tbuckley/cabot-search huggingface dataset:
Analyzing imbalance of short tandem repeats for pancreatic cancer detection.
Authors: Jonathan Levine, Sydney Finkelstein, Venkata Arun Timmaraju
Journal: Journal of Clinical Oncology (2024)

e16359 Background: Short tandem repeats (STRs), alternatively known as microsatellites, encompass repeat units of 1 to 6 base pairs (bp) in the genome and function as regulators of gene expression, impacting plasticity and complex traits. STRs are prone to hypermutation with alterations correlated to pathogenicity in multiple Mendelian and acquired disorders. STR variant classes include insertions, mobile element insertions (MEIs), deletions, and multi-allelic copy number variants (mCNVs). These can lead to repeat expansions, allelic imbalance (AI), and microsatellite instability (MSI) observed in diseases such as Huntington's disease, hereditary ataxia, and multiple cancers. In pancreatic cancer, AI and associated loss-of-heterozygosity (LOH) at tumor suppressor loci flanked by hypervariable STR regions correspond to a pathogenic phenotype with a risk of aggressive disease. Consequently, it is critical to develop accurate and robust methods to precisely identify and genotype pancreatic samples with varying specimen quality in a clinical setting to aid in diagnosis. Methods: Capillary electrophoresis (CE) and Sanger sequencing have been used to analyze STRs. The availability of newer tools such as 2nd generation short-read (NGS) and 3rd generation long-read (TGS) sequencers could allow for high throughput scaling, however, informatics challenges associated with analyzing repetitive regions remain. Here we developed amplification and enrichment methods for targeted analysis for detection by CE, NGS and TGS. Results: Amplification and enrichment strategies for detecting 17 short tandem repeat regions that play a role in pancreatic carcinogenesis were developed. Methods were optimized for detecting STR alterations in cell-free nucleic acids isolated from endoscope-guided pancreatic fine needle aspirate biopsies. Furthermore, informatics tools were developed to analyze short-read and long-read sequencing data to accurately analyze repeat regions. Conclusions: Here we compared 3 platforms (CE, NGS, and TGS) and found that CE remains the gold standard for analyzing AI/LOH with data comparable to long-read TGS, while short-read NGS is not always amenable to accurate analysis dependent on the region of interest. Additionally, we found that artifacts of amplification persist, irrespective of the 3 platforms analyzed.
Development of a multi-analyte blood test for the early detection of pancreatic ductal adenocarcinoma (PDAC) and performance compared to CA19-9.
Authors: Alcibiade Athanasiou, Natasha Kureshi, Norma Alonzo Palma, Ralph Schiess, Thomas C. King
Journal: Journal of Clinical Oncology (2024)

e16360 Background: Early detection of PDAC can improve survival but is hampered by the lack of recognizable symptoms in early disease. Imaging has been the mainstay for surveillance of high-risk individuals but has proven to be cumbersome and may lack sensitivity to detect small tumors. CA19-9 is the only available blood biomarker for PDAC, but it is neither sensitive nor specific enough for it to be recommended for high-risk surveillance. A sensitive and specific blood biomarker for PDAC could positively impact this situation. Methods: Serum samples from patients across multiple centers with stage I and II PDAC (n = 75) and matched controls at high risk for PDAC (genetic and familial) (n = 83) were assessed for more than 2,900 protein analytes using O-link multiplex technology and conventional immunoassays for selected protein candidates. Machine learning was used to combine the biomarker candidates to create 4-plex signatures discriminating PDAC and controls. Results: ROC (receiver operating characteristic) curve analysis of these revealed signatures with performance superior to CA19-9 and a previously commercially available assay, IMMRay PanCan-d (AUC of 0.97 and 0.94 vs. 0.87 for CA19-9 and 0.88 for IMMRay). A subset of these candidate biomarkers has now been transitioned to standardized ELISA assays which are being used to construct a final signature for clinical validation in an independent set of PDAC and high-risk control samples. Conclusions: A novel multi-analyte blood test utilizing newly-discovered PDAC biomarkers has the potential to improve early detection of PDAC in high-risk individuals.
Prevalence of HER-2 expression and correlation with clinicopathological features in gynecological cancer: A single-center retrospective study in China.
Authors: Rui Chen, Juanhui Dong, Guangxin Li, Yi Peng, Haike Lei, Li Yuan, Xingtao Long, Qi Zhou
Journal: Journal of Clinical Oncology (2024)

e17500 Background: Targeted therapy for human epidermal growth factor receptor 2 (HER2) has become a standard of care in several HER2-expressing solid tumors. Nonetheless, there remains an unmet need for effective treatment, for instance, anti-HER2 antibody-drug conjugates (ADCs), in advanced stage gynecological cancer. In this context, we presented a retrospective study on the incidence of HER2 expression in primary gynecological cancer based on a single-center data from southwestern China. Methods: Paraffin-embedded tumor tissue blocks, clinicopathological, and survival data of gynecological cancer patients were collected from Chongqing University Cancer Hospital. HER2 IHC scoring was carried out according to the updated ASCO/CAP guidelines for breast and gastroesophageal adenocarcinoma by two pathologists independently. Data analysis was performed using SPSS v.24. Results: A total of 104 cases of cervical cancer, 102 cases of endometrial cancer and 103 cases of ovarian cancer were included between 2019 and 2023. HER2 expression was detected in 31.7% samples, with scores of 1+, 2+, and 3+ in 23.9% (74/309: 36/104, 16/102, 22/103), 5.8% (18/309: 7/104, 7/102, 4/103), and 1.9% (6/309: 2/104, 1/102, 3/103) of patients, respectively. Notably, ultra-low HER2 expression with incomplete and faint staining in ≤10% of tumor cells was observed in 41.1% (127/309: 37/104, 53/102, 37/103) of patients. Metastasis and lymphovascular invasion were associated with elevated HER2 expression in endometrial cancer (p=0.037, 0.040, respectively), while a larger tumor size was associated with elevated HER2 expression in cervical cancer (p=0.004). However, no positive association between HER2 status and overall survival (OS) was found in cervical, endometrial or ovarian cancer. In our cohort, metastasis was the only risk factor related to reduced OS of gynecological cancer patients by COX regression analysis (HR=14.00, 95%CI=1.32-148.21, p=0.028). Conclusions: Our data revealed a considerable number of patients with HER2-low and ultra-low gynecological cancer. It might represent a significant portion in real-world scenarios and warrant more consideration in selecting candidates for HER2-targeted ADCs, especially for those with relapsed or refractory conditions. Given the inherent challenge in interpretation, the study highlights the necessity for a consensus on evaluating HER2 immuno-staining results in gynecological cancer. Clinical trial information: MR-50-23-019676 . [Table: see text]
Experience of seven Spanish centres with echoendoscopically implanted <sup>32</sup>P microparticles associated with chemotherapy in locally advanced pancreatic adenocarcinoma.
Authors: Carmen Guillen-Ponce, Victoria Lopez-Gomez, Ignacio Juez, Ignacio Navales, Mariano Ponz-Sarvise, Jorge Adeva, Maria Purificacion Rodriguez Cernuda, Maria Garrido, Ana Garcia Garcia De Paredes, Javier Zamora
Journal: Journal of Clinical Oncology (2024)

e16358 Background: 32 P brachytherapy delivered by echoendoscopy (EUS) represents an innovative therapy in locally advanced pancreatic cancer (LAPC). The device to implant it is approved in unresectable LAPC in combination with gemcitabine-based chemotherapy. Our aim is to present the preliminary efficacy and safety results of a series that brings together the experience of seven centres in Spain. Methods: After being assessed by a multidisciplinary committee and meeting eligibility criteria (Table 1), patients signed consent to receive intratumoural 32 P by EUS within the international observational registry OSPREY (March 2022-February 2024). Complications associated with intratumoural 32 P injection via EUS, associated adverse events (AEs) and preliminary efficacy results (progression-free survival [PFS], distant and locoregional, and overall survival [OS]) were analysed. Results: Thirteen patients (7 females; age 65 years [range 48, 79]; 10 ECOG 1) with unresectable LAPC (7 in head, 3 in uncinate and 3 in body; tumour size 36.8 mm [range 25, 60]) were included. The median time from tumour diagnosis to procedure was 5 months [1.4, 28.9]. Only 4 patients (30 %) had received a previous line of treatment. Eleven patients (85%) received gemcitabine-based chemotherapy concomitant with intratumoural 32 P (8 gemcitabine plus nabpaclitaxel; 3 gemcitabine monotherapy). There were no complications or AEs related to 32 P injection or EUS. A total of 7 patients (54%) had chemotherapy-related AEs, with 2 cases of G3 neutropenia; 6 had G1-2 toxicities: neutropenia (1), thrombopenia (2), anaemia (1), nausea (1), asthenia (1), diarrhoea (1) and constipation (1). Two patients underwent surgery after intratumoural treatment. With a median follow-up of 17.3 months after injection, 8 patients (61.5 %) have progressed, all of them distantly, and three also locoregionally. The median PFS since 32 P injection is 8.4 months (95% CI 2.7, NR). Six patients are alive at the end of follow-up (46.2 %) with a median OS since 32 P injection of 13.8 months 95% CI [10, NR]. At data cut-off, five patients remain on-treatment. Conclusions: Our initial experience suggests that intratumoural 32 P associated with gemcitabine-based chemotherapy is safe. Patients after 32 P injection achieve long overall survival. Our ongoing prospective registry will allow evaluation of the oncological outcomes of this therapy at longer follow-up times. [Table: see text]
CRS-HIPEC following neo-adjuvant pressurized intraperitoneal aerosol chemotherapy (PIPAC) with systemic chemotherapy in primarily advanced inoperable epithelial ovarian cancer: An ISPSM collaborative study.
Authors: S.P. Somashekhar, Rohit Kumar C. Chandrashekar, Ashwin K. Rajgopal, Aaron Marian Fernandes, Esha Shanbhag, Susmita Rakshit, Vijay Kumar Ahuja
Journal: Journal of Clinical Oncology (2024)

e17504 Background: PIPAC has shown improved objective response rate with improved quality of life in combination with IV chemotherapy when compared to IV chemotherapy alone in salvage situations. Methods: All patients with primarily inoperable advanced epithelial ovarian cancer not been able to receive optimal IV chemotherapy or not responding to first line of chemotherapy who could not undergo CRS-HIPEC were challenged with PIPAC &amp; IV chemotherapy as a salvage situation after discussion in MDT. Patients who subsequently underwent CRS-HIPEC were analysed to study their clinical characteristics, extent of disease and peri-operative outcomes. PIPAC was given with Cisplatin 15mg/m2 and doxorubicin 3mg/m2. Intravenous chemotherapy was given within one week of PIPAC. Each cycle was repeated once in 4-5 weeks. Patients who underwent subsequently CC0 cytoreduction got HIPEC with Injection cisplatin 100mg/m2. All outcomes were prospectively entered in the registry and analysed retrospectively. Results: 120 PIPAC applications were done in 45 patients. 30 patients received 3 cycles of PIPAC with IV chemotherapy given within one week of PIPAC. Mean PCI initially was 25±5 with nearly 55% of them having ECOG 2 performance status and mean ascities volume of 500±55 ml . Out of 45 patients 28 underwent CRS-HIPEC subsequently. Mean age 54.5±10.74, PCI 15±5, duration of surgery 9.6±1.2 hrs. The mean drop in PCI who completed 3 PIPAC with IV chemotherapy was 10±3. Out of 45 patients nearly 60% showed PRGS 1, 25% PRGS 2 and 15% PRGS 3. 30.4% had total peritonectomy, 12.7% had multivisceral resection, 30% required diaphgramatic resections, 25%required mesentric stripping, 45.8% had one bowel resections and stoma rate was 4.5%. Overall G3-G5 morbidity was 25.4% with major ones being post-operative intra-abdominal collection (21.8%), electrolyte imbalance (16.4%), pulmonary (16.4%) followed by hematological (12.7%). The 30 day mortality was 3.8%. During PIPAC + IV chemotherapy no significant grade 3-4 morbidity was seen. Conclusions: Neo-adjuvant PIPAC with Intravenous chemotherapy might be a promising combination for inducing good response rates in advanced epithelial ovarian carcinoma. CRS-HIPEC following neo-adjuvant PIPAC + IV chemotherapy is safe, feasible and tolerable. PIPAC repeated every 4-5 weeks along with systemic chemotherapy provides a ideal scenario to monitor &amp; assess response to loco regional and systemic chemotherapy.
Unfolding the role of cell state on stress granule heterogeneity and function in pancreatic cancer.
Authors: Alexandra Redding
Journal: Journal of Clinical Oncology (2024)

e16357 Background: A major impediment to cancer therapy is the reality that cancer is a heterogeneous disease. A single tumor can consist of many genotypic or phenotypic profiles, which are marked by degrees of sensitivity to different therapeutics. Identifying and targeting origins of cancer cell heterogeneity is critical for predicting patient outcome and enhancing treatment efficacy. We observe a novel source of cancer cell heterogeneity that involves one of the largest stress-sensing platforms described to date: the stress granule (SG). Stress granules are non-membranous, cytoplasmic organelles that assemble in response to stress, and promote cell survival. Deregulation of SGs has been linked to several pathological conditions, including cancer, neurodegeneration, ischemia, and viral infections. SGs have been shown to promote tumor growth and metastasis, as well as contribute to mechanisms of chemo-resistance. Thus, these signaling hubs are emerging as a potential target in cancer. Methods: To induce SG formation, human pancreatic ductal adenocarcinoma (PDAC) cell lines were treated with sodium arsenite, thapsigargin, or exposed to hypoxic conditions. Immunoflourescent staining of core SG proteins was then conducted. To investigate cell cycle-driven mechanisms of SG heterogeneity, cell cycle stage was identified by expression of a Fluorescent ubiquitination-based cell cycle indicator (Fucci) lentiviral system. To investigate cPLA2’s role in SG formation, the chemical inhibitor Pyrrophenone, an shRNA targeting cPLA2, and an exogenous full-length or cleaved form of cPLA2, were used. In vivo, ES149 cells expressing Luciferase and the Fucci system were orthotopically implanted into C57BL/6 mice. Established tumors were treated every 3 days with Vehicle, Oxaliplatin, Pyrrophenone, or a combination of the latter. Tumor size was tracked via IVIS Spectrum. Fucci flourescence was used to identify cell cycle phase. SGs and cell death were assessed by immunoflourescent staining of tumors. Results: Cancer cells show a high degree of heterogeneity in their production of SGs. Cell cycle phase dictates SG heterogeneity. G2 phase cells have significantly higher levels of SG formation as compared cells in G1/S. This process is regulated by cleavage of the cPLA2 protein. Oxaliplatin administration increases G2 phase content in tumors. Co-treatment with Oxaliplatin and Pyrrophenone significantly decreases SG formation, increases cell death, and leads to tumor regressions in vivo. Conclusions: G2 phase cancer cells develop higher levels of SGs when exposed to stressful stimuli, as compared to G1/S phase counterparts. The cPLA2 protein is cleaved into a catalytically dead form that is present in G1/S phases, but absent in G2 phase. Oxaliplatin treatment in vivo leads to an increase in G2 phase tumor cells. When paired with cPLA2 inhibition, this results in increased cancer cell death and decreased tumor growth.
Identification of immune biomarkers in treatment-naive patients with metastatic pancreatic cancer treated with the GSK-3 inhibitor elraglusib (9-ING-41) in combination with gemcitabine/nab-paclitaxel in the 1801 phase 2 study.
Authors: Taylor Weiskittel, Austin Koukol, Caroline Kellinger, Leiqing Zhang, Benedito A. Carneiro, Hu Li, Andrey Ugolkov, Wafik S. El-Deiry, Andrew Paul Mazar
Journal: Journal of Clinical Oncology (2024)

e16331 Background: Elraglusib (9-ING-41), a potent and selective GSK-3 inhibitor, is a targeted anticancer agent with clinical activity in phase 1 trial and undergoing clinical development for the treatment of metastatic pancreatic ductal adenocarcinoma (mPDAC). Elraglusib (9-ING-41) displayed immune-modulatory activity in preclinical models and modulation of serum cytokine profile in clinical specimens. Here, we investigated the correlation between plasma levels of cytokines/chemokines/soluble cell receptors/growth factors (CCSG) and clinical outcomes of patients with mPDAC treated with elraglusib and gemcitabine/nab-paclitaxel (GnP) in an exploratory study. Methods: CCSGs were evaluated in the pre-dose plasma samples of patients with newly diagnosed mPDAC enrolled in the 1801 phase 2 study (NCT03678883) treated with GnP (n = 13) or elraglusib/GnP (n = 32). Using a Luminex immunoassay, 40 CCSGs were screened as predictive biomarkers of median overall survival (mOS) in the elraglusib/GnP arm using 5-fold cross-validation and maximally selected rank statistic cutpoint determination. A subset of CCSGs (n = 10) was remeasured using an MSD immunoassay with greater sensitivity. Maximally selected rank statistic cutpoint determinations were conducted using MSD results for elraglusib/GnP samples with mOS and median progression free survival (mPFS). P values &lt; 0.05 were considered statistically significant. Results: Luminex screening revealed several CCSGs significantly stratified elraglusib/GnP patients by mOS. IL-6 and IL-8 were identified as top candidates with stable and significant results on cross-validation. Using the MSD assay, both were confirmed to stratify elraglusib/GnP patients by OS and extended to analyze PFS. Low level of IL-8 conferred a better OS prognosis (HR: 0.0919, 95%, CI: 0.0205-0.411, P &lt; 0.001) than low IL-6 (HR: 0.205, 95%, CI: 0.063-0.665, P = 0.005) in the elraglusib/GnP treated patients. Correlations with mPFS were similar in the elraglusib/GnP patients for IL-6 (HR: 0.248, 95% CI: 0.072-0.848, P = 0.02) and IL-8 (HR: 0.297, 95%, CI: 0.111-0.743, P = 0.01). Conclusions: Preliminary results of our exploratory study identified low plasma levels of IL-6 and IL-8 prior to elraglusib/GnP treatment as potential predictive biomarkers associated with improved outcomes in previously untreated patients with mPDAC. The 1801 Part 3 Arm B clinical trial recruitment has been completed. We plan to analyze additional pre-dose plasma samples obtained from approximately 200 patients by April 2024. These will be analyzed using interim OS data available by April 2024 and included in the final presentation. Clinical trial information: NCT03678883 .
Correlation of significant delays and ethnic disparities in the receipt of treatment, palliative care, and supportive care interventions in pancreatic adenocarcinoma.
Authors: Aakash Rai Gupta, Jefferson Richards, Leo Sakai, Farris Al-Manaseer, Brian Nguyen, Ethan Miles, Gregory Michael Cote, Betty R. Ferrell, Maud Joachim-Celestin, Susanne Montgomery, Monica Saumoy, Mark Evan Reeves, Nikhil Ravi Thiruvengadam
Journal: Journal of Clinical Oncology (2024)

e16355 Background: In patients with pancreatic adenocarcinoma (PDAC), immediate treatment initiation is preferred. Early palliative care initiation has also improved quality of life and symptom burden. However, the timing of real-world treatment and palliative care initiation and possible ethnic disparities are not well understood. The objective of this study was to evaluate the timing of care initiation in a mainly Hispanic population of PDAC patients. Methods: We conducted a retrospective cohort study that included patients diagnosed with PDAC from 2014 to 2023 at Loma Linda University Health (the only tertiary care center for two large Hispanic-majority counties with large rural populations). Data were obtained on the presence and timing of appropriate provider referrals, care establishment, treatment, advanced care planning, and hospital admissions. We used a Wilcoxon rank-sum test to compare Hispanic and non-Hispanic patients regarding the time to treatment initiation and palliative care initiation. Results: 263 PDAC patients were identified (mean age 66, 57% female, 47% Hispanic, 67% head tumor, 78% stage III/IV). After diagnosis, 93% of patients were referred to medical oncology, 82% to surgical oncology, 61% to palliative care, and 30% to genetic testing. An advanced directive or physician orders for life-sustaining treatment was completed for 24% of patients. The time to care initiation is as follows: a median of 23 days (IQR 14, 54) from diagnosis to the first medical oncology visit, 13 days (IQR 6, 37) to the first surgical oncology visit, 73 days (IQR 24, 132) to the first palliative care visit and 133 days (IQR 47, 329) to hospice referral. 64% of hospice referrals were placed within the last two weeks of life. Hispanic patients had a significantly longer time to treatment initiation (68 days vs. 48 days, p= 0.008) but similar times to palliative care initiation (73 vs 74 days, p= 0.64). Hispanics also had a lower rate of completing genetic testing (45% to 66%, p= 0.07). Conclusions: In our retrospective cohort study, significant delays in establishing care with oncology, palliative care, and hospice initiation in patients with PDAC were noted. Low rates of advanced care planning were also noted despite guideline recommendations for early-focused symptomatic interventions and advanced care planning. Hispanic patients had significantly longer time to treatment initiation and lower rates of genetic testing. These results indicate a need for improved targeted patient care navigation for multidisciplinary PDAC management, particularly in Hispanic patients.