Organ-on-a-chip systems are miniaturized microfluidic 3D human tissue and organ models designed to recapitulate the important biological and physiological parameters of their in vivo counterparts. ...They have recently emerged as a viable platform for personalized medicine and drug screening. These in vitro models, featuring biomimetic compositions, architectures, and functions, are expected to replace the conventional planar, static cell cultures and bridge the gap between the currently used preclinical animal models and the human body. Multiple organoid models may be further connected together through the microfluidics in a similar manner in which they are arranged in vivo, providing the capability to analyze multiorgan interactions. Although a wide variety of human organ-on-a-chip models have been created, there are limited efforts on the integration of multisensor systems. However, in situ continual measuring is critical in precise assessment of the microenvironment parameters and the dynamic responses of the organs to pharmaceutical compounds over extended periods of time. In addition, automated and noninvasive capability is strongly desired for long-term monitoring. Here, we report a fully integrated modular physical, biochemical, and optical sensing platform through a fluidics-routing breadboard, which operates organ-on-a-chip units in a continual, dynamic, and automated manner. We believe that this platform technology has paved a potential avenue to promote the performance of current organ-on-a-chip models in drug screening by integrating a multitude of real-time sensors to achieve automated in situ monitoring of biophysical and biochemical parameters.
Purpose
Patients harboring high-grade non-muscle-invasive bladder cancer (NMIBC) experience high rates of both recurrence and progression. Currently, few treatment options besides cystectomy exist ...for this at-risk population, especially those with BCG-unresponsive disease. The purpose of this review is to present the current status and describe future directions of immunotherapy in NMIBC.
Methods
The PubMed and Google Scholar databases were searched for articles pertaining to immunotherapy in NMIBC. Relevant planned and ongoing clinical trials were identified using
www.ClinicalTrials.gov
. Published randomized control trials, reviews, other retrospective and prospective studies deemed relevant were used in this review paper.
Results
Novel immunotherapies used in the treatment of high-grade NMIBC and BCG-unresponsive disease allow patients more options and have the potential to reduce the need for radical cystectomy. Currently, several options target the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) axis as this mechanism of immunotherapy has been shown to be effective in several cancers, including bladder, melanoma, and lung cancers. In addition, other immunotherapy options for the treatment of NMIBC include viral gene therapies, interleukin-15 superagonists, small molecule inhibitors of indoleamine (2,3)-dioxygenase 1, and vaccines.
Conclusions
The current landscape of immunotherapy in bladder cancer is rapidly evolving, with much literature pertaining to muscle-invasive and metastatic disease. However, the implementation of these treatment options in high-grade NMIBC may allow patients to avoid life-altering surgery. Reliable biomarkers for response are needed to further select patients who may benefit from such therapies.
Objectives
Response to immune checkpoint inhibitor (ICI) remains limited to a subset of patients and predictive biomarkers of response remains an unmet need, limiting our ability to provide precision ...medicine. Using real-world data, we aimed to identify potential clinical prognosticators of ICI response in solid tumor patients.
Methods
We conducted a retrospective analysis of all solid tumor patients treated with ICIs at the Mount Sinai Hospital between January 2011 and April 2017. Predictors assessed included demographics, performance status, co-morbidities, family history of cancer, smoking status, cancer type, metastatic pattern, and type of ICI. Outcomes evaluated include progression free survival (PFS), overall survival (OS), overall response rate (ORR) and disease control rate (DCR). Univariable and multivariable Cox proportional hazard models were constructed to test the association of predictors with outcomes.
Results
We identified 297 ICI-treated patients with diagnosis of non-small cell lung cancer (N = 81, 27.3%), melanoma (N = 73, 24.6%), hepatocellular carcinoma (N = 51, 17.2%), urothelial carcinoma (N = 51, 17.2%), head and neck squamous cell carcinoma (N = 23, 7.7%), and renal cell carcinoma (N = 18, 6.1%). In multivariable analysis, good performance status of ECOG ≤ 2 (PFS, ORR, DCR and OS) and family history of cancer (ORR and DCR) associated with improved ICI response. Bone metastasis was associated with worse outcomes (PFS, ORR, and DCR).
Conclusions
Mechanisms underlying the clinical predictors of response observed in this real-world analysis, such as genetic variants and bone metastasis-tumor microenvironment, warrant further exploration in larger studies incorporating translational endpoints. Consistently positive clinical correlates may help inform patient stratification when considering ICI therapy.
e20049 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the frontline treatment of choice for patients with EGFR-mutant non-small cell lung cancer (NSCLC). ...However, EGFR-TKIs are associated with unique and dramatic dermatologic side effects that negatively impact patients’ quality of life, potentially resulting in poor adherence, including dose reductions or premature treatment cessation. Thus, it is crucial for the oncologists to be familiar with the array of dermatologic manifestations caused by these drugs for effective patient management. Methods: We performed a systematic search of PubMed, Embase, Web of Science, and Cochrane library for phase 3 randomized controlled trials (RCTs) comparing EGFR-TKI monotherapy with placebo or chemotherapy in patients with NSCLC. We calculated the odds ratio (OR) of all- and high-grade 10 dermatologic adverse events (dAEs). We conducted a meta-analysis using a random-effects model to compare the risk of dAEs in patients receiving EGFR-TKIs versus placebo/chemotherapy. Subgroup analysis based on control arm (placebo or chemotherapy) and individual EGFR-TKIs (afatinib, dacomitinib, erlotinib, gefitinib of osimertinib) were conducted. Results: 35 RCTs comprising 16,151 patients were included. In addition to all- and high-grade rash (all-grade: 12.21, 95% CI: 9.00-16.56; high-grade: OR 7.83, 95% CI: 5.11-12.00), EGFR-TKIs were associated with a significantly increased risk of all-grade acne (OR 12.24, 95% CI: 3.11-48.2), dermatitis acneiform (OR 8.46, 95% CI: 4.03-17.8), dry skin (OR 6.15, 95% CI: 4.02-9.40), palmar-plantar erythrodysesthesia syndrome (OR 11.14, 95% CI:3.00-41.4), paronychia (OR 31.97, 95% CI: 17.9-57.1), pruritus (OR 2.86, 95% CI: 2.17-3.77), skin exfoliation (OR 7.62, 95% CI: 2.55-22.8), and skin fissures (OR 11.59, 95% CI:4.86-27.6). The increased risk of EGFR-TKI-related dAEs was more prominent when compared with chemotherapy than placebo. In subgroup analyses of individual EGFR-TKIs, the risk of high-grade rash was significantly increased in patients treated with erlotinib or gefitinib but not in those treated with other EGFR-TKIs. Conclusions: This is the most comprehensive meta-analysis summarizing currently available evidence on cutaneous toxicity profile of EGFR-TKIs. These findings provide physicians with a better understanding for prompt recognition and management of these dAEs, to avoid unnecessary dose modifications and/or termination, and to prevent impairments in patients' quality of life.
The combination of; gemcitabine and docetaxel (Gem/Doce) as intravesical chemotherapy has been considered as a possible alternative to BCG installations when treating patients with non-muscle ...invasive bladder cancer (NIMBC), the Gem/Doce combination gained popularity in 2021 due to worldwide BCG shortage. Lately, several research articles assessed the efficacy of this therapy in different settings.; We seek to determine the efficacy of the treatment in patients with low and intermediate risk disease using 2 different protocols using Gem/Doce induction only versus; Gem/Doce induction with maintenance.
Our single institution prospectively maintained database identified consecutive patients who were diagnosed with NIMBC during 2020-2023, included were low risk and intermediate BCG naïve patients with non-muscle invasive bladder cancer who received Gem/Doce induction and maintenance courses. Patients were stratified according to the treatment protocol. Bladder cancer risk-group stratification was performed using AUA guidelines 2016. Baseline characteristics, pathology, cystoscopy, and cytology reports were collected from electronic medical charts. Study findings were reported using descriptive statistics. Kaplan-Mayer survival analysis was performed to detect Recurrence-free survival (RFS). A p-value of <0.05 was considered statistically significant. R programming language version 4.3 was used for all statistical analyses.
A total of 49 patients were included in the study, the median age was 74 (IQR 64-78).; Thirteen patients (27%) were females. The median follow-up time was 9 months (IQR 4-15), risk-group stratification yielded 5 patients with low-risk disease (10%) and 44 patients with Intermediate-risk disease (90%). Four patients (8%) had prior BCG exposure more than 2 years before initiation of treatment. Overall, 21 patients (43%) had recurrences at any point. One patient at the induction with maintenance arm developed a metastatic disease and died as a consequence. RFS at 3, 6, and 12 months for the Gem/Doce induction only was 97%,70%, and 51% and for Gem/Doce induction + maintenance 100%,;94%,;and 94%. Gem/Doce Induction with maintenance arm had better RFS at median follow-up time than induction only arm (Figure 1.). Baseline characteristics stratified according to treatment arm are presented in Table 1.
The use of Gem/Doce induction with maintenance resulted in superior recurrence free survival than induction only in patients with low and intermediate risk non-muscle invasive bladder cancer. However, further prospective trials with bigger cohorts and longer follow-up time are necessary to validate our results.
The combination of; gemcitabine and docetaxel (Gem/Doce) as intravesical chemotherapy has been considered as a possible alternative in the adjuvant setting of treating patients with non-muscle ...invasive bladder cancer (NIMBC), the Gem/Doce combination gained popularity in 2021 due to worldwide BCG shortage. Lately, several research articles assessed the efficacy of this therapy in different settings.; We seek to determine the efficacy of the treatment with 2 different protocols using BCG induction with Gem/Doce maintenance versus Gem/Doce induction with maintenance.
Our single institution prospectively maintained database identified consecutive patients who were diagnosed with NIMBC during 2020-2023, included patients with non-muscle invasive bladder cancer, patients who had received;Gem/Doce maintenance course with either a BCG or Gem/Doce induction. Patients were stratified according to the treatment protocol. Bladder cancer risk-group stratification was performed using AUA guidelines 2016. Baseline characteristics, prior exposure to BCG, pathology, cystoscopy and cytology reports were collected from electronic medical charts. Kaplan-Mayer survival analysis was performed to detect Recurrence-free survival (RFS), study findings were reported using descriptive statistics. R programming language version 4.3;were used for all statistical analyses.
A total of 55 patients were included in the study, the median age was 75 (IQR 71-81).; Eleven patients (20%) were females. The median follow-up time was 15 months (IQR 8-25), risk-group stratification yielded 2 patients with low-risk disease (4%), 18 patients with Intermediate-risk disease (33%) and 35 patients had high-risk disease (64%), CIS was present in 14% of the patients. Seven (17%) had prior BCG exposure. Overall, 12 patients (22%) had recurrences at any point. None of the patients underwent radical cystectomy. In the Gem/Doce induction + maintenance arm 2 patients (5%) developed metastatic-disease of them 1 died. RFS at 6, 12 and 18 months for the BCG induction + Gem/Doce maintenance was 100%,90% and 75% and for Gem/Doce induction + maintenance 97% and 95%; and 77% respectively. No difference in RFS was found between the treatment arms (Figure 1.). Baseline characteristics stratified according to treatment arm are presented in table 1.
With the premise of alternative intravesical adjuvant therapies in patients with non-muscle invasive bladder cancer, our study results indicate the Gem/Doce maintenance therapy can be used after BCG induction without compromising RFS. However, further prospective trials with bigger cohorts are needed to validate our results.
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