 32 (53.3%), ypT1 in 15 (25.0%), ypT2 in 10 (16.7%) and ypT3 in 3 (5.0%). ypN0 stage in 40 patients (66.7%), ypN1 in 11 (18.3%), ypN2 in 6 (10.0%), and ypN3 in 3 (5.0%). There was a high statistical difference between cT and ypT in pre and post-chemotherapy (P<0.0001), between cN and ypN in pre and post-chemotherapy (P=0.001) and between M and ypM in pre and post-chemotherapy (P=0.002). The mass location (P=0.005) and tumor size (P = 0.011) had significantly impacted on BC responses post NACT. 18(30.0%) had clinical complete response (cCR), 32 women (53.3%) had partial response (cPR), six cases (10.0%) had stable disease, and four cases (6.7%) had progressive disease. The cCR was better seen in T1 (77.8%) than T2 (22.2%), with statistical significant difference (P=0.002). The cCR was better seen in N0 (61.1%) than N1 (38.9%), with a high statistical significant difference (P<0.0001). Conclusions. The commonest age breast cancer is four to five decade. The IDC and mass situated at UOQ are the most common features of BC. Approximately, 30.0% of women have clinical complete response (cCR), 53.3% have partial response (cPR), 10.0% have stable disease, and 6.7% have progressive disease post NACT. The ER positive, PR positive, and HER2neu negative are the mostly frequent subtype recorded in this study. The cCR is better seen in T1 and N0 stages. ER+ and PR+ are more reported after NACT whereas HER2neu- is more post NACT.

Chromosomal instability is associated with prognosis and efficacy of bevacizumab after resection of colorectal cancer liver metastasis

Introduction Individualized treatment of colorectal cancer liver metastases (CRLM) remains challenging due to differences in the severity of metastatic disease and tumour biology. Exploring specific prognostic risk subgroups is urgently needed. The current study aimed to investigate the prognostic value of chromosomal instability (CIN) in patients with initially resectable CRLM and the predictive value of CIN for the efficacy of bevacizumab. Methods Ninety-one consecutive patients with initially resectable CRLM who underwent curative liver resection from 2006 to 2018 at Sun Yat-sen University Cancer Center were selected for analysis. CIN was evaluated by automated digital imaging systems. Immunohistochemistry (IHC) was performed to detect interleukin-6 (IL-6), vascular endothelial growth factor A (VEGFA) and CD31 expression in paraffin-embedded specimens. Recurrence-free survival (RFS) and overall survival (OS) were analysed using the Kaplan–Meier method and Cox regression models. Results Patients with high chromosomal instability (CIN-H) had a worse 3-year RFS rate (HR, 1.953; 95% CI, 1.001–3.810; p = 0.049) and a worse 3-year OS rate (HR, 2.449; 95% CI, 1.150–5.213; p = 0.016) than those with low chromosomal instability (CIN-L). CIN-H was identified as an independent prognostic factor for RFS (HR, 2.569; 95% CI, 1.078–6.121; p = 0.033) and OS (HR, 3.852; 95% CI, 1.173–12.645; p = 0.026) in the multivariate analysis. The protein levels of IL-6, VEGFA and CD31 were upregulated in patients in the CIN-H group compared to those in the CIN-L group in both primary tumour and liver metastases tissues. Among them, 22 patients with recurrent tumours were treated with first-line bevacizumab treatment and based on the clinical response assessment, disease control rates were adversely associated with chromosomal instability (p = 0.043). Conclusions Our study showed that high chromosomal instability is a negative prognostic factor for patients with initially resectable CRLM after liver resection. CIN may have positive correlations with angiogenesis through expression of IL-6–VEGFA axis and be used as a potential predictor of efficacy of bevacizumab.

Development of Granzyme B-targeted Smart Positron Emission Tomography Probes for Monitoring Tumor Early Response to Immunotherapy.

Granzyme B is an immune-related biomarker that closely correlates with cytotoxic T lymphocytes (CTLs), and hence detecting the expression level of granzyme B can provide a dependable scheme for clinical immune response assessment. In this study, two positron emission tomography (PET) probes [18F]SF-M-14 and [18F]SF-H-14 targeting granzyme B are designed based on the intramolecular cyclization scaffold SF. [18F]SF-M-14 and [18F]SF-H-14 can respond to granzyme B and glutathione (GSH) to conduct intramolecular cyclization and self-assemble into nanoaggregates to enhance the retention of probe at the target site. Both probes are prepared with high radiochemical purity (>98%) and high stability in PBS and mouse serum. In 4T1 cells cocultured with T lymphocytes, [18F]SF-M-14 and [18F]SF-H-14 reach the maximum uptake of 6.71 ± 0.29 and 3.47 ± 0.09% ID/mg at 0.5 h, respectively, but they remain below 1.95 ± 0.22 and 1.47 ± 0.21% ID/mg in 4T1 cells without coculture of T lymphocytes. In vivo PET imaging shows that the tumor uptake in 4T1-tumor-bearing mice after immunotherapy is significantly higher (3.5 times) than that in the untreated group. The maximum tumor uptake of [18F]SF-M-14 and [18F]SF-H-14 in the mice treated with BEC was 4.08 ± 0.16 and 3.43 ± 0.12% ID/g, respectively, while that in the untreated mice was 1.04 ± 0.79 and 1.41 ± 0.11% ID/g, respectively. These results indicate that both probes have great potential in the early evaluation of clinical immunotherapy efficacy.

Evaluation of early response in association with pathological response in patients with breast cancer receiving neoadjuvant chemotherapy.

e12628 Background: Neoadjuvant therapy (NAT) has now been widely used for patients with operable breast cancer (BC) to test drug sensitivity. Studies have indicated that early assessment of clinical response to NAT can help identify patients who are resistant to initial regimens, providing an additional opportunity to change treatment plan. However, there is a lack of evidence regarding the optimal timing for conducting early evaluations of clinical response. This prospective study was conducted to evaluate the association between early evaluation of clinical response at different timing (post 2 cycles versus post 4 cycles) and pCR post NAT, in order to determine the most appropriate timing for NAT response evaluation. Clinical evaluations using ultrasound and MRI (magnetic resonance imaging) were also compared. Methods: A prospective cohort study including BC patients who received NAT was conducted between January 2018 and December 2023. Multivariable logistic regression analysis was used to estimate the Odds Ratios (OR) and 95% confidence intervals (CI) for the clinical response evaluated at different timings in association with pCR. The heterogeneity of the associations for the post-cycle 2 and post-cycle 4 assessments was assessed. Linear regression analyses were used to assess the associations between extent of tumor reduction post 2 cycles and that post 4 cycles of NAT. Agreement of tumor measurements using ultrasound and MRI was also assessed. Results: A total of 186 BC patients were consecutively enrolled and included in this analysis. 55 (29.6%) of them achieved pCR. Partial response (PR) post 2 cycles and 4 cycles of NAT were both significantly associated with pCR post NAT, though the point estimate of association for PR post 2 cycles of NAT (OR=5.06, 95%CI:2.29-12.09) was more evident than that post 4 cycles (OR=2.79, 95%CI:1.20-7.21). Extent of tumor reduction post two cycles of NAT was highly correlated with that post four cycles (r=0.89, 95%CI=0.79-0.98, P< 0.01). Poor concordance was observed between ultrasound and MRI measurements of tumor size, whether at initial diagnosis (r=0.66, adjusted r2=0.43) or after two cycles of NAT (r=0.59, adjusted r2=0.35). Among those patients who had PR post 2 cycles of NAT, tumor reduction by greater than 50% was not associated with higher probability of reaching pCR in comparison to those lower than 50% (OR=1.86, 95%CI=0.82-4.37, P=0.143). Conclusions: Tumor response assessed using MRI after two cycles of NAT was highly correlated with pCR, and may be adopted as an optimal strategy for early evaluation of the efficacy of NAT regimen. Further studies are warranted to evaluate changes in treatment plan at early phase of NAT for those resistant to initial regimens.

Concordance between physician response assessment and a novel method per Lugano criteria in patients with lymphoma using real-world data.

e19082 Background: Clinical response assessment criteria, such as RECIST v1.1 and Lugano 2014, provide a standardized approach to assess treatment effectiveness in oncology clinical trials. Corresponding methodologies are needed for real-world data (RWD) to improve interpretability alongside clinical trial data and facilitate replication of results across RWD studies. We developed a RWD novel methodology, real-world Lugano (rwLugano), derived from Lugano 2014 criteria to classify lymphoma treatment response among patients with diffuse large B-cell lymphoma (DLBCL). Methods: A retrospective multisite RWD study identified adult patients with DLBCL treated with first line chemoimmunotherapy in US clinical practice (01JAN2015-31DEC2022). Participating sites abstracted clinical data via medical chart review and positron emission tomography-computed tomography (PET-CT) reports. Deidentified digital PET-CTs taken at treatment initiation and first response assessment were uploaded for BICR. Three distinct methods were used to assess treatment response: 1) physician-reported obtained from unstructured clinical notes in medical records, 2) rwLugano calculated using data (i.e., components of Lugano 2014) from PET-CT reports, and 3) BICR adjudication by two lymphoma radiologists using Lugano 2014 criteria. We compared the proportion of patients by response category: complete (CR), partial (PR), stable (SD) and progressive (PD) for each method. Analyses included agreement (%), concordance (Cohen’s kappa [κ]), and odds ratios with 95% confidence interval (OR; 95%CI) estimated using multivariable generalized linear mixed models (GLMM) adjusted for baseline characteristics. Results: The study identified 174 patients with DLBCL (female n=71 [41%]; white n=135 [78%]; Hispanic n=13 [7%]; mean age 66 years). Fewer patients were classified as CR at initial response via physician-reported response (n=111, 64%) compared to rwLugano (n=145, 83%), and BICR (n=142, 82%). Overall and CR agreement with BICR (see Table) was higher for rwLugano (overall: 83%, κ=0.49; CR: 86%, κ=0.50) than physician-charted response (overall: 72%, κ=0.45; CR: 76%, κ=0.43). In GLMM models, physician-charted response underestimated CR compared to BICR (OR=0.22, 95%CI:0.12-0.43), whereas rwLugano was statistically similar to BICR (OR=1.2, 95%CI:0.6-2.4). Conclusions: This study found that physician-reported response may underestimate CR at initial response, and rwLugano may be more consistent with BICR for treatment response assessment. Use of rwLugano warrants further evaluation as a methodology to assess treatment response in RWD lymphoma research. [Table: see text]

Outcomes of neoadjuvant chemotherapy and radical hysterectomy for locally advanced cervical cancer at Kigali University Teaching Hospital, Rwanda: a retrospective descriptive study

BackgroundHalf of countries in Africa lack access to radiation (RT), which is essential for standard treatment of locally advanced cervical cancers. We evaluated outcomes for patients treated with neoadjuvant chemotherapy (NACT) followed by radical hysterectomy in settings where no RT is available.MethodsWe performed a retrospective descriptive study of all patients with FIGO stage IB2-IIA2 and some exceptional stage IIB cases who received NACT and surgery at Kigali University Teaching Hospital in Rwanda. Patients were treated with NACT consisting of carboplatin and paclitaxel once every 3 weeks for 3–4 cycles before radical hysterectomy. We calculated recurrence rates and overall survival (OS) rate was determined by Kaplan-Meier estimates.ResultsBetween May 2016 and October 2018, 57 patients underwent NACT and 43 (75.4%) were candidates for radical hysterectomy after clinical response assessment. Among the 43 patients who received NACT and surgery, the median age was 56 years, 14% were HIV positive, and FIGO stage distribution was: IB2 (32.6%), IIA1 (7.0%), IIA2 (51.2%) and IIB (9.3%). Thirty-nine (96%) patients received 3 cycles and 4 (4%) received 4 cycles of NACT. Thirty-eight (88.4%) patients underwent radical hysterectomy as planned and 5 (11.6%) had surgery aborted due to grossly metastatic disease. Two patients were lost to follow up after surgery and excluded from survival analysis. For the remaining 41 patients with median follow-up time of 34.4 months, 32 (78%) were alive with no evidence of recurrence, and 8 (20%) were alive with recurrence. One patient died of an unrelated cancer. The 3-year OS rate for the 41 patients who underwent NACT and surgery was 80.8% with a recurrence rate of 20%.ConclusionsNeoadjuvant chemotherapy with radical hysterectomy is a feasible treatment option for locally advanced cervical cancer in settings with limited access to RT. With an increase in gynecologic oncologists skilled at radical surgery, this approach may be a more widely available alternative treatment option in countries without radiation facilities.

Abstract 4244: Clinical response assessment of immune checkpoint inhibitors in mismatch repair-deficient endometrial cancer using a T cell organoid coculture system

Abstract Endometrial cancers with the mismatch repair deficiency (MMR-D) phenotype exhibit characteristics such as an increased burden of tumor mutations and the presence of tumor-infiltrating lymphocytes (TILs) involved in tumor invasion. While monotherapy using immune checkpoint inhibitors (ICIs) has shown clinical improvement in MMR-D endometrial cancer (EC), observed response rates ranging from 30% to 50% suggest the existence of inherent resistance mechanisms. One notable feature of MMR-D tumors is the high proportion of tumor-infiltrating lymphocytes (TILs) encompassing various lymphocytes with diverse effects on immune interactions. Therefore, we aim to assess the feasibility of a self T-cell-tumor organoid co-culture platform for individual MMR-D endometrial cancer patients. We provide evidence that co-culturing self-tumor organoids with peripheral blood lymphocytes can be utilized to evaluate ICI responsiveness in MMR-D endometrial cancer patients. The application of a specific T-cell organoid co-culture platform to a cohort of patient resistant to monotherapy ICIs offers a means to anticipate the timing for minimal immunotherapeutic intervention and the appropriate timing for combination therapy. Citation Format: Ju Hee Oh, Eun Hye Choi, Ji Eun Lee, Eun Ji Nam. Clinical response assessment of immune checkpoint inhibitors in mismatch repair-deficient endometrial cancer using a T cell organoid coculture system [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 4244.

Laser Test Spots: A Scoping Review.

Laser test spots are commonly suggested for the assessment of clinical response and adverse effects, but use by laser operators is not well described. To describe the use of laser test spots in the existing published literature regarding methodology (location, treatment parameters) and objective (clinical efficacy, safety, other). This scoping review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines and included indexed studies performing test spots in human subjects for dermatologic conditions with clinical reassessment at a subsequent visit. Among 5,261 identified publications, 103 studies with 959 test spots were selected for inclusion. Test spots conducted were mostly on lesional skin (89.3%) assessing both clinical response and adverse effects (76.9%). Most test spots used multiple laser parameters with a single wavelength (48.3%). Fluence was most frequently adjusted either alone (30.1%) or in combination with pulse duration or spot size. Other described test spots examined single set of laser parameters, multiple wavelengths with various parameters, or were left unspecified. Laser test spot methodology was diverse and performed for dual objectives of efficacy and safety. The authors have compiled clinical considerations to assist laser operators in deciding whether performing a test spot may be beneficial to their patient.

Nursing diagnoses in patients undergoing prostatectomy at the central hospital of Nampula, 1st semester of 2019

Introduction: The nursing diagnosis is a clinical assessment of a human response to health conditions/life processes, or a vulnerability to that response, by an individual, family, group or community. The research aims to describe the main nursing diagnoses in patients undergoing prostatectomy admitted to Surgery II at the Hospital Central de Nampula. Objectives: This is a descriptive study with a quantitative approach, involving patients admitted to surgery II undergoing prostatectomy. All patients with the medical diagnosis of benign prostatic hyperplasia or prostate cancer who underwent prostate surgery were included, thus all patients who underwent prostate surgery but who had other chronic diseases were excluded. Data were analyzed with SPSS statistical package to obtain descriptive analysis, percentage and use of the following Q-square statistical test of independence. Results: the study involved 33 patients undergoing prostatectomy, 54.5% of these patients had primary schooling and the most predominant age group was 66-75 years old (39.4%). A total of 461 nursing diagnoses were found, and the most frequent were: Impaired walking 5.4%, Constipation 4.8, Risk of infection 6.9, Risk of vascular trauma 7.4%, Acute pain 5.4% and Deficit in self-care for bathing 6.7%. The following diagnoses were associated with the nursing diagnosis: impaired walking p value 0.000, dentition p value 0.006, constipation (p value 0.001), risk of electrolyte imbalance p value 0.000) and risk of falls (p value 0.000). Conclusion: the use of the nursing process by nurses facilitates the survey of health problems in sick patients in order to intervene in care using real nursing diagnoses, risk and health promotion.

P797 Assessment of pharmacokinetics and clinical response in patients transitioning from intravenous to subcutaneous vedolizumab

Abstract Background Vedolizumab is a humanized monoclonal antibody directed against α4β7 integrin used in inflammatory bowel disease (IBS) patients1. The usual dosage of Vedolizumab is 300 mg intravenously (iv). Recently the subcutaneous (sc) formulation (108 mg every 2 weeks) has been approved, which provides more independence for the patient, avoiding visits to the hospital and possible inconveniences associated with it2. Methods The aim of the study is to evaluate the clinical and biochemical response of IBS patients treated with vedolizumab, 16 weeks after transitioning from iv to sc. An observational, prospective, single-center cohort study was performed. Patients with IBS and maintenance treatment with vedolizumab, stable for at least 4 months, were offered to switch to sc formulation. At the same time of treatment administration a blood test was performed, with vedolizumab levels and fecal calprotectin. Clinical index as Harvey-Bradshaw Index (HBI)/Simple Clinical Colitis Activity Index (SCCAI) and questionaries (IBDQ-9 and TSQM) were performed on each visit. Results 43 patients were included, 12 of them (27.9%) chose to transition to sc formulation. Baseline characteristics of both groups are shown in Table 1. 34 (79.1%) patients were prescribed vedolizumab due to previous biologic failure, 7 (16.3%) in first line due to comorbidities and 2 (4.7%) because of adverse effects in prior treatment. All included patients remained in remission during follow-up. At week 16 (w16), no significant differences were found in calprotectin levels in patients on iv treatment (mean 146.6 ± SD 45.9) vs sc (159.26 ± 53.9) (p 0.9). Vedolizumab serum levels at w16 were higher in the sc group (22364.3 ± 5141.6) vs. iv (11425.9 ± 1514.2), with statistically significant differences (p 0.009). At w16, 9 (75%) of the patients in the SC group were highly satisfied with the medication and 11 (91.7%) considered it easy to administer. 1 patient (8.3%) in the sc group returned to iv treatment. 4 patients (12.9%) in iv and 2 (16.6%) in sc treatment presented mild adverse effects. The 2 cases (100%) of the sc group the adverse event was local inflammation at the injection site. Conclusion In our experience, vedolizumab sc is a safe and convenient alternative to iv administration. Vedolizumab serum levels in patients who transitioned to sc were higher than iv formulation. 1. Smith, Michael A et al. "Vedolizumab: an α4β7 integrin inhibitor for inflammatory bowel diseases." The Annals of pharmacotherapy vol. 48,12 (2014): 1629-35. 2. Vermeire, Séverine et al. "Efficacy and Safety of Subcutaneous Vedolizumab in Patients With Moderately to Severely Active Crohn's Disease: Results From the VISIBLE 2 Randomised Trial." Journal of Crohn's & colitis vol. 16,1 (2022): 27-38.

Initial safety assessment of the endoscopically injected oncolytic virus OBP-301 in medically inoperable esophageal cancer: NRG-GI007.

341 Background: Definitive chemoradiation (CRT) is a standard-of-care for patients (Pts) with medically inoperable esophageal cancer (EC). The NRG/RTOG 0436 study of cisplatin/paclitaxel and RT (+/- cetuximab) as definitive therapy showed that about half of Pts have locally persistent disease. OBP-301 is a conditionally restricted, replication-competent adenovirus derived from human adenovirus type 5 that adds a human Telomerase Reverse Transcriptase (hTERT) gene promoter, replicating only in tumor cells to cause lysis. It may cause immunogenic cell death, enhance RT, and improve local control. OBP-301 was previously studied with RT in Japanese esophageal cancer Pts and shown to be safe and has promising activity.1 Methods: In NRG-GI007, a phase 1 study (NCT04391049), OBP-301 is added to weekly carboplatin/paclitaxel and RT (50.4 Gy/28 fractions) for Pts with medically inoperable EC. Pts receive 1-2mL of intratumoral OBP-301 1×1012virus particles/ml via endoscopy 3 days prior to and then at days 12 and 26 of CRT. The primary endpoint is dose-limiting toxicity (DLT), defined as adverse events (AEs, by CTCAE v5) definitely or probably attributed to OBP-301 that meet either of the following: (1) leading to a >14-day cumulative delay in CRT or (2) any grade ≥ 3 AE EXCEPT: grade 3 nausea/vomiting, grade 3 esophagitis or dehydration, first occurrence of grade 3/4 neutropenia, or grade 3/4 lymphopenia. Initially, 6 evaluable Pts (eligible and started protocol treatment) are enrolled. If protocol defined DLT occurs in ≤1 of 6 Pts, the dose will be deemed safe and an expansion cohort of 9 more will be enrolled to further assess safety and obtain a preliminary assessment of clinical complete response. If ≥2 Pts have a DLT then one de-escalated OBP-301 dose will be assessed. Results: From June 2020 to April 2023, 6 evaluable Pts were enrolled. Median age was 73.5 years, all male. Five Pts had adenocarcinoma and 1 had squamous cell carcinoma; 3 Pts had node-positive disease. All Pts received all planned OBP-301 injections, along with 50.4 Gy RT. Four out of 6 Pts received all 5 weekly doses of chemo for > 85% of planned total dose, and 2 got 4 weekly doses for > 70% of planned total dose. No Pt experienced ³7 day treatment delay. The following treatment-related (attributed as definitely, probably, or possibly related to CRT and/or OBP-301) grade 3 AEs were reported across 5 Pts: decreased neutrophil count (3 Pts), decreased lymphocyte count (2 Pts), decreased WBC (2 Pts), and fever and fatigue (1 Pt each). There were 4 Pts with AEs reported as definitely or probably related to OBP-301, all grade ≤2. No DLT occurred. Conclusions: No DLTs in the 6 evaluable Pts were observed and it is concluded that the initial OBP-301 dose level is safe. NRG-GI007 was reopened on August 7, 2023 to the expansion cohort. Full toxicity and treatment data will be presented. 1. Eur J Cancer 2021;153:98. Clinical trial information: NCT04391049 .

Co-Administration of Proton Pump Inhibitors May Negatively Affect the Outcome in Inflammatory Bowel Disease Treated with Vedolizumab.

Concomitant medications may alter the effect of biological therapy in inflammatory bowel disease. The aim was to investigate the effect of proton pump inhibitors on remission rates in patients with inflammatory bowel disease treated with the gut-selective vedolizumab. Patients from the Hungarian nationwide, multicenter vedolizumab cohort were selected for post hoc analysis. Primary outcomes were the assessment of clinical response and endoscopic and clinical remission at weeks 14 and 54. Secondary outcomes were the evaluation of the combined effect of concomitant steroid therapy and other factors, such as smoking, on remission. A total of 108 patients were identified with proton pump inhibitor data from 240 patients in the original cohort. Patients on steroids without proton pump inhibitors were more likely to have a clinical response at week 14 than patients on concomitant PPI (95% vs. 67%, p = 0.005). Non-smokers with IBD treated with VDZ were more likely to develop a clinical response at week 14 than smokers, particularly those not receiving PPI compared with patients on co-administered PPI therapy (81% vs. 53%, p = 0.041, and 92% vs. 74%, p = 0.029, respectively). We found that the use of PPIs in patients treated with VDZ may impair the achievement of response in certain subgroups. Unnecessary PPI prescriptions should be avoided.

Development of Oral Azacitidine with Cedazuridine for Myelodysplastic Syndrome (MDS) and Myeloproliferative Neoplasms (MPN) Including CMML (Chronic Myelomonocytic Leukemia) By Targeting Pharmacokinetic AUC Equivalence Vs Subcutaneous Azacitidine

Introduction/ Background: Hypomethylating agents (HMAs) such as azacitidine (AZA) and decitabine (DEC) are FDA-approved for patients with MDS/CMML and acute myeloid leukemia (AML). Treatment is generally administered parenterally as a daily injection or infusion over 5-7 days per four-week cycle. The oral fixed-dose combination of decitabine with cedazuridine, ASTX727, was approved by regulators in the USA and Canada for patients with MDS and CMML based upon the demonstration of biologically equivalent pharmacokinetics (PK) area under the curve (AUC) vs IV decitabine. ASTX030 is a combination of AZA and cedazuridine (CED), a cytidine deaminase inhibitor (CDAi), which enables oral AZA to achieve systemic AUC similar to that of parenteral (subcutaneous) AZA. Development and approval of an oral AZA providing equivalent PK exposure to the parenteral therapy has the potential to markedly reduce the treatment burden associated with parenteral treatment. This Phase I trial is designed to determine the dose combination for oral AZA plus CED to replicate SC AZA AUC exposures in subjects with MDS and MDS/MPN, including CMML. Methods: Adult patients with confirmed MDS, CMML, and other MDS/MPN or AML who are candidates to receive benefit from single agent AZA were enrolled in this open label Phase 1 trial. In addition to assessing safety and efficacy of each combination, the primary PK endpoint was to achieve oral AZA PK AUC 0-24 equivalence versus subcutaneous AZA (at the approved dose of 75 mg/m 2 over the span of 7 days). In the first cycle, patients received oral AZA alone on Day -3, followed by SC AZA at 75 mg/m 2 on Day 1. Subsequently, oral ASTX030 (combination of AZA with CED) was given at varying dose combinations of AZA and CED for each cohort. After cycle 1, patients received oral ASTX030 on Days 1-7 for each 28-day cycle. Dose levels for cohorts in escalation were determined by the data safety and review committee based on safety and PK results. Pharmacodynamic (PD) impact was assessed by changes in LINE-1 DNA methylation in peripheral blood cells. Clinical response assessments were based upon International Working Group (IWG) 2006 criteria for MDS patients and IWG 2015 criteria for MDS/MPN and CMML patients. Results: As of 05 JUL 2023, 65 patients were treated across 8 different dose combinations, with ≥6 patients per cohort. The median age was 72 years old (range 26-87), 36.9% (n=24) were female, 6.2% (n=4), had previously received HMA treatment (unlimited). Of the enrolled patients, 69% (n=45) had MDS, 25%(n=16) had CMML, and 6% (n=4) had MDS/MPN (other). Evaluated dose levels for AZA ranged from 60-136mg and CED dose ranged from 20-100 mg. In cohorts 1-2, tablet formulation was tested first (AZA ranging 80-100mg with CED ranging 80-100mg). Starting with cohort 3, capsule formulation was introduced for AZA to optimize the interaction effect of CDA inhibition by CED. In both tablet and capsule formulation, grade ≥3 AE's (regardless of causality) were observed in 75.9% of patients. The most common Grade ≥3 AE's regardless of relation to drug were leukopenia (25%), thrombocytopenia (20%), and anemia (20%). Gastrointestinal toxicity were similar (for example, nausea 70% ASTX030 vs 71% SC AZA) to those reported for SC AZA (VIDAZA USPI)). No dose limiting toxicity was observed in any of the cohorts. The CED dose of 20 mg resulted in ~100% bioavailability for AZA, suggesting inhibition in a linear range. LINE-1 demethylation results were similar to those reported historically with SC AZA. Although a clinical response comparable to SC AZA was observed, the immature nature of the data requires continued analysis to yield results on treatment efficacy. Conclusion: ASTX030 successfully achieved the primary endpoint of PK equivalence versus SC AZA based on total cycle AUC. The dose combinations evaluated were well tolerated, and the safety profile similar to that of SC AZA, with no unique AE's. LINE-1 demethylation and clinical response confirm the clinical activity of ASTX030. Phase 1B dose expansion for the ASTX030 study at the recommended dose combination of 144mg AZA with 20mg CED will begin soon to confirm PK equivalence for this dose level. An orally bioequivalent AZA based HMA offers significant opportunity for novel combinations and improved convenience for patients with high grade myeloid malignancy.

Quality of Life and Global Response Score in Cutaneous T-Cell Lymphoma

Background: Cutaneous T-cell lymphoma (CTCL) encompasses a heterogenous group of conditions that are typically incurable and managed as chronic, life-long diseases. Clinically, CTCL is associated with pruritus, and skin lesions that can cause pain and cosmetic discomfort, resulting in reduced health-related quality of life (HRQoL) for patients. As these patients often receive life-long therapy, any proposed therapy should maximize therapeutic safety and efficacy as well as patient HRQoL. Improvement in HRQoL may provide an indication to continue therapy, even for patients with partial response. Clinical trial response assessments for CTCL utilize a global response score, which includes skin, nodal and blood assessments (Olsen et al, JCO 2011). Dermatology-specific instruments, such as Skindex-29 (Chren 2012, Dermatol Clin 30), and oncology-specific instruments such as the Functional Assessment of Cancer Therapy - General (FACT-G) (Cella et al, JCO 1993), have been used to assess quality of life in this population. Disease entity, stage, age, sex, education, and treatment regimen are related to the extent of HRQOL impairment in patients with CTCL (Porkert et al, EJC 2018). Correlation between clinical response and HRQoL response has been reported in other cancers, such as renal cell carcinoma (Grimm Oncol Ther 2017) and other dermatologic conditions such as psoriasis (Acta Derm Venereol 2017), but has not been reported in CTCL. We evaluated changes in HRQoL in relation to the global response score in CTCL. Methods: Global response data, as well as Skindex-29 and FACT-G scores, were obtained from the phase III MAVORIC study (Kim et al, Lancet Oncol 2018). Patients with stage IB-IVB mycosis fungoides or S ézary syndrome were prospectively enrolled. Global response score was assessed every 8 weeks. Skindex-29 and FACT-G questionnaires were administered every 8 weeks. Patients with at least a baseline value for Skindex-29 or FACT-G score, at least one subsequent visit with both Skindex-29 or FACT-G value, and an overall response value were included. Changes in scores were calculated from baseline to the first visit with best overall response. A higher score in Skindex-29 indicated worse HRQoL. A higher score on FACT-G indicated improvement in HRQoL. Wilcoxon rank-sum test was performed. Correlation was calculated by Pearson coefficient. Results: 324 patients were evaluable for total Skindex-29 analysis. First visit with best overall response for patients with PD/SD occurred at a median of 1.26 cycles (IQR; 1.26, 14.26); 5.98 cycles (IQR; 1.26, 48.98) for PR; and 10.98 cycles (IQR; 3.98, 36.98) for CR. Patients with CR/PR as best response (n=121) had median change in Skindex-29 of -16 (IQR; -31, -8) and patients with SD/PD as best response rate had median change in Skindex-29 of -4 (IQR; -12, 3) (p <0.001) (Table 1). 333 patients were evaluable for total FACT-G analysis. Patients with CR/PR as best response rate had median change in FACT-G of 6 (IQR; -2, 16) and patients with SD/PD as best response rate had median change in FACT-G of 2 (IQR; -6, 8) (p <0.001) (Table 1). Skindex-29 correlates with global response score overall and across all domains. FACT-G correlates with global response score overall and across all domains, with the exception of social well-being. There was a moderate reverse correlation between change in total Skindex-29 and change in total FACT-G score (R=-0.61, p<0.001) (Figure 1). Conclusion: HRQoL as measured by the Skindex-29 and FACT-G correlate with complete or partial response to therapy in the global response score in patients with CTCL. There is moderate correlation between skin-specific quality of life and general quality of life in this population. Further exploration of factors affecting social well-being in patients with CTCL is warranted. Incorporation of QOL scales in global response score criteria should be considered.

Assessment of clinical outcomes and patient response to gingival depigmentation using a scalpel, ceramic bur, and diode laser 980 nm

ObjectiveThis research compares the clinical outcomes of gingival depigmentation procedures with conventional scalpel, ceramic trimmer bur, and diode laser techniques.Materials and methodsTwenty-four individuals with physiologic gingival hyperpigmentation received random allocation to one of three treatment groups: scalpel, ceramic bur, or diode laser. Pain score, operation time, bleeding index, degree of epithelialization, wound healing, Dummett-Gupta Oral Pigmentation Index (DOPI), and Takashi Index score changes were all investigated at different time points.ResultsAt 12-h follow-up, significant variations in pain scores were seen between the laser and scalpel groups (p = 0.003) but not between the laser and ceramic bur groups. The diode laser group completed the procedure significantly quicker than the scalpel and ceramic bur groups (p = 0.004 and p = 0.001, respectively). The ceramic trimmer bur and diode laser groups showed significantly less bleeding tendency than the scalpel group. Wound healing and the degree of epithelialization were similar in all groups. DOPI and Takashi indices significantly decreased compared to baseline in all groups, with no significant difference recorded between all groups.ConclusionWhile diode lasers are a safe and effective treatment option for gingival hyperpigmentation, providing optimal aesthetics with reduced discomfort to patients, a ceramic trimmer bur can also be used as a simple and affordable alternative to a laser in gingival depigmentation procedures.Clinical relevanceGingival hyperpigmentation is a major aesthetic issue for many individuals. Laser and ceramic trimmer bur treatments produce equivalent aesthetic outcomes for gingival hyperpigmentation.

Upfront tofacitinib in patients with biological-naïve ulcerative colitis - An Indian multicentric experience.

Tofacitinib is a Janus Kinase inhibitor used for treating moderate to severe ulcerative colitis (UC), mainly after the failure of biological therapy. There is a paucity of data on the outcome of tofacitinib in biological-naïve UC patients. The present study wasaimed at analyzing the safety and efficacy of tofacitinib in biological-naïve Indian patients with UC. The present study retrospectively evaluated consecutive patients with biological-naïve moderate-to-severe active UC from six tertiary care centers in India receiving tofacitinib from September 2020 to September 2022. Clinical remission or response assessment was based on partial Mayo score (PMS) calculated at baseline and weeks eight, 16 and 24. Total 47 cases (57.4% male, median age: 32years) were included. After eightweeks of therapy, 33 (70.2%) achieved clinical remission and eight (17.0%) had a primary failure. The baseline serum albumin at treatment initiation was the only independent predictor of remission at eightweeks (Odds ratio: 11.560, 95%CI: 1.478 - 90.404), but not at 16weeks. By 24weeks, 59.6% (28/47) of the patients were in remission and 29.8% (14/47) had stopped tofacitinib either due to failure (27.6%) or adverse events (AEs) (2.1%). Among the 47 patients, 10 (21.2%) cases developed AEs during follow-up, including two tuberculosis (4.2%), one cytomegalovirus (CMV) colitis (2.1%) and one herpes zoster (2.1%). Four patients with infection required temporary drug discontinuations. One required permanent discontinuation (mania). Upfront tofacitinib is effective in biologic-naïve Indian patients with moderate-severe UC. Further randomized studies are required to validate the study findings.