Assessment Of Clinical Response Research Articles

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.

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.

Randomized Controlled Trial of Neoadjuvant Short-Course Radiotherapy Followed by Consolidation Chemotherapy Versus Long-Course Chemoradiotherapy in Locally Advanced Rectal Cancer: Comparison of Overall Response Rates.

Management of locally advanced rectal cancer (LARC) is evolving with current emphasis on the addition of chemotherapy to short course radiotherapy (SCRT). We primarily aimed to analyse the difference in overall response rates between SCRT with sequential chemotherapy and standard long-course chemoradiotherapy (LCCRT)in LARC. After randomization, patients in arm A received 45Gy in 25 fractions over 5weeks with concurrent capecitabine while patients in arm B received 25Gy in 5 fractions over 1week followed by 3 cycles of CAPOX (capecitabine and oxaliplatin) chemotherapy. Clinical and radiological response assessment was made after the completion of neoadjuvant treatment, a week prior to surgery. Adjuvant chemotherapy was added to complete 6months of peri-operative chemotherapy. Surgery was performed between 8 and 10weeks of completion of radiation treatment in both arms. Of the 33 patients recruited in this study between February 2020 to July 2021, 17 patients were randomized to arm A and 16 to arm B. The rates of complete tumour regression were 23.1% in arm A versus 35.7% in arm B (p-value = 0.683). Pathological complete response (pCR) rate was 20% arm A versus 30% in arm B (0.446). A higher number of patients in arm B experienced grade 3 diarrhoea, whereas acute skin toxicity was seen only in arm A. SCRT had fewer treatment interruptions compared to LCCRT. SCRT followed by three cycles of CAPOX chemotherapy in the neoadjuvant setting is comparable to LCCRT in terms of tumour response. This may be a better alternative regimen with fewer treatment interruptions in a resource-limited setting.

Paediatric B lymphoblastic leukaemia with hyperdiploidy and a false-positive KMT2A fluorescence in situ hybridization result

The dramatic improvement in the event-free survival of paediatric B-lymphoblastic leukaemia (B-ALL) has led to risk-stratified treatment. Through a combination of clinical features, cytogenetic abnormalities and assessment of treatment response, patients are stratified to receive different intensities of therapy. The presence of high hyperdiploidy (>50 chromosomes) is considered a favourable genetic feature. Conversely, KMT2A fusion genes in B-ALL are associated with a poor prognosis, resulting in intensification of treatment. We present a seven-year-old female with B-ALL, a high hyperdiploid karyotype (56 chromosomes) and KMT2A rearrangement detected on FISH, but with no productive fusion identified. Single nucleotide polymorphism (SNP) array suggested the KMT2A rearrangement was due to chromosome 11 chromothripsis. Subsequent targeted RNA fusion panel and whole transcriptomic sequencing (mRNA-seq) did not detect an expressed KMT2A fusion. Differential expression analyses of the mRNA-seq data led to clustering of this case with other hyperdiploid cases, consistent with the hyperdiploid cytogenetic results. Given the additional intensity and potential toxicity of high-risk treatment, unusual findings by chromosome analysis, FISH and/or chromosomal microarray should prompt consideration of testing for a KMT2A fusion by another method to avoid misclassification.

Performance of pre- and post-pembrolizumab vesical imaging–reporting and data system (VI-RADS) to predict the pathological response and efficacy outcomes in muscle-invasive urothelial bladder cancer (MIBC): Full data analysis from the PURE-01 trial.

65 Background: The VI-RADS is a standardized reporting system that uses multiparametric magnetic resonance imaging (mpMRI) parameters to differentiate non muscle-invasive bladder cancer (NMIBC) from MIBC. Limited data on clinical response assessment to neoadjuvant therapy are currently available. In this study, we aimed to analyze the performance of VI-RADS to predict the pT0 or pT≤1 response post-neoadjuvant immunotherapy in MIBC. Methods: In PURE-01 study (NCT02736266) patients (pts) were staged with mpMRI before and after treatment (3 cycles of Pembrolizumab) prior to radical cystectomy (RC). Logistic regression models analyzed pre- and post-pembro VI-RADS, with clinical and tumor-related variables, against ypT≤1N0 (primary endpoint) and ypT0N0 (secondary endpoint). VI-RADS scores were dichotomized between 0-3 (0 = no evidence of disease) and 4-5 (5 = extension to extravescical fat). Event-free survival (EFS) and overall survival (OS) analyses based on VI-RADS were performed. Comprehensive genomic profiling and transcriptome-wide expression profiling data were matched with VI-RADS scores. Model performance was also tested in the ongoing NureCombo (nivolumab+nab-paclitaxel; NCT04876313) and SURE-01 (sacituzumab govitecan; NCT05226117) neoadjuvant studies. Results: In total, 110 patients treated with neoadjuvant pembrolizumab between 02/2017 and 07/2020 had centrally reviewed scans (N=220 mpMRI). Pre-pembrolizumab, 21 patients (19.1%) had no measurable disease (VI-RADS=0), 34 (30.9%) had a VI-RADS 1-3 score, and 55 (50%) had a VI-RADS 4-5 score. Both pre-pembrolizumab and post-pembrolizumab VI-RADS 0-3 scores were the only significant covariates that predicted the ypT≤1N0 endpoint on multivariable analyses (MVA): the strongest effect was seen with post-pembrolizumab VI-RADS 0-3 predicting the ypT≤1N0 response (odds ratio [OR]: 23.4, 95%CI: 7-95.3, p<0.0001). The area-under-the-curve (AUC) of this model was 0.90. Post-pembrolizumab VI-RADS 0-3 also predicted longer EFS (p<0.001) and OS (p=0.044). The scores of several gene signatures from baseline tumors differed between pre-pembrolizumab VI-RADS 0-3 and 4-5 categories. RAF1 mutations were enriched in pre-pembrolizumab VI-RADS 0-3 group (p=0.045). Conclusions: VI-RADS scores post-pembrolizumab revealed a robust association with pathological downstaging and survival. VI-RADS scores were also characterized by distinct biomarker features. These results indicate that VI-RADS is emerging as an important tool to design next-generation trials in MIBC. Clinical trial information: NCT02736266 .

Review of the use of radiomics to assess the risk of recurrence in early-stage non-small cell lung cancer.

Radiomics is an emerging field of advanced image analysis that has shown promise as a non-invasive, companion diagnostic in predicting clinical outcomes and response assessments in solid tumors. Radiomics aims to extract high-content information from medical images not visible to the naked eye, especially in early-stage non-small cell lung cancer (NSCLC) patients. Although these patients are being identified by early detection programs, it remains unclear which patients would benefit from adjuvant treatment versus active surveillance. Having a radiomic signature(s) that could predict early recurrence would be beneficial. In this review, an overview of the basic radiomic approaches used to evaluate solid tumors on radiologic scans, including NSCLC is provided followed by a review of relevant literature that supports the use of radiomics to help predict tumor recurrence in early-stage NSCLC patients. A review of the radiomic literature from 1985 to present focusing on the prediction of disease recurrence in early-stage NSCLC was conducted. PubMed database was searched using key terms for radiomics and NSCLC. A total of 41 articles were identified and 13 studies were considered suitable for inclusion based upon study population, patient number (n>50), use of well described radiomic methodologies, suitable model building features, and well-defined testing/training and validation where feasible. Examples of using radiomics in early-stage NSCLC patients will be presented, where disease free survival is a primary consideration. A summary of the findings demonstrates the importance of both the intratumor and peritumoral radiomic signals as a marker of outcomes. The value of radiomic information for predicting disease recurrence in early-stage NSCLC patients is accumulating. However, overcoming several challenges along with the lack of prospective trials, has inhibited it use as a clinical decision-making support tool in early-stage NSCLC.

Development of a dual energy CT based model to assess response to treatment in patients with high grade serous ovarian cancer: a pilot cohort study

BackgroundIn patients with cancer, the current gold standard for assessing response to treatment involves measuring cancer lesions on computed tomography (CT) imaging. The percentage change in size of specific lesions determines whether patients have had a complete/partial response or progressive disease, according to RECIST criteria. Dual Energy CT (DECT) permits additional measurements of iodine concentration, a surrogate marker of vascularity. Here we explore the role of changes in iodine concentration within cancer tissue on CT scans to assess its suitability for determining treatment response in patients with high grade serous ovarian cancer (HGSOC).MethodsSuitable RECIST measurable lesions were identified from the CT images of HGSOC patients, taken at 2 different time points (pre and post treatment). Changes in size and iodine concentration were measured for each lesion. PR/SD were classified as responders, PD was classified as non-responder. Radiological responses were correlated with clinical and CA125 outcomes.Results62 patients had appropriate imaging for assessment. 22 were excluded as they only had one DECT scan. 32/40 patients assessed (113 lesions) had received treatment for relapsed HGSOC. RECIST and GCIG (Gynaecologic Cancer Inter Group) CA125 criteria / clinical assessment of response for patients was correlated with changes in iodine concentration, before and after treatment. The prediction of median progression free survival was significantly better associated with changes in iodine concentration (p = 0.0001) and GCIG Ca125 / clinical assessment (p = 0.0028) in comparison to RECIST criteria (p = 0.43).ConclusionChanges in iodine concentration from dual energy CT imaging may be more suitable than RECIST in assessing response to treatment in patients with HGSOC.Trial RegistrationCICATRIx IRAS number 198179, 14 Dec 2015, https://www.myresearchproject.org.uk/.

Assessment of Clinical Response to V937 Oncolytic Virus After Intravenous or Intratumoral Administration Using Physiologically-Based Modeling.

Oncolytic viruses (OVs) represent a potential therapeutic strategy in cancer treatment. However, there is currently a lack of comprehensive quantitative models characterizing clinical OV kinetics and distribution to the tumor. In this work, we present a mechanistic modeling framework for V937 OV, after intratumoral (i.t.) or intravascular (i.v.) administration in patients with cancer. A minimal physiologically-based pharmacokinetic model was built to characterize biodistribution of OVs in humans. Viral dynamics was incorporated at the i.t. cellular level and linked to tumor response, enabling the characterization of a direct OV killing triggered by the death of infected tumor cells and an indirect killing induced by the immune response. The model provided an adequate description of changes in V937 mRNA levels and tumor size obtained from phase I/II clinical trials after V937 administration. The model showed prominent role of viral clearance from systemic circulation and infectivity in addition to known tumor aggressiveness on clinical response. After i.v. administration, i.t. exposure of V937 was predicted to be several orders of magnitude lower compared with i.t. administration. These differences could be overcome if there is high virus infectivity and/or replication. Unfortunately, the latter process could not be identified at the current clinical setting. This work provides insights on selecting optimal OV considering replication rate and infectivity.

Clinical validation of next-generation sequencing-based clonality assays for minimal residual disease tracking in multiple myeloma.

e20037 Background: The prognosis of multiple myeloma (MM) patients is dependent on minimal residual disease (MRD) status after treatment. Multicolor flow cytometry (MFC) as a clinical MRD evaluation method has certain limitations regarding sample requirement, sensitivity and specificity. Next-generation sequencing (NGS)-based B cell receptor (BCR) clonality assessment has an edge in lymphoid clone MRD detection, with easier sample preparation and higher sensitivity. NGS-based BCR clonality assays were performed to evaluate curative effect and track MRD of MM patients, and its performance in testing samples with limited DNA contents was explored. Methods: In this retrospective study, newly diagnosed or relapsed MM patients with paired sample collected before and after initial treatment were included, and OriMIRACLE L NGS assay were used for BCR clonality detection in genomic DNA (gDNA) extracted from clinical residual marrow smear samples. The quantitative accuracy of NGS was compared to MFC. The concordance of MRD between MFC, NGS and clinical response assessment were analyzed. Results: From December 2016 to April 2022, 29 patients were included with a median age of 65 years old. The gDNA input of the sample collected before treatment was 100.0 ng, and the median DNA content of the sample collected after treatment was 1673.4 ±594.8 ng. The quantitative results of NGS and MFC were consistent in samples with a frequency of cancer cells of above 1x10-4 among all nucleated cells. BCR clonality detection in 23 newly diagnosed and 6 relapsed cases showed a 100% sensitivity at diagnosis. For post-treatment monitoring, patients with positive MRD by both MFC and NGS (n = 18), the MRD results were consistent with clinical response assessment. One of the patients achieved complete response (CR), while the remaining patients were unable to achieved CR. The CR patient was relapsed after 134 days. The clinical responses of 11 cases with negative MRD by MFC and positive MRD by NGS were reviewed. There were 7 cases with CR, 3 cases with very good partial response or partial response, and one case with stable disease. Among those CR patients, except for one patient who was lost to follow-up, 4 patients who underwent continuous treatment were still CR and 2 patients who had treatment discontinued recurred at 67 and 134 days. Conclusions: OriMIRACLE L NGS assay showed the higher sensitivity and specificity of MRD evaluation than MFC. For patients with negative MRD by MFS and positive MRD by NGS, recurrence might occur in case of treatment discontinuation. It is recommended to consider carefully that whether maintenance treatment is required in such cases.