tbuckley/cabot-search huggingface dataset:
Phase Ib trial of durvalumab plus tremelimumab in combination with particle therapy in patients with advanced hepatocellular carcinoma with macrovascular invasion: DEPARTURE trial.
Authors: Keisuke Koroki, Sadahisa Ogasawara, Hirokazu Makishima, Masaru Wakatsuki, Asahi Takahashi, Hiroaki Kanzaki, Kazufumi Kobayashi, Masanori Inoue, Soichiro Kiyono, Masato Nakamura, Naoya Kanogawa, Takayuki Kondo, Shingo Nakamoto, Yuki Shiko, Yoshihito Ozawa, Yosuke Inaba, Tomoya Kurokawa, Hideki Hanaoka, Shigeru Yamada, Naoya Kato
Journal: Journal of Clinical Oncology (2024)

34 Background: The HIMALAYA trial established the combination of durvalumab and tremelimumab (STRIDE) as first-line treatment for advanced hepatocellular carcinoma (HCC). Carbon ion radiotherapy (C-ion RT) allows precise tumor targeting while sparing nearby normal tissue. Our strategy used C-ion RT to target a key tumor with macrovascular invasion (MVI) for disease management and potential MVI control, complemented by STRIDE. Recognising that C-ion RT stimulates immune responses, we posited that merging C-ion RT with STRIDE might enhance therapeutic effects. We present updated data of additional follow-up. Methods: This is a Phase Ib, multicenter study evaluating durvalumab with particle beam radiotherapy in HCC patients with MVI (Cohort A) and STRIDE (Cohort B). Both cohorts began with patients resistant to standard treatments. After safety confirmation, the study expanded to include therapy-naïve patients, totaling 15. C-ion RT begins after day 8 of the first cycle, following the initial drug dose. The relative biological effectiveness weighted dose is set at 60 Gy in four fractions over one week, targeting one representative intrahepatic nodule with MVI. The primary endpoint is adverse event rates, including dose limiting toxicity (DLT), with secondary endpoints on progression free survival (PFS) and overall survival (OS) (jRCT2031210046). This analysis of OS was conducted from the additional follow-up data from the primary analysis. Results: From July 2021 to January 2023, 15 advanced HCC patients were enrolled in our study (Cohort A: 3, Cohort B: 12). Four in Cohort B were systemic therapy-naïve. All cases confirmed MVI radiologically; with tumor invasion observed in the main portal vein for 4 patients and in the inferior vena cava for one. DLT evaluations in 3 from each cohort showed no incidents. While Cohort A had no adverse events, 4 patients in Cohort B (26.7%) experienced serious treatment-related adverse events. The median PFS was a significant 4.67 months (95%CI, 1.35–6.64). At the clinical cut-off date of March 31, 2024, 10 OS events were observed. The median OS was 10.4 months (95% CI, 5.6–15.2), and the 6- and 12-month OS rates were 66.7% and 46.7%, respectively. Conclusions: The safety of STRIDE in combination with particle therapy has been confirmed in advanced HCC with MVI. This combination, especially the irradiation of tumors with MVI using C-ion RT, holds promise in managing prognostic determinant tumors and potentially enhancing OS. Clinical trial information: jRCT2031210046 .
Exploratory phase I study of HF1K16 for the treatment of patients with refractory/recurrent advanced glioma.
Authors: Ruofan Huang, Anjie Zheng, Yuhong Xu, Xiaochen Zhang, Jinsong Wu
Journal: Journal of Clinical Oncology (2024)

TPS32 Background: Glioblastoma (GBM) is the most common primary and aggressive malignant brain tumor in adults. Almost all patients with glioblastoma eventually have disease relapse and the median overall survival (OS) remains at only 30 weeks for those recurrent GBM patients. However, very few therapies had been approved over the past two decades, emphasizing the need for novel treatments. It is now wildly acknowledged that the immune microenvironment in brain offers adequate opportunities to implement immunotherapy for the treatment. Since most recurrent tumors had previously been exposed to the genotoxic stress of irradiation and/or chemotherapy, it is predicted to resulted in a higher mutational load and more immunogenic. However, The limited success of T cell immunomodulatory approach for advanced glioma has prompted a deeper understanding of the brain tumor and the immune microenvironment. GBM tumors are well-appreciated to be a immunosuppressive and a hallmark of GBM immunosuppression is the appearance of circulating myeloid-derived suppressor cells (MDSCs) at higher levels. Our preliminary data suggests that HF1K16, a liposome ATRA (all trans retinoic acid) suspension, is capable of relieving immune suppression induced by MDSCs. Further, we recently completed a phase I dose escalation study which showed that HF1K16 is safe, well-tolerated with preliminary efficacy in brain tumor. Thus, we hypothesized that HF1K16 may reverse GBM-associated immune suppression and leading to an increase in TILs and improved survival. Methods: This is an advanced glioma-specific expansion arm for adult patients with prior confirmed brain tumor and failed standard treatment. We plan to enroll 20~30 evaluable patients. Key eligibility criteria include candidates age ≥ 18 years, Karnofsky performance status ≥ 60 with and at least one measurable lesion. The primary endpoint is determination of overall response rate (ORR), duration of response (DOR), disease control rate (DCR) and progression-free survival (PFS) according to RANO criteria. Secondary endpoints include longitudinal assessment of the peripheral immune response by changes in MDSC and T cell subsets and numbers. HF1K16 infusions were administered in 21-day cycles (q.o.d days 1-14). Prior to and during treatment, peripheral blood mononuclear cells were collected and analyzed with flow cytometry to monitor the changes in myeloid cell phenotype and T cell composition. The recruitment of patients is anticipated completed in 2024. Clinical trial information: NCT05388487 .
First implementation of artificial intelligence empowered all-in-one radiotherapy workflow for nasopharyngeal carcinoma.
Authors: Guan-Qun Zhou, Yu-Xian Yang, Xin Yang, Xiao-Bo Jiang, Li Lin, Guang-Yu Wang, Wen-Zhao Sun, Kang Zhang, Bing-Huan Li, Hua Li, Le-Cheng Jia, Zi-Quan Wei, Yan-Fei Liu, Dan-Ning Fu, Jun-Xiang Tang, Wei Zhang, Jing-Jie Zhou, Chi Feng, Xiao-Yan Huang, Ying Sun
Journal: Journal of Clinical Oncology (2024)

134 Background: To establish an artificial intelligence (AI)-empowered All-In-One (AIO) workflow for providing one-stop radiotherapy to patients with nasopharyngeal carcinoma (NPC), and evaluate its feasibility and performance. Methods: The NPC-specific AIO workflow operates on a CT-integrated linac and integrates AI contouring and AI planning modules. A 3D U-net was employed for contours generation and 3D dose distribution. Knowledge-based planning approach and a protocol-based approach were used for plan optimization. MRI datasets with contours of primary gross tumors, CT datasets with contours of targets and organs at risk, and radiotherapy treatment planning datasets were collected from 877, 139, and 243 patients, respectively, for the training, validation, and testing of AI contouring and planning models. The NPC-specific AIO workflow underwent real-world clinical testing with an end-to-end evaluation involving 120 patients with NPC. The technical characteristics, implementation procedures and performance of AIO workflow were described and evaluated. Results: From March 2022 to October 2023, 120 patients with newly-diagnosed, non-metastatic NPC underwent AIO workflow, and 117 patients completed it in a median time of 23.2 min (range: 16.3 to 45.8 min). Median translation motions were 0.2 mm (CT scan to planning approval) and 0.1 mm (during beam delivery). AI-generated contours required little revision for clinical target volume (CTV1) and organs at risk (OARs), minor revision for cervical lymph nodes (GTVn) and clinical target volume (CTV2), with median Dice similarity coefficients (DSCs) of 0.98 and 0.94, respectively; more revision for GTVp, with a median DSC of 0.84. Of the 117 AI-generated plannings, 108 (92.3%) passed after initial auto-optimization. Volumes receiving ≥ 100% of the prescribed dose for all planning target volumes was ≥ 97.8%. Mean dosimetric parameters met dose constraints for all OARs except the thyroid and submandibulars. One patient died from acute renal failure after 10 fractions of radiotherapy. At week 12 after radiotherapy completion, 115 patients achieved complete response;1 had stable disease. Grade 3-4 acute effects were reported by 54 of 115 patients (36%). Conclusions: We successfully established an AI-empowered AIO workflow for initial radiotherapy of NPC, confirming its feasibility and safety for clinical application.
A roadmap towards improving outcomes in multiple myeloma
Authors: Mohamad Mohty, Thierry Facon, Florent Malard, Jean-Luc Harousseau
Journal: Blood Cancer Journal (2024)

Multiple myeloma (MM) is a chronic hematologic malignancy that remains incurable, because most patients eventually relapse or become refractory to current treatments. MM is a major health problem, with a globally increasing incidence. While, increase in the choice of MM treatment, including new immunotherapies (bispecific monoclonal antibodies and chimeric antigen receptor (CAR)-T cell therapy), may allow to further improve MM patients' outcomes, some non-therapy-related key issues may represent a pre-requisite towards improving MM outcomes in the next few years. This includes, the necessity of real-world evidence data, of a better definition of frailty, of a dynamic disease risk assessment, of a better definition of high-risk disease, broader accessibility to novel drugs, and to ensure diversity and representation of underrepresented groups. These key issues will be discussed in the current perspective review.
Cryoablation versus transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma with lenvatinib from a real-world study.
Authors: Xiujuan Chang, Di Wang, Wei Zhang, Jiagan Huang, Zhen Zeng
Journal: Journal of Clinical Oncology (2024)

54 Background: Hepatocellular carcinoma (HCC) is characterized by hypovascularity, the efficacy of transcatheter arterial chemoembolization (TACE) has been suboptimal. This study sought to evaluate and compare the efficacy and safety profiles of cryoablation (CRYO) plus lenvatinib (LEN) against TACE plus LEN for unresectable hepatocellular carcinoma (u-HCC) patients within a real-world clinical practice. Methods: A prospective study was conducted involving 234 patients with u-HCC who underwent treatment with LEN plus either CRYO or TACE at the Fifth Medical Center of the Chinese PLA General Hospital from October 2018 to May 2023. Treatment selection was determined through multidisciplinary discussions among a liver cancer board, weighing the pros and cons. The final decision was made by the patients and clinicians based on consensus. Clinical characteristics were balanced using propensity score matching (PSM). The primary endpoint was overall survival (OS), while secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Tumor response was based on RECIST v1.1 and mRECIST by blinded independent imaging review, AEs by CTCAE v5.0. Results: In this study, 212 (90.6%) were male, with an average age of 56 years. 206 (88%) patients were infected with hepatitis B virus (HBV), and 178 (76.1%) and 77 (32.9%) patients were classified as Child-Pugh A and BCLC B. After PSM, the clinical characteristics were comparable between the CRYO plus LEN and the TACE plus LEN group. Over a median follow-up of 31.8 months, 124 patients (53%) died. The CRYO plus LEN group demonstrated similar OS (24.2 vs. 22.0 months, P = 0.64), PFS (8.7 vs. 11.9 months, P = 0.48), ORR (53.1% vs. 53.1%, P = 1.00), and DCR (86.5% vs. 78.1%, P = 0.19) compared to the TACE plus LEN group after PSM, with consistent results observed before PSM. The two groups exhibited comparable AEs. In addition to similar LEN-related AEs, the most common CRYO-related AEs included 50% elevated ALT, 50% elevated AST, and 38.5% fever, which were consistent with the TACE related AEs. Notably, the incidence of abdominal pain was higher in the TACE plus LEN group compared to the CRYO plus LEN group (7.5% vs. 0.8%, P = 0.021), while pleural effusion was more prevalent in the CRYO plus LEN group than that in the TACE plus LEN group (6.2% vs. 0, P = 0.038). Conclusions: The CRYO plus LEN group exhibited comparable efficacy and well-tolerated safety with TACE plus LEN for u-HCC patients within a real-world clinical setting. It offers a viable alternative for HCC characterized by hypovascularity, presenting a promising therapeutic approach in the clinical management of u-HCC. Clinical trial information: ChiCTR2200058643 .
Sustained remission following finite duration bispecific antibody therapy in patients with relapsed/refractory myeloma
Authors: Rajshekhar Chakraborty, Heloise Cheruvalath, Anannya Patwari, Aniko Szabo, Carolina Schinke, Binod Dhakal, Suzanne Lentzsch, Anita D’Souza, Ghulam Rehman Mohyuddin, Kelley Julian, Shonali Midha, Patrick Costello, Martin Kaiser, Melissa Ng Liet Hing, Simon J. Harrison, Edward R. Scheffer Cliff, Meera Mohan
Journal: Blood Cancer Journal (2024)

Sustained remission following finite duration bispecific antibody therapy
Clinical outcome of patients hospitalized for pancreatic-biliary malignancy with comorbid acute decompensated heart failure: An analysis from National Inpatient Sample (NIS).
Authors: Thanathip Suenghataiphorn, Phuuwadith Wattanachayakul, Narathorn Kulthamrongsri, Sakditad Saowapa, Tuntanut Lohawatcharagul, Chalermkiat Kansuttiviwat, Jerapas Thongpiya, Pojsakorn Danpanichkul, Natapat Chaisidhivej
Journal: Journal of Clinical Oncology (2024)

81 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 &lt; 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 &lt; 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 &lt; 0.001), and heightened risk of acute kidney injury (aOR 1.57; 95% CI: 1.24, 1.99, p &lt; 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.
Real-world insights from comprehensive genomic profiling across multiple cancer types.
Authors: Ling-Jen Hung, Chen-Yang Huang, Jen-Shi Chen, Wen-Kuan Huang, Chih-Chung Hsu, Yueh-Fu Fang, Chih-Liang Wang, Ping-Chi Liu, Kun-Yun Yeh, Pei-Hung Chang, John Wen-Cheng Chang, Yung-Chang Lin, Shiu-Feng Huang, Wen-Chi Chou
Journal: Journal of Clinical Oncology (2024)

106 Background: This retrospective study was conducted to analyze tumor tissue profiling data to assess the potential of applying comprehensive genomic profiling (CGP) in patient care across diverse solid tumors. Methods: Patients with newly diagnosed or recurrent stage IIIB or IV lung adenocarcinoma with the null immunophenotype, esophageal, gastric, pancreatic, or bile duct cancer between January 2020 and July 2023 at two medical centers in Taiwan were included in the National Biobank Consortium of Taiwan project. The tumor samples were subjected to CGP using FoundationOneCDx, with therapeutic implications determined using OncoKB classification. Results: FoundationOneCDx testing of 574 patients was successful in 456 (79.4%) patients. Clinically actionable genomic alterations were detected in 21.1% (96/456) of the patients, including 17.5%, 2.9%, and 0.7% of patients at evidence levels 1, 2, and 3, respectively. Lung adenocarcinoma accounted for the largest proportion of samples with at least one actionable gene alteration (63.2%), followed by bile duct (26.9%), gastric (17.6%), esophageal (4.0%), and pancreatic (3.1%) cancer. Based on the CGP results, 43 patients (9.4%) received matched targeted therapy. The median overall survival of patients who received matched therapy or not was 26.1 months (95% confidence interval (CI), 16.7–35.5 months) and 10.6 months (95% CI, 8.1–13.1 months; hazard ratio, 0.28, 95% CI, 0.14–0.55, p &lt; 0.001), respectively. Conclusions: This study provides comprehensive insights into genomic profiling across diverse cancers in Taiwan, highlighting the crucial role of CGP in identifying actionable genomic alterations and guiding effective therapeutic strategies in real-world practice.
The role of P53 gene and p53 protein in non-Hodgkin malignant lymphoma.
Authors: Gabriel Petre Gorecki, Delia Nica-Badea, Aurelian Udristioiu
Journal: Journal of Clinical Oncology (2024)

TPS177 Background: Background and study aim P53 gene mutations are the most common genetic abnormalities of cancer. They have been extensively studied in various mature B-cell malignancies, including chronic lymphocytic leukemia (CLL). In recent years, more attention has been paid to the importance of the p53-expressed protein in CLL, and a combination with low survival and non-response to classical conventional chemotherapy, due to mutations in the p53 gene, with progression to Richter Syndrome. Identifying different p53 gene mutations is very important because these mutations have an impact on the patient's clinical course in CLL. Methods: The frequency of p-53 protein expression in 85 patients diagnosed with CLL was analyzed by the Enzyme-Linked Immune-Absorbent Assay (ELISA) technique to investigate the relationship of this protein to the stage of the disease, as well as the impact on response to treatment and survival. Cell extracts 10³×10³/L in 100 μl lysis buffer were applied to ELISA plates coated with PAb 240 capture antibody. Clinical trial information: ISRCTN12539707 .
Non-invasive minimal residual disease detection of liver cancer using circulating tumor DNA features and α-fetoprotein: A prospective study.
Authors: Yinyin Chang, Qingqi Ren, Shiyong Li, Liangliang Zhang, Yumin Feng, Guanghui Long, Mao Mao
Journal: Journal of Clinical Oncology (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 (P HCC ), was utilized to detect the cancer signal in each blood sample. MRD status determined by P HCC 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.
Quantitative evaluation of oncogenic KRAS signaling and therapeutic effects of molecular-targeted drugs in living cells by single-molecule imaging.
Authors: Ryoma Yokoi, Jesse Yu Tajima, Shigeru Kiyama, Yoshihiro Tanaka, Katsutoshi Murase, Manabu Futamura, Kenichi Suzuki, Nobuhisa Matsuhashi
Journal: Journal of Clinical Oncology (2024)

76 Background: Oncogenic KRAS mutations pose challenges due to their constitutive activation and resistance to drugs in colorectal cancer. However, several aspects remain unresolved. Single-molecule imaging has revealed distinct behaviors of KRAS. Inactive KRAS wild-type (WT) molecules exhibit continuous lateral diffusion on the plasma membrane, while activated or oncogenic KRAS molecules display slower diffusion and transient trapping due to interactions with signaling molecules. These observations suggest that the overall signal intensity of KRAS within a cell is finely regulated by integrating short-term pulse signals during transient trapping. Methods: We conducted single-molecule observations of KRAS (WT, G13D, and G12D/C/V) in living colon cancer cells, both with and without molecular-targeted drugs, before and after EGF stimulation. We quantitatively analyzed their diffusional behavior to evaluate KRAS signaling and the therapeutic effects of molecular-targeted drugs. Results: The temporal fraction of trapped KRAS WT was highest at 2 minutes (6.4%) and decreased to pre-activation level (3.0%) at 5 minutes after EGF stimulation. Although the temporal fractions of trapped KRAS mutants were higher than those of KRAS WT both before stimulation (5%) and after stimulation (10%), their diffusional behaviors were mutation-specific. The temporal fraction of trapped KRAS G13D increased sharply, and those of KRAS G12D and G12C increased at a moderate rate, while that of KRAS G12V did not elevate after EGF stimulation. Cetuximab treatment significantly reduced the temporal fraction of trapped KRAS WT after stimulation, but only moderately decreased those of KRAS mutants. Notably, transient trappings of KRAS G12D and G12C were abrogated by KRAS inhibitors, and the combined therapy of KRAS inhibitors and cetuximab demonstrated additive effects. Conclusions: Our findings indicate that the mutation-specific diffusional behavior of oncogenic KRAS can be quantitatively assessed by single-molecule imaging. This method serves as a powerful tool to uncover the mechanisms underlying oncogenic KRAS signaling and evaluate the therapeutic efficacy of molecular-targeted drugs in living cells.