tbuckley/cabot-search huggingface dataset:
Unveiling the influence of hyponatremia on morbidity, mortality, and resource utilization in colorectal carcinoma: Insights from a 5-year nationwide study.
Authors: Priya Hotwani, Vikash Kumar, Bhavyakumar Vachhani, Mrunanjali Gaddam, Jayalekshmi Jayakumar, Manasa Ginjupalli, Ankushi Sanghvi, Dhairya Nanavaty, Jincy Clement
Journal: Journal of Clinical Oncology (2024)

e15657 Background: Historically, Hyponatremia has been associated with higher mortality rates and longer hospital stays in patients with solid tumors. The existing literature contains limited information on the connection between hyponatremia and Colorectal cancer (CRC). Thus, our study aimed to assess the impact of hyponatremia on mortality, morbidity, and resource usage in patients with CRC. Methods: A retrospective analysis using the National Inpatient Sample database and International Classification of Diseases, Tenth Revision codes was conducted to examine the impact of hyponatremia on mortality, morbidity, and resource utilization in patients with CRC. Categorical variables were compared using chi-square tests, while continuous variables were compared using t-tests. Multivariable regression analyses were performed, adjusting for demographics, hospital-level characteristics, and relevant comorbidities. Confounding variables were adjusted using multivariate logistic and linear regression analyses. These included gender, race, Charlson Comorbidity Index, chronic kidney disease, congestive heart failure, cirrhosis, nephrotic syndrome, hypothyroidism, adrenal insufficiency, alcohol use disorder, and admission for hypovolemia or psychogenic polydipsia and various patient and hospital characteristics. Results: A total of 337,190 patients with a primary diagnosis of colon cancer were included in the study, of which 12.6% (3,369) presented with hyponatremia (Table 1). The in-hospital mortality rate was 7.8% for patients with hyponatremia, compared to 4.1% for patients without hyponatremia. After adjusting for confounding factors, hyponatremia was found to significantly increase the odds of mortality (adjusted odds ratio [aOR] for mortality 1.85, 95% confidence interval [CI]: 1.68–2.03, P &lt; 0.01). Patients with colon cancer and hyponatremia also had higher odds of developing sepsis (OR = 2.60), acute kidney injury (OR = 2.63), peritonitis (OR = 2.25), and ICU admission (OR = 2.12) (Table 1). Additionally, hyponatremia was associated with increased resource utilization, as evidenced by a longer mean length of stay and higher mean total hospital charges. Conclusions: This retrospective analysis demonstrated that hyponatremia significantly increases mortality, morbidity, and resource utilization in individuals with CRC. Patients with colorectal cancer and hyponatremia have substantially higher mortality rates, underscoring the importance of monitoring sodium levels and implementing appropriate interventions to prevent and manage this electrolyte imbalance. The high incidence rates of sepsis, acute kidney injury, and peritonitis, along with frequent ICU admissions, provide further evidence of the negative impact of hyponatremia on patient outcomes.
Hospitalization outcomes of patients with colorectal cancer (CRC) admitted with Clostridioides difficile colitis.
Authors: Aditya Sanjeevi, Samikchhya Keshary Bhandari, Himal Kharel, Zeni Kharel, Abdullah Ahmad Orakzai, Purva Shah, Basant Eltaher, Rashmi Verma, Aniket Rao, Chengu Niu, Daniel Idoate Domench
Journal: Journal of Clinical Oncology (2024)

e15649 Background: Clostridioides difficile colitis poses a significant healthcare burden and is a leading cause of diarrheal disease. Emerging studies have suggested that certain C. difficile strains may potentially drive colonic tumorigenesis and C. difficile was more frequently isolated from colorectal cancerous lesions compared to healthy tissue. In addition, cancer patients are more likely to receive antibiotics. These factors place CRC patients at a high risk of acquiring C. difficile infection. This national inpatient sample (NIS) study aims to study the hospitalization outcomes of patients with CRC admitted with C. difficile colitis. Methods: A retrospective analysis of the NIS database from 2016 to 2020 was conducted using International Classification of Diseases (ICD-10) codes to identify hospitalizations with C. difficile colitis. STATA version SE18.0 was used for statistical analysis. We used multivariate regression analysis to calculate the effect on mortality, length of stay, ileus and cost of hospitalization of colorectal cancer along with other variables as listed below. Results: There were 246685 hospitalizations with a primary diagnosis of C. difficile colitis. Among these, 2250 patients had a secondary diagnosis of colorectal cancer. Multivariate logistic regression showed that CRC was associated with increased mortality with odds ratio (OR) of 2.24 [95% confidence interval (CI) 1.13-4.44, p-value = 0.02], ileus (OR of 1.99, 95% CI 1.16-3.41, p-value = 0.01) and cost of hospitalization (10,585$ higher than patients without CRC, p-value = 0.001). CRC was not associated with increased length of stay (OR of 1.31, 95% CI 0.63-1.99). The effect of other pertinent variables is summarized in Table 1. Conclusions: Among the analyzed variables, we observed that colorectal cancer was associated with increased mortality, ileus and total cost of hospitalization in patients admitted with C. difficile colitis. Limitations of this study include failure of the multivariate model to account for other possible variables, coding errors and risk of bias due to the retrospective nature of data. [Table: see text]
Adjuvant donafenib for patients with hepatocellular carcinoma at high risk of recurrence following radical resection: A multi-center, retrospective study in China.
Authors: ShenYu Zhang, Guibing Yang, Ruipeng Song, Wei Wang, Fanzheng Meng, Dalong Yin, Jiabei Wang, Shugeng Zhang, Wei Cai, Yao Liu, Jizhou Wang, Dayong Luo, Lianxin Liu
Journal: Journal of Clinical Oncology (2024)

e15129 Background: The implementation of adjuvant therapy in reducing tumor recurrence of hepatocellular carcinoma (HCC) is an essential approach for extending the prognosis of patients. The exploration of treatment strategies that are both efficacious and secure remains a prominent area of research in recent years. Donafenib is a novel, oral, small-molecule, multikinase inhibitor, and has demonstrated promising efficacy and safety profiles in preclinical and clinical studies. However, there is currently a lack of reported data on the adjuvant donafenib for HCC following radical resection (R0). The present study aimed to explore the efficacy and safety of adjuvant donafenib for HCC patients at high risk of recurrence following R0. Methods: This retrospective study analyzed 196 patients who underwent R0 for HCC between April 2021 and October 2022. All patients exhibited at least one of the following high risk recurrence factors:① single lesion &gt; 5 cm or multiple lesions of any size; ② microvascular invasion (MVI); and ③ satellite nodules. Among these patients, 49 received donafenib, while 147 (control group) did not. In the donafenib group, donafenib was administered at a dose of 100 or 200 mg bid until tumor recurrence and serious adverse events (AEs). The 1-year and 2-year recurrence-free survival (RFS) rates and overall survival (OS) rates were compared between the two groups, as well as the incidence of adverse events (AEs) in the donafenib group. Inverse probability of treatment weighting (IPTW) was used. Results: The patient population consisted of 167 males and 29 females, with a median age of 59 (range 30-83). All patients exhibited a high risk of recurrence (number of tumors single/multiple, 167/29; tumor size within 5.0/above 5.0 cm, 78/118; MVI yes/no, 140/56; satellite nodules yes/no, 39/157). The median follow-up was 21.8 (range 3.8-32.0) months. Before IPTW, the donafenib group exhibited significantly higher 1-year and 2-year RFS rates compared to the control group (83.7%, 68.0% vs 66.7%, 47,6%, p = 0.023), while no significant difference in 1-year and 2-year OS rates (97.8%, 93.9% vs 91.8%, 80.6%, p = 0.120). After IPTW, the 1-year, 2-year RFS rates and OS rates were more favorable for the donafenib group compared to the control group (86.6%, 72.5% vs 64.8%, 45.0%, P = 0.004; 97.9%, 95.6% vs 89.5%, 77.9%, P = 0.043, respectively). In the donafenib group, AEs occurred in 44 patients, including 39 with grade 1 or 2 AEs and 5 with grade 3 AEs. The most common AEs included hand-foot skin reaction, decreased platelet count, and diarrhea. Conclusions: Adjuvant donafenib may improve RFS of HCC patients at high risk of recurrence following R0, while exhibiting favorable safety. This finding deserves further exploration.
Results of a first-in-human, dose-escalation phase 1 study of the ERK1/2 inhibitor ATG-017 in patients with advanced solid tumors.
Authors: Sara Wahlroos, Christina Teng, Ben Tran, Mark Voskoboynik, Hui Kong Gan, Andrew Spencer, Anupa Kudva, Ming Song, Kevin Lynch, Zhinuan Yu, Jayesh Desai, Charlotte Rose Lemech
Journal: Journal of Clinical Oncology (2024)

e15114 Background: This open-label, first-in-human, phase 1 study evaluates the safety, pharmacokinetics, and maximum tolerated dose (MTD) of ATG-017, an oral, potent, and highly selective inhibitor of ERK1/2, in patients with refractory advanced solid tumors. Methods: Twenty-one patients with solid tumors harboring activating alterations in the RAS-MAPK pathway were enrolled in the 3+3 design dose-escalation phase for continuous dosing: 5 mg QD (n=1), 5 mg BID (3), 10 mg BID (3), 20 mg BID (7), 30 mg BID (4), and 40 mg BID (3). Results: Safety: All patients reported at least 1 treatment-emergent adverse event (TEAE). Fourteen patients (66.7%) experienced serious adverse events. At 40mg BID, 2 of 3 patients experienced a dose-limiting toxicity (DLT) (grade 3 diarrhea and grade 3 retinopathy). At 30mg BID, 2 of 4 patients experienced a DLT (grade 3 acneiform dermatitis and grade 2 blurred vision). All DLTs resolved with drug interruption. At 20mg BID, a potentially biologically active dose, 7 patients were treated with no DLTs observed. At all dose levels, the most commonly observed TEAEs were consistent with previously reported toxicities with other ERK pathway inhibitors (gastrointestinal, skin, and ocular adverse events). Pharmacokinetics: Between 5mg BID and 30mg BID, exposure increased proportionally. At doses 20mg BID or higher, the concentration in the whole dosing interval (≥ 328ng/mL, geometric mean) was higher than the target concentration (231 ng/mL) for effective ERK inhibition derived from preclinical PK/PD models. Efficacy: Of the 21 treated patients, one patient (4.8%) with mesonephric-like ovarian adenocarcinoma (KRAS G12V mutation) in the 30 mg BID cohort achieved a best response of partial response (sustained for six cycles of treatment), and 8 (38%) patients were assessed as having stable disease (sustained over an average of five cycles), based on RECIST v1.1. Conclusions: In patients with solid tumors, 20mg BID continuous dosing of ATG-017 was identified as the MTD and delivers exposure that is likely to be active in inhibiting ERK. This dose is currently being explored in a dose expansion phase. A combination regimen with nivolumab is also being investigated. Clinical trial information: NCT04305249 .
DYRK1B blockade promotes tumoricidal macrophage activity in pancreatic cancer
Authors: Anna Brichkina, Miriam Ems, Roman Suezov, Rajeev Singh, Veronika Lutz, Felix S R Picard, Andrea Nist, Thorsten Stiewe, Johannes Graumann, Michael Daude, Wibke E Diederich, Florian Finkernagel, Ho-Ryun Chung, Detlef K Bartsch, Katrin Roth, Corinna Keber, Carsten Denkert, Magdalena Huber, Thomas M Gress, Matthias Lauth
Journal: Gut (2024)

Highly malignant pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant immunosuppressive and fibrotic tumour microenvironment (TME). Future therapeutic attempts will therefore demand the targeting of tumours and stromal compartments in order to be effective. Here we investigate whether dual specificity and tyrosine phosphorylation-regulated kinase 1B (DYRK1B) fulfil these criteria and represent a promising anticancer target in PDAC.
Acquired gene alteration patterns and post-progression survival: PARADIGM study analysis.
Authors: Hiroyuki Uetake, Riu Yamashita, Kohei Shitara, Takayuki Yoshino, Jun Watanabe, Hirofumi Yasui, Hisatsugu Ohori, Manabu Shiozawa, Kei Muro, Kentaro Yamazaki, Eiji Oki, Takeo Sato, Takeshi Naitoh, Yoshito Komatsu, Takeshi Kato, Junpei Soeda, Kouji Yamamoto, Kiwamu Akagi, Atsushi Ochiai, Katsuya Tsuchihara
Journal: Journal of Clinical Oncology (2024)

3507 Background: In the phase 3 PARADIGM trial (NCT02394795), adding panitumumab (PAN) to FOLFOX6 improved overall survival (OS) compared with bevacizumab (BEV) in patients (pts) with RASWT mCRC. In this exploratory analysis, we investigated the role of acquired gene alterations in pts who experienced progressive disease (PD) and the impact of these alterations on post-progression survival (PPS). Methods: PPS was defined as the interval from PD to death. Pre- and post-treatment cell-free DNA (cfDNA) was analyzed using the custom PlasmaSELECT-R 91 PGDx panel (NCT02394834). PFS, OS, and PPS were compared by patterns of acquired gene alterations. Results: Among the enrolled 802 pts, 390 discontinued treatment due to PD, of which 276 (70.8%) had evaluable pre- and post-treatment cfDNA samples (PAN, 126; BEV, 150). PAN pts with acquired RTK/RAS alterations had shorter PPS than those without alterations (13.2 vs 18.8 mo, HR 1.88 [95% CI: 1.28–2.76]) with the same trend in OS. BEV pts with acquired CIMP pathway alterations had shorter PPS than those without (14.9 vs 18.6 mo; HR 1.58 [1.09–2.29]); OS had similar results. Co-occurrence of gene alterations was more frequent in PAN vs BEV (overall 52.4% vs 43.3%, RTK/RAS gene co-alterations 25% vs 10%). Co-occurrence of gene alterations resulted in shorter PPS only in PAN pts. Conclusions: Distinctive patterns of acquired gene alterations were observed in PAN- and BEV-treated pts with PD. Co-occurrence of gene alterations, particularly in the RTK/ RAS pathway, was more prevalent with PAN than BEV. Clinical trial information: NCT02394834 .
Next-generation sequencing in patients with lung cancer undergoing immunotherapy: Retrospective analysis.
Authors: Akshee Batra, Atulya Aman Khosla, David Alejos, Jinah Kim, Sienna Searles, Akshit Chitkara, Karan Jatwani, Abhinav Vyas, Hibba tul Rehman, Shahid Sattar Ahmed, Rohit Singh
Journal: Journal of Clinical Oncology (2024)

e15071 Background: Identifying targetable oncogenic drivers and resistance mechanisms by Next-generation sequencing (NGS) is critical in Non-Small Cell Lung Cancer (NSCLC). Methods: We conducted a retrospective study at the University of Vermont Center to assess the utilization of NGS in NSCLC. We examined the medical records of NSCLC patients who received Immune Checkpoint Inhibitors (ICIs) as a first-line therapy between January 2017 and June 2022. We collected demographic data, including age, sex, ethnicity, cancer stage, NGS, mutations and survival data. Survival analysis was performed for the most common mutation by measuring the Hazard Ratio (HR) via Cox regression of different mutations compared to the whole cohort. Results: We identified 95 NSCLC patients with 52.6% males, 94.7% whites and a mean age of 63.4 years (Standard Deviation (SD): 11.34). 67.4 % received Pembrolizumab and 30.5% got Durvalumab. Most patients had stage 4 and stage 3 cancers, with 54.7% and 35.8%, respectively. Mean ECOG of 0.9 (SD: 0.7), 34% had average body mass index, and overall mortality was 41%. PD L1 expression and NGS were reported in 81% of cases. NGS was reported in 88.5% of stage 4 and 76.5% of stage 3 categories. 41.8% had a type of KRAS mutation, with KRAS p.G12C being the most common. 24.1% of cases had no mutation. The mean survival months ranged from 7.6 months in MET to 52.4 months in RET mutation. Survival analysis showed decreased mortality in EGFR mutation, as seen in Table. Conclusions: The rate of NGS testing at our rural academic center in Vermont is on the higher side of the national average NGS testing, but the turnaround time (TAT) of 28 days is suboptimal compared to NCI centers. Strategies to reduce TAT need to be implemented to get timely essential for tailoring therapies in patients with NSCLC. Further research is needed to explore the prognostic utility of mutations in NSCLC patients undergoing ICIs. [Table: see text]
Evaluating the significance of next-generation sequencing (NGS) testing in Indian patients with advanced malignancies: An observational study on clinical outcomes and treatment costs.
Authors: Pradnya Modak, Muthulingeshkumar K, Varsha Ravindra Bhandarkar, Poonam Maurya, Vishwanath Sathyanarayanan
Journal: Journal of Clinical Oncology (2024)

e15091 Background: The widespread use of Next-Generation Sequencing (NGS) panels to guide targeted therapy in advanced malignancies has raised questions regarding their real-world impact on clinical outcomes and affordability. Methods: This observational study included 126 patients, conducted between January 2022 and December 2023 aimed to assess the utility of NGS testing in both the initial and subsequent lines of treatment for Indian patients facing advanced malignancies. Results: In the first-line setting, NGS was extensively employed for patients with metastatic Colorectal Cancer (mCRC) and Non-Small Cell Lung Cancer (NSCLC). Analysis of RAS and BRAF mutations in mCRC patients (n=21) informed the choice between EGFR and VEGFR-directed therapy, resulting in a median Progression-Free Survival (PFS) of 7.5 months. In NSCLC patients (n=37), the NGS identified targetable mutations in 30 cases, leading to significantly improved mPFS (12 months vs 6 mo with chemotherapy alone). NGS was also employed for HRR, HRD and BRCA testing in advanced breast (n=45) and ovarian carcinoma (n=11), which helps in determining prognosis, role of targeted therapy and genetics. No adverse events noted till date. For patients undergoing subsequent lines of treatment (n=12), NGS detected targetable mutations in 9 cases. NGS revealed actionable mutations (ERBB2, CD74/NRG1fusion and KRAS12C mutation) in metastatic NSCLC patients (n=3), leading to appropriate treatment and PFS of 4-6 months. In metastatic NSCLC patients, T790M mutation was detected in 1 patient confering PFS of 6 months with change to Osimertinib and EGFR exon 20 insertion mutation detected in another, survival didn't improve with addition of amivantamab due to poor general condition. Alpelisib was started for PIK3CA mutation in metastatic Ca Breast (HR+,HEr2-), which was discontinued due to poor tolerance after 3 months. In Metastatic Neuroendocrine Carcinoma (NEC) Lung, detection of EGFR l858R mutation did not confer a PFS benefit despite the addition of Geftinib to chemotherapy. Due to financial constraints, targeted therapy couldn't be started for 2 patients with pathogenic target detected. Conclusions: The study's findings suggest that NGS testing offers tangible clinical benefits in both initial and subsequent lines of treatment for advanced malignancies in the Indian population. Despite the varying costs of NGS in India (ranging from 240 to 1800 USD), the data implies an overall affordability, making it a viable option for patients with advanced malignancies. However, NGS didn't improve outcomes in patients with rapidly progressing disease, poor general condition and financial constraints.
Serabelisib, sapanisertib (PIKTOR) and paclitaxel: A combinatorial approach to improve PI3K/mTOR/AKT pathway inhibition and treatment response in solid tumors.
Authors: David Starks, Petros A Tyrakis, Georgie Steele, Domen Kampjut, Deborah Chirnomas, Casey B. Williams, Oliver D. K. Maddocks
Journal: Journal of Clinical Oncology (2024)

e15134 Background: Despite high mutation rates in genes of the PI3K/mTOR/AKT pathway in cancer, therapeutic strategies to inhibit this pathway featuring single targeted therapies have achieved limited clinical success. An alternate approach inhibiting multiple parts of the pathway simultaneously demonstrated improved activity (Starks et al, GynOnc 2022). The Phase 1 study combined the targeted PI3K-alpha and mTOR inhibitors serabelisib and sapanisertib (PIKTOR) with paclitaxel showing reasonable safety and promising clinical efficacy in patients with advanced endometrial, breast and ovarian tumors that had progressed on prior taxane. The ORR was 47% including 3 complete responses, with a PFS of 11 months in 15 evaluable subjects (NCT03154294). We sought to better understand the mechanistic basis for the efficacy of this triplet drug combination in models of endometrial and breast cancer to support successful clinical development of this regimen. Methods: Signaling activity in PI3K/mTOR/AKT pathway was probed by western blot for phospho-S6 and phospho-4EBP1 in human endometrial and breast cancer cell lines with PI3K/mTOR/AKT mutations. Single and combinatorial dose-response curves were established for serabelisib, sapanisertib and paclitaxel versus FDA-approved pathway inhibitors. Mechanisms of cytotoxicity and paclitaxel sensitization were probed with cell death assays. The impact of single and combined agents on tumor growth was assessed with in vivo xenograft studies. Results: In human endometrial and breast cancer cell lines, the combination of serabelisib and sapanisertib achieved markedly improved PI3K/mTOR/AKT pathway inhibition versus FDA-approved single agents. Serabelisib and sapanisertib increased the cytotoxicity of paclitaxel, supporting prior work that identifies PI3K/mTOR/AKT pathway activation as a key mediator of taxane resistance. Further, interrogation of a range of clinically relevant doses and scheduling led to an optimized regimen in which serabelisib and sapanisertib substantially improved the response to paclitaxel in vivo. Conclusions: Simultaneous inhibition of PI3K-alpha, mTORC1 and mTORC2 with PIKTOR offers potential for superior PI3K/mTOR/AKT pathway inhibition, suggesting that rational drug combination approaches may offer two important benefits: (1) more complete PI3K/mTOR/AKT pathway inhibition by targeting multiple signaling nodes, and (2) greater tumor cell cytotoxicity by sensitization to taxanes. These data, combined with the promising efficacy and safety signal from PIKTOR plus paclitaxel in a Phase 1 trial (NCT03154294), provide a compelling rationale for further clinical investigation. Future studies will focus on tumors known to have high rates of PI3K mutations including gynecologic tumors where there is a high unmet need.