bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of prognostic factors for oral tongue squamous cell carcinoma: Significance of intratumoral tumor-infiltrating lymphocytes, lymph node ratio, and depth of invasion.
Authors: Lee Jongwon
Published: August 2024

132

Background: Oral tongue squamous cell carcinoma (SCC) is an aggressive malignancy with a variable prognosis. Identifying reliable prognostic factors is crucial for developing personalized treatment strategies and improving patient outcomes. This study examined the prognostic significance of clinicopathological factors in oral tongue SCC. Methods: A retrospective cohort study was conducted on 192 patients who underwent surgical resection at Asan Medical Center between 2010 and 2017. Clinicopathological data, including age at diagnosis, American Joint Committee of Cancer (AJCC) 8th edition stages, depth of invasion (DOI), extranodal extension (ENE), intratumoral and stromal (invasive front) tumor-infiltrating lymphocytes (TILs), lymphovascular invasion (LVI), margin status, metastatic-to-examined lymph nodes ratio (LNR), number of metastatic lymph nodes, perineural invasion (PNI), sex, size, tumor budding, tumor differentiation, tumor-to-stromal ratio (TSR), and worst pattern of invasion (WPOI) were analyzed. The total cohort, early-stage group, and late-stage group were analyzed separately. Results: Most variables showed significant associations with the survival rate. The multivariate Cox proportional hazard models for the total cohort showed significant results for intratumoral TILs, DOI grade, and LNR. However, other factors failed to show statistical significance. Intratumoral TIL was the only consistently potent factor for survival in all study groups. Conclusions: Our findings highlight the need for increased focus on the prognostic significance of intratumoral TILs. The DOI grade and LNR were also powerful prognostic factors, especially in late-stage tongue SCCs. Our data suggest that the prognostic significance of certain variables, such as the WPOI, may have been overestimated in the literature, thereby warranting a reassessment of the currently utilized prognostic markers in oral tongue SCC.
Characterization of estrogen receptor mutant breast cancer in 3D cell culture.
Authors: Mayer Olivia , Wright Jordan , Rinderle Caroline , Bunnell Bruce
Published: August 2024

14

Background: Breast cancer is a leading cancer in women worldwide. Many primary breast cancers are estrogen receptor positive (ER+) and responsive to anti-estrogenic therapies. These tumors can mutate estrogen receptors to survive, allowing the tumors to become more triple-negative-like and therefore more dangerous. Triple-negative breast cancer (TNBC) has been particularly challenging to treat due to its lack of estrogen (ER), progesterone (PR), and human epidermal growth factor (HER2) receptors. Due to the lack of treatment options, TNBC has a poor prognosis and contributes to a significant percentage of breast cancer mortalities. These ER mutants act more like TNBC, resulting in worse clinical outcomes. Current research on these ER mutants has been conducted using two-dimensional (2D), monolayer cell culture, which does not translate effectively in animal models, and ultimately, humans. Three-dimensional (3D) cell culture, which allows for the formation of spheroids, mimics actual tumors and provides results more consistent with tumor treatment in vitro. Due to the lack of research on these ER mutants in 3D culture, they must be characterized to determine baseline gene expression and behavior. After characterization, identifying changes resulting from drug treatment will be possible. Methods: Parental, ER+ MCF7-Luc cells, and daughter D538G and Y537S mutants were seeded at a density of 3000 cells/well in a low-attachment, round-bottomed 96-well plate. 48 hours and 7 days post-seeding, newly-formed spheroids were imaged. Using ImageJ analysis software, diameter, area, perimeter, circularity, aspect ratio, roundness, and solidity were determined. After 7 days in culture, spheres were collected for RNA extraction. Next, cDNA was synthesized, and qRT-PCR was performed to assess gene expression differences. Results: The wild-type ER+ spheres have smaller diameters, spherocity values closer to one, and are more compact. They express different levels of EMT markers from the controls, indicating alterations to signaling pathways. These 3D cultures vary in expression from the 2D cultures of the same cell lines. Conclusions: MCF-7 ER+ breast cancer cells aggregate more readily than ER+ mutants. The ER must be involved in signaling that promotes aggregation, as reduced ER signaling decreases the ability for spheroid formation. This phenomenon and the differences in gene expression may explain why mutants tend to behave in a more triple-negative manner. Cells cultured in 3D express some genes to different extents, confirming the importance of 3D culture for identifying future therapies – cells behave differently in different culturing contexts, 3D being more consistent with tumor behavior. Therefore, characterizing ER+ mutants prior to drug treatment studies is crucial to understanding how compounds affect cancer cells, as well as for identifying differences in various ER+ mutants for better treatment outcomes.
In-training and private physicians' knowledge, attitudes, practices and perceived barriers on the utilization of low dose chest CT scan as lung cancer screening for high-risk patients in a tertiary hospital: Single center experience.
Authors: Palec Jesilyn , de Dios Ivy Dimayuga
Published: August 2024

150

Background: Lung cancer is the leading cause of cancer-related deaths worldwide. Aside from smoking cessation efforts and guidelines from all proficient panels, utilizing Low dose CT scan (LDCT) of the chest as lung cancer screening (LCS) has been poorly adopted. Methods: This was conducted after institutional review board approval. The respondents were handed hard copy or electronic consent forms and survey questionnaire depending on the platform of their choice. Results: Majority of the respondents were in-training female physicians with median age of 31 years old who specialized in Internal Medicine practicing between 1-5 years who catered to more than 10 patients per week in outpatient clinics. Nearly half of the respondents answered that the recommended frequency for lung cancer screening (LCS) for high-risk individuals is done bi-annually. Majority agreed that lung cancer screening is effective in decreasing lung cancer mortality and morbidity. Most respondents have initiated discussion about the risks and benefits of low dose chest CT scan (LDCT) as lung cancer screening among eligible high-risk patients. However, most of the respondents disagreed that lung cancer screening is cost effective. The top three perceived barriers on the utilization of Low dose chest CT scan as lung cancer screening reported in descending order revealed that it is not cost-effective, some forgets to screen patients and lung cancer screening has the potential to cause mental anguish or anxiety to patients. Conclusions: This study recommends conducting further studies exploring the socio-economic burden and impact assessment of lung cancer in the Philippines to enable translation of more meaningful strategies for local and national lung cancer screening access, health policies and financing. Promoting continuous lung cancer screening forums, lectures and information dissemination of annual LDCT of the chest among high risk patients will encourage and strengthen interdepartmental and multidisciplinary referral and collaboration in increasing earlier detection of lung cancer and decreasing related morbidity and mortality.
Disparities in self-reported pain control among cancer survivors.
Authors: Santos Teles Marco , Modugu Ganesh , Silva Isabel C. , Malhotra Raj , Rahbe Munir , Eskander Mariam F.
Published: August 2024

151

Background: Cancer survivors often suffer from chronic pain. However, not all patients have access to medication and other pain management strategies, making pain control challenging. We aim to determine the association of sociodemographic factors with self-reported pain control in cancer survivors with cancer-related chronic pain. Methods: A cross-sectional analysis was conducted using data from the 2022 Behavioral Risk Factor Surveillance System survey. Cancer survivors who self-reported physical pain from cancer or treatment were included. Non-melanoma skin cancer survivors were excluded. The outcome of interest was pain control. Univariate analysis with chi-square and multivariable logistic regression were used to determine the sociodemographic characteristics associated with pain control. Models were adjusted for age, sex, marital status, income, insurance coverage, BMI, smoking status, and cancer site. Results: 1,670 cancer survivors with self-reported cancer-related chronic pain were identified. 9.2% were aged < 40, 61.5% were female, and 71.6% were non-Hispanic white. 97.2% were insured, 50.5% earned ≥ $50,000, and 27.6% were college graduates. 29.8% of survivors reported a history of breast cancer, followed by melanoma (6.3%), and lung cancer (6.1%). Young adults (age 18-39) reported significantly lower pain control compared to older survivors (52% vs. 77.7%, p <0.001). Non-Hispanic Black survivors reported the highest rates of pain control, followed by non-Hispanic white, and Hispanic survivors (87.7% vs. 77.5% vs. 60.6%, respectively, p= 0.013). Employed survivors reported significantly higher pain control than those out of the workforce (83.2% vs. 73.7%, p= 0.008, respectively). College graduates reported better pain control than those without a college degree (82.9% vs. 74.7%, p=0.009, respectively). There was no significant association between pain control and insurance coverage or income. On multivariate analysis, young adults had lower pain control than older adults (OR: 0.454; 95% CI: 0.219-0.942). Compared to non-Hispanic white survivors, being Hispanic was associated with worse pain control (OR: 0.324; 95% CI: 0.142-0.737); no significant association was found for non-Hispanic Black survivors (OR: 1.964; 95% CI: 0.851-4.631). Employment was associated with better pain control (OR: 1.997; 95% CI: 1.235-3.231). College degree attainment was not significantly associated with pain control on multivariate analysis (OR: 1.414; 95% CI: 0.934-2.142). Conclusions: Age, race/ethnicity and employment were associated with pain control among cancer survivors. Young adults, Hispanic and unemployed survivors were most likely to have poor pain control. Further research should elucidate the factors driving these relationships in order to achieve more equitable pain management in this population.
Utilizing an automated cloud-based platform, Palantine Foundry, to generate and build large databases for clinical research applications.
Authors: Nguyen Quynh , Weng Julius , Edelkamp Paul , Knafl Mark , Roy Paul , Qian David C , Liao Zhongxing X. , Woodman Scott Eric
Published: August 2024

165

Background: Academic institutions are adopting automated tools to help develop and maintain large databases. Leveraging advances in clinical data warehouses and artificial intelligence can potentially decrease resource utilization and the time required to conduct research by reducing intensive manual human curation of data. Methods: This research was performed as part of the institutional Data-Driven Determinants for COVID-19 Oncology Discovery Effort (D3CODE), IRB-approved protocol 2020-0348. Data were obtained from both structured and unstructured data sources within the MD Anderson electronic health record to validate a retrospective analysis for COVID-19 positive patients undergoing radiation treatments. Multiple data sources were identified, integrated and analyzed using the Syntropy Foundry platform, part of the Context Engine Data Management System at M.D. Anderson Cancer Center (MDACC) to include patient demographics, clinical notes, laboratory values, radiology reports, and oncology treatments. The platform allows real-time updating of these data-sources with integrated statistical packages to streamline rapid statistical analyses. We conducted a retrospective review of patients treated within 3 weeks of COVID infection between March 2020 and November 2022. Patient data was obtained using Foundry. Patients who tested positive for COVID-19 and had their treatment postponed were categorized as having a treatment delay. Patients who started radiation therapy and subsequently had an interruption in treatment due to contracting COVID-19 were categorized as having a treatment break. The Kaplan-Meier method was used to compare survival outcomes and was conducted within Foundry. Results: Syntropy Foundry helped develop a database comprising of 380 COVID-19 positive patients treated with radiation therapy between March 2020 through November 2022. It validated patient demographic information and research variables including patient age, histology, cancer stage, treatment plans, radiographic scans, recurrences, and follow up time that were separately performed manually. It reduced the time and human resources required to retrospectively collect and review these patient charts. Conclusions: Syntropy Foundry and ongoing efforts to leverage machine learning models to facilitate the interpretation of the large amount of accessible clinical data can potentially improve quality and reduce resources needed to generate large research databases. Future applications using artificial intelligence with Foundry to identify clinical recurrence and report patient outcome are under development.
Validating process mining in pediatric oncology: Demonstrating protocol adherence and variability in neuroblastoma treatment.
Authors: van Barneveld Astrid , Berkhout Matthijs , Van Noesel Max , Kemmeren Patrick , Tytgat Lieve
Published: August 2024

166

Background: Neuroblastoma is the most common extracranial tumor in children. The mortality rate for patients with metastatic disease is over 50%. In the Netherlands, 30 new patients are diagnosed annually. Current clinical treatment guidelines are complex and include multiple treatment arms consisting of chemotherapy, surgery, radiotherapy, and immunotherapy (IT). Although poor patient health and complications are known to cause adaptations to the otherwise standardized treatment regimen, the extent to which these variations occur is unknown. This study aimed to validate the use of process mining, a data-driven technique, to retrospectively examine protocol adherence and variability within current clinical guidelines based upon the GPOH-DCOG NBL2009 neuroblastoma treatment protocol. Methods: Data was extracted from electronic health records, as well as laboratory, pathology, and pharmaceutical databases, to create individual event logs for each patient. Process mining was performed using a fuzzy mining algorithm. The treatment courses for all neuroblastoma patients were mapped. Commonalities and variations were highlighted, and the throughput time for key treatment phases was calculated. Subsequently, conformance with protocol was determined. Results: Analysis of 70 patients treated between 2018-2022 showed 62 distinct treatment processes, revealing significant variations in patient care. Patients with high-risk disease showed the least variation (n=47, 42 variants). Notably, 17 variants were identified among 18 patients who died, indicating a highly personalized approach in the advanced stages of the disease. Subgroup analysis of 17 high-risk patients who received IT consisting of alternating cycles of anti-GD2 antibody and retinoic acid showed 6 variants. 12/17 patients (70.6%) completed the full IT regimen. Other treatment adjustments included shortened anti-GD2 infusions for two patients (5 and 8 days versus the prescribed 10 days, respectively), potentially indicating treatment toxicity. One patient received a 15-day infusion, exceeding the prescribed limit of 11 days. The recorded interval between the administration of anti-GD2 and retinoic acid was a median 5.5 hours (range: 60 seconds – 6.4 days), deviating from the prescribed interval of 24 hours and warranting further investigation. Conclusions: Process mining is a valuable tool for analyzing protocol performance and adherence in neuroblastoma treatment. Despite standardized treatment protocols, significant heterogeneity was observed in the treatment of neuroblastoma patients, especially those with poor prognosis. Throughput time analysis revealed variabilities in the IT regimen that warrant further investigation. This study underscores the potential of data-driven approaches to optimize treatment protocols and support evidence-based practices in clinical oncology.
Mortality and economic cost in common primary cancer admitted with COVID-19: Analysis of NIS 2020.
Authors: Suenghataiphorn Thanathip , Wattanachayakul Phuuwadith , Srikulmontri Thitiphan , Kulthamrongsri Narathorn , Xanthavanij Nutchapon , Tribuddharat Narisara , Buasri Kochakorn , Danpanichkul Pojsakorn , Saowapa Sakditad , Lohawatcharagul Tuntanut , Osataphan Soravis Alm
Published: August 2024

182

Background: Recent data showed the detrimental effects of COVID-19 infection on various conditions, resulting in a wide range of health disparities and worsening outcomes, as well as an increased burden of cost. However, limited information exists on the impacts of COVID-19 infection on the most commonly admitted with primary cancer, regarding clinical and economic impact. Methods: We analyzed the 2020 U.S. National Inpatient Sample (NIS) to investigate the effects of COVID-19 infection on cases primarily admitted with the most common admitted with primary cancer, using relevant ICD-10 CM codes. Adjusted odds ratios (aORs) for specified outcomes were calculated through multivariable logistic and linear regression analyses. The primary outcome was inpatient mortality, with secondary outcomes including the cost of hospitalization and length of stay. Statistical significance was established at a p-value of 0.05. Results: We estimated 919,104 hospitalizations with a primary discharge diagnosis of cancer conditions. Of these, 0.54% (4,985/919,104) had a concurrent diagnosis of COVID-19 infection and 46.1% were female. The mean age was 63.6 years old and Caucasians dominated the majority of the records (69.7%), followed by Hispanics (13.1%). In a multivariable logistic and linear regression model adjusting for patient and hospital factors, COVID-19 infection was associated with higher in-hospital mortality for all cancer conditions and other outcome. The txable denotes all-type and subpopulation analysis. Conclusions: In conclusion, our study encompasses all most common admitted primary cancer conditions and shed light how COVID-19 infection is associated with higher in-hospital mortality, prolonged hospital stays, and increased economic burden in various condition. Future longitudinal studies are warranted to comprehensively assess the long-term health sequelae in this population. [Table: see text]
Delayed addition of PD-1/PD-L1 inhibitors into chemotherapy on the outcomes for patients with extensive-stage small cell lung cancer: A propensity score-matched study.
Authors: Lu Shuangqing , Tian Yaru , Zhu Hui
Published: August 2024

208

Background: Immunotherapy in combination with chemotherapy has become the first-line treatment for extensive-stage small cell lung cancer (ES-SCLC). However, some patients failed to undergo simultaneous immunotherapy at the time of initial chemotherapy, and whether this will have an impact on the efficacy of immunochemotherapy has not been fully explored. Methods: Between January 2020 and December 2022, the study included 416 patients diagnosed with ES-SCLC and receiving first-line immunotherapy, divided into two groups: delayed-IO (administering PD-1/PD-L1 inhibitors at 2-4 Cycles of chemotherapy) and early-IO (administering PD-1/PD-L1 inhibitors concurrent with first-cycle chemotherapy). Propensity score matching (PSM, 1:1) was performed to balance the baseline characteristics of the two groups. The primary endpoints were OS and PFS. Calculations were performed using the Kaplan-Meier method and comparisons were made using the log-rank test. Results: Mainly due to the fact that PD-L1/PD-1 inhibitors were not included in the medical insurance, which was difficult for patients to afford and the poor physical condition of some patients, taking into account the safety of the patients themselves, 72 patients in the delayed-IO group (2 cycles of chemotherapy: 41; 3 cycles: 16; 4 cycles: 15), and 344patients were included in the early-IO group. The median OS and PFS were 24.00 months and 8.75 months in the delayed-IO group, and those were 18.59 months and 7.57 months in the early-IO group, respectively, before PSM. There was no significant difference in OS and PFS between the two groups (HR 0.72; P = 0.054 and HR 0.86; P = 0.281, respectively). After PSM, there were 72 patients in each of the two groups. The median OS in the delayed-IO group and the early-IO group was 24.00 months and 18.79 months, respectively (HR 0.60, 95% CI 0.38-0.97; P = 0.037). Median PFS was 8.75 and 6.49 months in the two groups, respectively (HR 0.69, 95% CI 0.48-0.99; P = 0.044). There was a statistically significant difference between the two groups. The overall adverse event profile was comparable between the two groups. Conclusions: Our findings suggest that administering PD-1/PD-L1 inhibitors at 2-4 Cycles of chemotherapy was superior to administering PD-1/PD-L1 inhibitors concurrent with first-cycle chemotherapy in patients with ES-SCLC, while the safety profile of both was similar.
Long-term survival after metasectomy in patients with bone or soft-tissue metastases from renal cell carcinoma.
Authors: Higuchi Takashi , Miwa Shinji , Hayashi Katsuhiro , Yamamoto Norio , Tsuchiya Hiroyuki
Published: August 2024

227

Background: Renal cell carcinoma (RCC) is reported to be associated with long-term survival, and surgical resection is now recommended in patients with metastatic lesions. This study evaluated the long-term outcome of surgery for bone or soft tissue metastases from RCC. Methods: Between 1993 and 2014, 58 patients (46 men and 12 women) underwent surgery, excluding palliative surgery, for bone or soft tissue metastatic lesions from RCC at our institution. These patients were retrospectively evaluated for factors associated with prognosis by using the log-rank test and Cox proportional hazards analysis. Results: The patients’ mean age was 60 years, and the mean follow-up period was 52 months. The surgical sites included the spine (33 patients), limb bone (10 patients), pelvis (8 patients), thoracic bone (4 patients), and soft tissue (3). The surgical procedures were total en bloc spondylectomy (TES) in 33 patients, wide excision in 13 (6 of them were also treated with prosthesis), and curettage and bone grafts in 12 (4 of them were treated with internal fixation). The 3-, 5-, 10-, and 15-year overall survival (OS) rates were 75%, 62%, 48%, and 25%, respectively. According to the surgical methods, the 5-year OS was 64% for TES, 62% for wide excision, and 46% for curettage and bone grafts. According to the surgical site, the median survival time was 127 months for the spine, 140 months for the limb bone, and 54 months for the pelvis. In multivariate analysis, preoperative lung metastasis and the pathological type, except for clear cell carcinoma, were independent risk factors for poor prognosis. However, age, performance status, Motzer classification, and abnormal blood test results were not significant risk factors. Conclusions: Our findings suggest that the surgical resection of bone and soft tissue metastatic lesions from RCC is a favorable option for improving prognosis even in patients with unfavorable conditions such as an advanced age or poor performance status. Now that treatment outcomes for renal cell carcinoma are improving, bone metastases can be treated with surgery.
Non-invasive minimal residual disease detection of liver cancer using circulating tumor DNA features and α-fetoprotein: A prospective study.
Authors: Chang Yinyin , Ren Qingqi , Li Shiyong , Zhang Liangliang , Feng Yumin , Long Guanghui , Mao Mao
Published: August 2024

229

Background: Liver cancer hasahigh recurrence rate of 50%-70% for early-stage patients. Minimal residual disease (MRD) is closely correlated with cancer early recurrence. Here, we developed SeekInCure, a non-invasive assay to detect MRD and predict the prognosis of liver cancer patients after radical surgery. Methods: 32 liver cancer patients undergoing radical surgery were prospectively enrolled. 8 mL peripheral blood was collected from each patient before and after surgery, respectively. SeekInCure assay, which integrated the protein tumor marker (AFP) and cancer genomic hallmarks: copy number aberration, and fragment size from ctDNA to calculate a score (PHCC), was utilized to detect the cancer signal in each blood sample. MRD status determined by PHCC value was correlated with the clinical outcome (OS) and the benefit of treatment after radical surgery. Results: Out of the 32 liver cancer patients, 78.1% (25/32) were at early stages (Stages I/II: 65.6%/12.5%), and 59.4% (19/32) received systemic treatment after surgery. MTB- patients (12.5%, 4/32) showed better overall survival (OS) than MTB+ patients (87.4%, 28/32) with a high hazard ratio (HR) value of 1.19. After radical surgery, 23 HCC patients were MRD-, including 4 MTB- patients remaining negative; meanwhile, 9 out of 28 MTB+ patients remained MRD+. The OS of MRD- patients was significantly better than that of MRD+ patients (HR 5.67; 95% confidence interval (CI), 1.33 ~ 24.20; P = 0.008). Moreover, the OS of MRD- patients with and without systemic treatment showed no significant difference (P = 0.930). Conclusions: This prospective study demonstrated the potential clinical value of ctDNA in detecting MRD status to predict the prognosis in early-stage liver cancer patients and to identify patients who may benefit from avoiding overtreatment. This strategy requires validation in independent prospective studies.
Examining molecular landscape and drug sensitivity profiles of patient-derived xenografts from resected brain metastases.
Authors: Morikawa Aki , Rastogi Tusharika , Ulintz Peter , Serhan Habib , Nieblas-Bedolla Edwin , Heth Jason , Cheng Xu , Bao Liwei , Udager Aaron M. , Soellner Matthew , Merrill Nathan , Merajver Sofia Diana
Published: August 2024

28

Background: Brain metastases (BrMet) remain an unmet need. Preclinical models of BrMet are rare but can be a valuable tool to interrogate pathology and develop novel therapeutic approaches. We previously published molecular profiles and drug sensitivity screening using novel BrMet patient-derived xenograft (PDX) models established from resected BrMet from patients with breast cancer. We further expanded our study to include BrMet from other solid tumors. Methods: We ascertained the genomic profiles of thirteen novel non-breast BrMet PDX models from patients undergoing clinically indicated surgical resection of BrMet. We then conducted drug sensitivity screening on ex vivo organoids with a panel of over 350 drugs to interrogate drug responses. We also collected information on molecular alterations and clinical treatment history from matched source patient material to correlate molecular alterations between tissue and matched PDXs when available, as well as with drug response in PDXs. Results: The PDXs included tumors that commonly (lung and melanoma) and less commonly (ovarian and sarcoma) metastasize to the brain. We observed potentially targetable DNA alterations in the DNA damaging repair pathway ( ATM, BRCA, CHEK2) and ERBB2. Using the drug sensitivity score 3 (DSS3), we assessed the sensitivity of the drugs tested. While the panel did not include the recently approved anti-HER2 targeted drugs, lapatinib (anti-HER2 TKI), and PARP inhibitors, e.g. olaparib and niraparib, were inactive against these PDXs. The three most active drugs among the BrMet PDXs were romidepsin, bortezomib, and triptolide, similar to what we observed previously for breast BrMet PDXs. When available, we correlated the DSS3 from the PDX testing with the drug exposure history and potentially actionable alterations reported in the matched source patient clinical samples. Interestingly, one case with CDKN2A/1B homozygous deletion had differential sensitivity against CDK inhibitors (highly active to dinaciclib but inactive to abemaciclib and palbociclib). Conclusions: We observed prevalent gene alterations associated with homologous recombination deficiency and HER2 among these non-breast BrMet PDX models, opening an opportunity for novel cross cancer approaches as these alterations are also reportedly linked to BrMet from breast cancer, these mechanisms may contribute to the propensity for BrMet. We also found that there are common drugs that are active across BrMet from different solid tumor types. To further explore the shared molecular features of BrMet across various solid tumors, we have established additional PDX models (near 100) from multiple solid tumors and plan to report on the molecular features.
Hypoxia-responsive synthetic gene circuits to improve safety and potency of CAR T cell therapy for solid tumors.
Authors: Schreiber Yannick , Leonard Joshua
Published: August 2024

37

Background: Engineered cell therapies expressing a chimeric antigen receptor (CAR) in human T cells have demonstrated great promise for the treatment of hematological malignancies. However, unique challenges remain in translating the success of CAR T cell therapies to solid tumors, namely: (1) specificity: there are few truly unique antigens present on solid tumors, leading to off-target effects that damage normal tissue and pose safety risks; and (2) suppression: solid tumors develop microenvironments that are immunosuppressive and decrease T cell survival and tumor-directed cytotoxicity. To address these challenges and improve the safety and potency of solid tumor cell therapy, we engineered cells with synthetic genetic circuits containing a previously validated hypoxia biosensor (HBS) that responds to upregulation of the native HIF1α and HIF2α transcription factors by hypoxia, enabling the cells to sense and respond to the hypoxic tumor microenvironment ubiquitous among solid tumors. Methods: We evaluated CAR expression from circuit architectures containing the HBS promoter driving expression of both CAR and native HIF1α, HIF2α, as well as from circuit architectures containing the HBS promoter and our toolkit of synthetic transcription factors and promoters. Circuits were integrated into HEK293 cells via PiggyBac transposon vector to generate stable cell lines. Cells were subsequently cultured in normoxia (21% O2) and hypoxia (1% O2), and harvested for flow cytometric analysis to evaluate CAR surface expression across a three day time frame. Results: We identified novel circuits providing fast reporter output with minimal background signal under hypoxic conditions, and elucidated design rules that enable or restrict amplification of transgene in native HIF1α and HIF2α-containing circuits. We observed differences in CAR transgene expression in hypoxia between circuits containing HIF1α and HIF2α-mediated feedback, suggesting mechanistic differences in regulation of HIF1α and HIF2α when overexpressed. Additionally, we observed greatly amplified transgene expression in circuit topologies containing feedback mediated by our synthetic transcription factor and promoter toolkit compared to native HIF1α and HIF2α-containing circuits and cells constitutively expressing CAR. Conclusions: We present a new therapeutic technology that senses hypoxic environments and enables high-output sense and respond behaviors with therapeutic outputs. We envision that this technology will enable development of safer, more effective cell therapies for solid tumors, as well as provide new biological and mechanistic insights that can inform the future development of hypoxia-responsive cell therapies.
Evaluating interaction between tumor educated platelets and cancer stem cells on breast cancer subtypes.
Authors: Guha Aishwarya , Sultana Jasmine , Bhuniya Avishek , Chakravarti Mohona , Bera Saurav , Sarkar Anirban , Dhar Sukanya , Das Juhina , Ganguly Nilanjan , Das Tapasi , Alam Neyaz , Ghosh Indranil , Hajra Srabanti , Bose Anamika , Baral Rathindranath , Banerjee Saptak
Published: August 2024

5

Background: Thrombocytosis has been reported to be responsible for poor prognosis of numerous malignancies. This swarm of platelets acts as foe for the body but as mate for the cancer cells by providing a protective shield around them, helping them to escape immunosurveillance process. A bidirectional interaction between platelets and tumor cells promote their conversion to an activated tumor educated platelet (TEP) state. The present report reveals the critical role played by TEPs to promote metastasis in BC subtypes by interacting with cancer stem cells (CSCs). Methods: Status of intra-tumoral and humoral TEPs (CD41+/CD62P+) was screened in luminal A (LumA) and triple negative (TNBC) BC subgroups. The impact of TEPs on lin-/CD44+/CD24- CSCs of both the categories in-vitro, was deciphered by performing mammosphere assay, clonogeneic and migration assays, with final validation in murine system. Effect on various genes and proteins related to stemness, metastasis and angiogenesis as a result of this interaction was elucidated by RT-PCR, flow cytometry and western blotting. Results: High percentage of TEPs in the peripheral blood is a potential biomarker and responsible for poor prognosis in BC subtypes. Both Lum A and TNBC patients had elevated TEP frequency, compared to healthy blood. Further, patients in the pre-carcinogenic stage had platelet count of >3.5 lakhs. Additionally, screening of breast tumor sections revealed intra-tumoral enrichment of TEPs, comparatively to a greater extent in TNBC than LumA, supporting their role in disease aggression. Also, a positive correlation was noted between TEP and CSC frequencies proving their synergistic interactions. Moreover, in-vitro, TEP influenced CSCs exhibited enormous clonogenic and tumorigenic potentialities. Their metastatic nature was confirmed by their enhanced migratory, invasive, angiogenic capacities with higher VIMENTIN and TWIST along with HIF1α, CD31 and MMP9 expression compared to E-CADHERIN. In line with in-vitro observations, in-vivo too, TEP~CSC produced metastatic colonies in murine lungs. Upon investigation, it was disclosed that it is through WNT-βcatenin-VEGFR2 axis that this mutual interdependency was functioning. Conclusions: This study advocates for the importance of TEPs as potential biomarker in BC diagnosis. Their alliance with vicious CSCs to promote disease advancement acquiesce them as a novel restorative agent.
Effect of serum diamine oxidase activity derived from response to chemotherapy on adverse events and serum amino acid concentrations for esophageal cancer.
Authors: Sato Yuta , Tajima Jesse Yu , Tanaka Yoshihiro , Matsuhashi Nobuhisa
Published: August 2024

55

Background: The relationship between activity of the small intestinal villi and the effectiveness of chemotherapy remains unclear. This study aimed to investigate how serum diamine oxidase (DAO) activity affects antitumor effects, adverse events, and amino acid absorption. Methods: We performed a single-center prospective cohort study that enrolled 50 patients with esophageal cancer (EC) receiving docetaxel, cisplatin, and 5-fluorouracil therapy. We determined the cut-off value of serum DAO activity contributing to a response to chemotherapy using a generalized additive model. Additionally, we compared adverse events, inflammatory markers, blood amino acid levels, and quality of life between the high and low DAO activity groups during chemotherapy. Results: The cut-off value of serum DAO activity at the first visit that contributed to a chemotherapy response was 6.5 units/L. Leukopenia and neutropenia of Grade ≥3 were significantly higher in the DAO low (<6.5 units/L) group ( p = 0.044, 0.017, respectively). Interleukin-6 was significantly lower in the DAO high (≥6.5 units/L) group at the first visit and at 4 weeks after the end of chemotherapy ( p = 0.039, 0.011, respectively). Glutamine was higher in the DAO high group at all measurement points during chemotherapy. Fatigue was significantly lower in the DAO high group ( p = 0.001). Conclusions: Serum DAO activity may be a predictor of the response to chemotherapy in patients with EC. The absorption capacity of amino acids was maintained in the group with high DAO activity, which may have contributed to the anti-inflammatory effect and provided a background for reducing adverse events. Clinical trial information: UMIN000048273 .
Correlation of enriched specific subset of immune cells nearby tumor associated macrophage (TAM) with pathologic complete response (pCR) of concurrent chemoradiotherapy followed by nivolumab in locally advanced rectal cancer (LARC).
Authors: Imai Mitsuho , Bando Hideaki , Tsukada Yuichiro , Inamori Koji , Kato Takeshi , Komatsu Yoshito , Uemura Mamoru , Yuki Satoshi , Taketomi Akinobu , Fujisawa Takao , Nakamura Yoshiaki , Kojima Motohiro , Koyama Shohei , Song Sanghoon , Ock Chan-Young , Nishikawa Hiroyoshi , Ito Masaaki , Yoshino Takayuki
Published: August 2024

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Background: We previously reported tumor-infiltrating lymphocyte (TIL) dynamics predictive of pCR in microsatellite-stable (MSS) LARC. In the current analysis, we investigate whether an immune cell-to-cell spatial network may predict pCR in MSS LARC. Methods: VOLTAGE study is a phase I/II study to evaluate the efficacy of chemoradiotherapy (CRT) followed by nivolumab and subsequent surgery in LARC pts. H&E images and multiplex immunofluorescence (mIF) images containing a total of 35 markers for T cells, TAM, Myeloid-derived suppressor cells, and Dendritic cells were analyzed with the Lunit SCOPE platform (Lunit, Republic of Korea). The proportion of T cells among all DAPI-positive (-pos) cells in a 50-micrometer radius centered on the TAM cells was counted. Results: In the samples of MSS LARC pts gathered at baseline, pre-treatment (n=38), TIL density in tumor microenvironment (TME) analyzed by H&E images was significantly correlated with the proportions of CD8-pos, CD4-pos, and FOXP3-pos cells (coefficient [coeff] 0.635, 0.482, and 0.580, respectively), but loosely correlated with PDL1-pos, PD1-pos, and CTLA4-pos cells (coeff 0.255, 0.174, and 0.180, respectively). Interestingly, intratumoral TIL density was more strongly correlated with TAM markers such as CD68 (coeff 0.269), compared to stromal TIL density (coeff 0.086). pCR rate was 28.9% in all MSS LARC, with baseline TIL density in TME predicting pCR with area under the receiver operating characteristic curve (AUROC) of 0.636 (p = 0.101). Interestingly, the ratio of baseline PDL1-pos cell proportion nearby CD68-pos cells, over that in all TME area (hereafter referred to as 'TAM-PDL1-proximity score') showed the best predictive performance for pCR, with an AUROC of 0.768 (p = 0.005). At the optimal cutoff of 1.66 times TAM-PDL1-proximity score, pCR rates for pts ≥ the cutoff and < the cutoff were 44% (11/25) and 0% (0/13), respectively (p = 0.006). Conclusions: PDL1-expressing immune cells nearby tumor associated macrophages before treatment is a promising predictive biomarker for pCR of neoadjuvant CRT followed by nivolumab in MSS LARC.
Clinical outcome of patients hospitalized for pancreatic-biliary malignancy with comorbid acute decompensated heart failure: An analysis from National Inpatient Sample (NIS).
Authors: Suenghataiphorn Thanathip , Wattanachayakul Phuuwadith , Kulthamrongsri Narathorn , Saowapa Sakditad , Lohawatcharagul Tuntanut , Kansuttiviwat Chalermkiat , Thongpiya Jerapas , Danpanichkul Pojsakorn , Chaisidhivej Natapat
Published: August 2024

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Background: Recent data suggest an association between cardiovascular disease burden and biliary cancer patients. However, the outcomes of hospitalized patients for biliary-pancreatic malignancy with concurrent acute decompensated heart failure (ADHF) are not well understood. Therefore, our objective is to assess the impact of ADHF on patients hospitalized for biliary-pancreatic malignancy. Methods: We used the 2020 U.S. National Inpatient Sample (NIS) to study patients hospitalized for biliary tract and pancreatic malignancy with concurrent acute decompensated heart failure (ADHF) identified by ICD-10 CM codes. Adjusted odds ratios (aORs) for predefined outcomes were determined via multivariable logistic and linear regression analyses. The primary outcome examined was inpatient mortality, while secondary outcomes included complications related to various body systems. Results: We identified 43,009 patients with a primary discharge diagnosis of biliary tract and pancreatic cancer. The mean age was 68.5 years; 49.4% were female. Caucasians accounted for 68%, followed by Hispanics (13%). Of these, 6.27% (3,699/43,009) had a concurrent diagnosis of heart failure. In the survey's multivariable logistic and linear regression analysis, accounting for patient and hospital confounding factors, ADHF demonstrated significant associations with higher in-hospital mortality (aOR 1.63; 95% CI 1.09, 2.44, p = 0.015). In addition, a significant association between ADHF and various adverse in-hospital outcome was observed including prolonged mean length of stay (Beta 1.45; 95% CI 0.67, 2.24, p < 0.001), increased mean total hospital cost (Beta 3,757; 95% CI: 2,641, 36,630, p = 0.024), elevated risk of shock (aOR 2.75; 95% CI: 1.77, 4.26, p < 0.001), higher risk of sepsis (aOR 1.71, 95% CI: 1.09, 2.68, p = 0.018), increased risk of acute respiratory failure (aOR 3.18, 95% CI: 2.25, 4.51, p < 0.001), and heightened risk of acute kidney injury (aOR 1.57; 95% CI: 1.24, 1.99, p < 0.001). Conclusions: Among patients hospitalized for biliary-pancreatic malignancy, concurrent ADHF is linked to increased mortality risk and various in-hospital adverse complications. Additional long-term studies are required for a comprehensive understanding of this association.
Systemic treatment post curative-intent intervention based on tumor-informed circulating tumor DNA result for oligometastatic colorectal cancer.
Authors: Siripoon Teerada , O'Donnell Conor , Naleid Nikolas , Starlinger Patrick , Atwell Thomas D. , Thiels Cornelius A , Warner Susanne , Mitchell Jessica L. , Jethwa Krishan , Hallemeier Christopher Leigh , Mathis Kellie Leanne , Shawki Sherief , Mahipal Amit , Jin Zhaohui
Published: August 2024

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Background: Local therapies potentially offer a curative approach for patients with oligometastatic colorectal cancer (CRC). The effectiveness of systemic chemotherapy following definitive local treatment in this setting is not well-defined. Tumor-informed circulating tumor DNA (ctDNA) might guide management strategies after curative-intent local treatment. Methods: This is a single institution retrospective study of patients with CRC who underwent curative-intent local therapy to an isolated site of metastatic disease and had post-intervention tumor-informed ctDNA (Signatera) testing. The study was approved by the institutional review board. Clinical characteristics, including ctDNA results, were collected and evaluated. Kaplan-Meier method and log-rank test were used to calculate and compare disease-free survival (DFS). Factors associated with DFS were analyzed using multivariate Cox proportional hazards model. Results: 45 patients were included with median age of 59 years, 62% being male, 91% white, and 53% with stage IV disease at diagnosis. 37% of the patients had RAS mutations, no patient had BRAF mutation, and 2.2% patient had mismatch repair deficient disease. Isolated liver metastases were present in 80% of patients, lung metastases in 11% and other sites in 9%. 44 patients received chemotherapy prior to definitive treatment, with a median treatment duration of 16 weeks. ctDNA tests were done prior to local therapy in 23 patients, with 14 cases (61%) testing positive. Definitive treatment included resection (58%), ablation (13%), radiotherapy (4%), and multimodality (25%). Post-definitive treatment chemotherapy was administered to 24 (53%) patients. ctDNA positivity following definitive therapy was observed in 10 patients (22%), which was associated with a poorer prognosis, with a median DFS of 5.3 months compared to 21.3 months for the ctDNA-negative group (p<0.001). These findings were confirmed on multivariate analysis. In patients who had negative ctDNA after definitive local treatment, median DFS was 14.9 months for those who received post-intervention chemotherapy versus 21.3 months for those without post-intervention chemotherapy (p=0.835). Conclusions: Patients with negative ctDNA results following definitive local therapy for isolated metastatic CRC have better prognosis. Post-intervention chemotherapy in this group of patients was not associated with improved DFS. ctDNA guided omission of post-intervention chemotherapy following curative-intent local treatment of oligometastatic CRC warrants further study. [Table: see text]
CVM-1118: An oral anti-vasculogenic mimicry (VM) agent in combination with nivolumab in patients with unresectable advanced hepatocellular carcinoma (HCC)—A phase IIa study.
Authors: Yen Chia Jui , Huang Yi-Hsiang , Yeh Kun-Yun , Chen Pei-Jer , Lu Sheng-Nan , Gutheil John , Melink Teresa J. , Chen Yen-Ling , Chen Chun-Man , Chao Ting-Yu (Tiffany) , Chu Yi-Wen , Chien Du-Shieng
Published: August 2024

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Background: CVM-1118 is a potent anti-tumor new chemical entity with multiple mechanisms of action including induction of apoptosis, cell cycle arrest, and inhibition of VM network formation. This study evaluated the anti-tumor effect and safety profile of CVM-1118 plus nivolumab in patients with progressive unresectable advanced HCC following the first-line therapy with TKIs. Methods: Eligible pts had unresectable advanced HCC and were refractory to prior systemic therapy (e.g., sorafenib, lenvatinib, regorafenib, and/or ramucirumab), with the exception of prior immunotherapy. Patients received oral CVM-1118 at 200 mg BID (400 mg daily) in combination with intravenous nivolumab at 240 mg Q2W in 28-day cycles. The primary endpoint of objective response rate was evaluated using mRECIST. The secondary endpoints were overall response rate (ORR) (per RECIST 1.1), progression free survival (PFS), disease control rate (DCR), and duration of overall response (DoR). Results: A total of 31 evaluable pts were enrolled (25 M/6 F; median age 65 y, range 44–80 y). All patients were Child Pugh A, BCLC stage B (13%, n=4) or C (87%, n=27) at the start of treatment. The median number of prior lines of therapy was 1 (range 1–2). The duration of CVM-1118 and nivolumab treatment ranged from 1.5–17.7 mos (median 3.1 mos) with 5/31 (16%) pts remaining on treatment for ≥ 5.2 mos (range 5.2–17.7 mos). The best ORR was 19.4% (mRECIST) (2 CR (6%), 4 PR (13%)), with remaining responses including 11 SD (36%) and 14 PD (45%). The DCR was 54.8% (95% CI 37.3–72.3%), the median PFS was 3.53 mos (95% CI 1.9–5.4 mos) and the median DoR was 12.1 mos (95% CI 5.2–16.1 mos). The most common treatment-related AEs ³ grade 3 included AST increased (12.9%), neutrophil count decreased (9.7%), anemia (6.5%), and WBC decreased (6.5%). As opposed to therapy with atezolizumab plus bevacizumab, gastrointestinal hemorrhage and hypertension were not observed in this study. Pharmacokinetics data demonstrated that CVM-1118 was rapidly metabolized to CVM-1125 in all pts following administration. On Day 1, the mean drug exposure of CVM-1125 was Cmax 564 ng/mL and the AUC0-24 was 2154 ng·hr/mL. Intersubject variability of drug exposure appeared to be high; the T1/2 of CVM-1125 was ~1.7 hr. Conclusions: CVM-1118 combined with nivolumab demonstrated clinical activity in advanced HCC pts with a safety profile that appears favorable compared to atezolizumab plus bevacizumab. These data support further development of the combination of CVM-1118 and nivolumab in pts with unresectable advanced HCC. Clinical trial information: NCT05257590 .