tbuckley/cabot-search huggingface dataset:
Concurrent hyperthermic intraperitoneal chemotherapy and intraoperative radiotherapy with cytoreductive surgery in patients with rectal cancer with peritoneal carcinomatosis.
Authors: Tarek Arabi, Marwan Alaswad, Belal Nedal Sabbah, Abdullah Al Otry, Alwalid Hejazi, Aya Ismail, Heba Jaamour, Ziad Alhosainy, Samar Al Homoud, Ayman Azzam, Tarek Amin
Journal: Journal of Clinical Oncology (2024)

e15571 Background: Rectal cancer (RC) is often associated with peritoneal carcinomatosis (PC). Hyperthermic intraperitoneal chemotherapy (HIPEC) and intraoperative radiotherapy (IORT) have been shows to reduce recurrence and effectively treat PC across several cancers. However, little evidence is available regarding the concurrent use of HIPEC and IORT alongside cytoreductive surgery (CRS) in the literature. Methods: We retrospectively reviewed the medical records of RC patients with PC who received HIPEC plus IORT during CRS at the King Faisal Specialist Hospital and Research Centre. Demographic data, PC index (PCI), completeness of cytoreduction (CC), and tumor staging were collected. Overall survival (OS) was calculated from the time of surgery until death or last follow-up. Recurrence-free survival (RFS) was calculated from the time of surgery until recurrence or last follow-up. Unadjusted hazard ratios (HR) were used to determine the impact of parameters on OS or RFS. Results: 17 patients were included in our analysis. Basic demographic data can be found in Table 1. The most common operation performed was rectosigmoid resection in 7 (41.2%) patients, followed by low anterior resection in 6 (35.3%). The pT stage was T0 in 1 (5.9%), T4a in 7 (41.2%), and T4b in 9 (52.9%). The pN stage was N0 in 11 (64.7%), N1a in 1 (5.9%), N1b in 2 (11.8%), N1c in 2 (11.8%), and N2b in 1 (5.9%). There was positive resection margin in 2 patients. The PCI was ≤6 in 15 (88.2%), and the CC score was 0-1 in all patients. No patients had intraoperative complications. 12 (70.6%) received mitomycin C, 4 (23.5%) received cisplatin and mitomycin C, and one patient received a reduced dose of mitomycin C due to old age. 2 (11.8%) patients received two doses of IORT. 11 (64.7%) patients had postoperative complications, of which all were Clavein-Dindo grades 1-3b. Recurrence occurred in 11 (64.7%). The median OS was not reached, and the median RFS was 12 months. There were no parameters associated with OS. Male gender (HR: 7.7, 95% CI: 1.4-57.3), pM1 (HR: 4.5, 95% CI; 1.2-18.1), and perineural invasion (HR: 6.5, 95% CI: 1.2-49.3) were associated with poor RFS in univariate analysis. Conclusions: Incorporating HIPEC and IORT into CRS may be an effective treatment strategy for RC patients. Presence of distant metastasis and perineural invasion can be predictors of rapid recurrence. [Table: see text]
Efficacy and safety of neoadjuvant chemoradiotherapy combined with tislelizumab and thymalfasin in the treatment of locally advanced lower rectal cancer.
Authors: Hongwei Yao, Jiale Gao, Zhengyang Yang, Liting Sun, Pengyu Wei, Si Wu, Cong Meng, Rui Xu, Guangyong Chen, Guocong Wu, Zhigang Bai, Zhongtao Zhang
Journal: Journal of Clinical Oncology (2024)

e15612 Background: Thymalfasin, as an immunomodulator, can enhance the anti-tumor effects of T cells, NK cells, and macrophages. This study explored the efficacy and safety of a new adjuvant treatment regimen for rectal cancer, combining thymalfasin with chemoradiotherapy and the PD-1 inhibitor tislelizumab, and its impact on the immune microenvironment. Methods: This retrospective study enrolled 26 patients with locally advanced rectal cancer from March 2021 to December 2022. Thirteen patients received long-course concurrent chemoradiotherapy combined with concurrent tislelizumab treatment, and thirteen received thymalfasin combined with long-course chemoradiotherapy and concurrent tislelizumab treatment (radiotherapy: 50 Gy/25 f; capecitabine, 1000mg/m 2 , bid; tislelizumab: 200mg, every 21 days, 3 cycles; Thymalfasin: 1.6mg, biw). The postoperative pathological complete response rate (ypT0N0M0), tumor regression grade (AJCC 8 th Version), and adverse event (CTCAE 4.0) incidence were assessed, along with changes in the immune microenvironment before and after treatment using multiplex immunofluorescence staining. Results: The pathological complete response rates observed postoperatively were 61.5% in the treatment group, compared to 38.5% in the control group. The distribution of tumor regression grades 0, 1, 2, and 3 was 69.2%, 15.4%, 15.4%, 0% in the treatment group respectively, and 38.5%, 38.5%, 7.7%, 15.4%, in the control group respectively. The adverse event rates reached 84.6% in the treatment group and 76.9% in the control group, with all events classified as either grade 1 or 2 according to the CTCAE 4.0. Significant reductions in CD4+PD1+ cell density (p &lt; 0.001), CD8+PD1+ cell density (p = 0.024), CD68+ cell density (p = 0.007), the CD4/CD8 ratio (p &lt; 0.001), and the CD68+CD86+/CD68+CD163+ ratio (p = 0.012) were demonstrated through multiplex immunofluorescence following neoadjuvant treatment. The treatment group exhibited significant decreases in CD8+PD1+ cell density (p = 0.025) and CD68+CD163+ cell density (p = 0.021) when compared to the control group. Conclusions: Thymalfasin combined with chemoradiotherapy and tislelizumab as a neoadjuvant treatment regimen for patients with locally advanced lower rectal cancer has shown favorable efficacy and safety. Neoadjuvant chemoradiotherapy combined with immunotherapy restored T cell function and reduced the proportion of tumor-associated macrophages, but macrophages polarized towards an M2-like phenotype. Thymalfasin may play a role by synergizing with the PD-1 inhibitor to restore cytotoxic T cell function and block macrophage polarization towards M2 cells. Clinical trial information: NCT06024356 .
Synergistic cytotoxicity of histone deacetylase, poly-ADP ribose polymerase inhibitors and decitabine in breast and ovarian cancer cells: Therapeutic implications.
Authors: Apostolia Maria Tsimberidou, Benigno C. Valdez, Bin Yuan, Mehmet A. Baysal, Abhijit Chakraborty, Borje S. Andersson
Journal: Journal of Clinical Oncology (2024)

e15193 Background: Innovative strategies are needed for breast and ovarian cancer. We explored the synergistic cytotoxicity of histone deacetylase inhibitors (HDACi), poly(ADP-ribose) polymerase inhibitors (PARPi), and decitabine (DAC, D) in breast and ovarian cancer cells. The drugs affect epigenetic regulation and DNA repair, making them promising anticancer therapies. Methods: Breast (MDAMB231 and MCF-7) and ovarian (HEY-T30 and SKOV-3) cells were exposed to HDACi (panobinostat, Pano, P; vorinostat; Vori, V), PARPi (talazoparib, TLZ, T; olaparib, Ola, O) and DAC. Synergism was assessed by MTT and clonogenic assays. Changes in DNA damage response/repair markers were assessed with Western blotting. Results: The combinations of HDACi, PARPi, and DAC had synergistic effects in all cell lines, evidenced by combination index &lt;1. Clonogenic assay confirmed sensitivity of all cell lines to the 3-drug combinations (Pano, TLZ, DAC; Pano, Ola, DAC; Vori, TLZ, DAC; Vori, Ola, DAC). Cell proliferation was inhibited by 50% - 70%, and Annexin V positivity was 51% - 58% in all cells exposed to the combinations. Western blots showed inhibited protein PARylation, cleaved caspase 3 and PARP1 (suggestive of apoptosis), and down-regulated c-MYC. The 3-drug combinations induced more DNA damage (increased phosphorylation of ƔH2AX) than the individual drugs, impaired DNA repair (decreased ATM, BRCA1, ATRX proteins; Artemis), and altered gene expression (reduced NuRD complex subunits). DNA damage caused by HDACis and DAC may confer increased cellular dependence on protein PARylation, increasing sensitivity to combined HDACi, PARPi, and DAC. The P values comparing the inhibitory effects of each drug combination with that of individual drugs (MTT assay) are shown in Table ( P ≤ .05, statistically significant). Conclusions: The results support exploring HDACi, PARPi, and DAC combinations to overcome drug resistance and improve patient outcomes, and carefully designed clinical trials are warranted in breast and ovarian cancer. [Table: see text]
AURKA blockage as a strategy to overcome resistance to olaparib and platinum in high-grade ovarian cancer (HGOC).
Authors: Juan José Martínez-Pretel, Victoria Heredia, Miriam Ruiz Linuesa, Paloma Sanchez Serrano, Lidia Gonzalez Villena, Marta Mendiola, Andres Redondo, Begoña Pineda, Jose Alejandro Perez-Fidalgo
Journal: Journal of Clinical Oncology (2024)

e15198 Background: PARP inhibitors (PARPi) as olaparib (OLA) have become the new standard in maintenance treatment in high grade ovarian carcinoma (HGOC). Thus, there is an important need to identify the mechanisms for PARPi resistance and the strategies to overcome them. Our aim is to assess if in vitro inhibition of AURKA, a protein that plays a relevant role in centrosome spindle formation and mitotic regulation, might overcome olaparib resistance mechanisms in HGOC. Methods: Three HGOC cell lines (PEO1, Kuramochi and SKOV3) were selected, and isogenic resistant pairs generated in vitro, by pulsed exposure to OLA (PEO1-R) or by exposure to growing concentrations of OLA (Kuramochi-R and SKOV-R). AURKA expression was assessed by PCR and Western blot (WB). Cells were OLA-treated before and after the downregulation of AURKA expression by a specific small inhibitor RNA (siRNA) and by pharmacologic inhibition with alisertib. Cell viability was assessed by MTT assay and DNA damage by the evaluation of markers by WB. Combination index of the combo OLA+alisertib was assessed by Chou-Talalay method. Results: AURKA expression was lower at gene and protein levels in resistant cell lines compared to parental. Upon AURKA silencing (Si) of parental (OLA-sensitive) cell lines, no differences in the OLA IC50 values between AURKA-Si and control cells were seen. However AURKA-Si of the OLA-resistant cell lines was associated with a decreased in OLA IC50 as follows: 1) In PEO1R control scramble siRNA (sc) was 226 mM vs SI 128 mM, p &lt; 0.0001; 2) In Kuramochi-R scRNA 268.4 mM vs si 130.2 mM p &lt; 0.0001 and 3) in SKOV3-R scRNA 187 mM vs si 74.7 mM, p &lt; 0.0001 suggesting a role of AURKA-si in overcoming OLA-resistance. Pharmacologic AURKA targeting with the inhibitor alisertib in all 3 sensitive and resistant cell lines showed an increase of DNA damage measured by the expression of H2AX protein by WB. Combination index of the OLA+alisertib in all resistant cell lines showed a synergistic effect of the combination with PEO1-R FA50 = 0.25 (FA25-75 0.2-0.31), Kuramochi-R FA50 = 0.29 (0.19-9.36) and SKOV3-R FA50 = 0.24 (0.19-0.36). Conclusions: AURKA targeting either by silencing or pharmacologic inhibition increased OLA-induced apoptosis or had a synergistic effect in OLA-resistant cell lines suggesting AURKA as a potential target for overcoming OLA resistance.
Establishing optimized staining protocol and cutoff values of pan-TRK immunohistochemistry for detecting NTRK fusions in solid tumors: A Chinese multicenter cross-sectional study.
Authors: Shafei Wu, Yuchen Han, Zhihong Zhang, Gang Chen, Jian Wang, Wentao Yang, Bin Meng, Yan Sun, Yang Liu, Wencai Li, Shenglei Li, Lifeng Wang, Hongying Zhang, Lingchuan Guo, Yueping Liu, Xiaoding Liu, Ruping Hong, Kaimi Li, Zhiyong Liang
Journal: Journal of Clinical Oncology (2024)

e15160 Background: Using IHC to screen NTRK+ patients, followed by NGS confirmation, is a strategy recommended by ESMO guidelines. However, the current IHC staining protocol (Protocol) and cutoff value (CV) are suboptimal, resulting in limited screening performance. This study aims to optimize the Protocol and redefine the CV to improve the efficacy of pan-TRK IHC in screening NTRK fusions. Methods: 126 NTRK+ and 162 NTRK- solid tumor samples (spls), previously confirmed by NGS and/or FISH, were collected retrospectively from 12 hospitals across China in 2023. All spls were stained with VENTANA pan-TRK IHC assay by using two different Protocols: 1) the conventional one recommended by the manufacturer's instruction and 2) an amplification one that included additional amplification steps to enhance the staining. The IHC stained spls were interpreted based on the manufacturer's instruction, and the results were analyzed to calculate the CVs. The sensitivity, specificity, accuracy, PPV, and NPV based on these CVs and the CV reported in the literature were calculated. Results: 126 NTRK+ spls involve 25 fusion-partner types and 23 tumor types. IHC showed 35 NTRK- spls without staining, and 253 spls (126NTRK+/127NTRK-) stained. The staining predominantly localized to the cytoplasm and nucleus (132 cytoplasmic positive, 105 cytoplasmic and nuclear positive). Due to the limited samples with membrane staining, only CVs for cytoplasmic and nuclear staining were defined. In order to enhance the sensitivity and feasibility of the pan-TRK IHC assay in NTRK+ screening, the statistically calculated CVs were adjusted, and we recommended using the following CVs in clinical practice: 1) ≥1 intensity of cytoplasmic staining in ≥50% of tumor cells and/or 2) ≥1 intensity of nuclear staining in any percentage of tumor cells. Compared with the statistically calculated CVs, although the accuracy of the recommended CVs was slightly reduced (87.5% vs 93.75%), the sensitivity was improved (94.44% vs 89.68%). The sensitivity and specificity of the recommended CVs were higher than that of the previously reported CV (≥1%): sensitivity (94.44% vs. 87.9%) and specificity (82.1% vs. 81.1%). Conclusions: The pan-TRK IHC assay demonstrated high sensitivity while maintaining good specificity and accuracy, improving screening and enrichment efficacy for identifying NTRK fusions in solid tumors by utilizing the amplification protocol and the recommended CVs. Clinical trial information: ChiCTR2200066850 . [Table: see text]
Impact of breakthrough SARS-CoV-2 infections on vaccinated patients with colorectal cancer: A retrospective cohort study.
Authors: Hana Qasim, Saqr Alsakarneh, Ibrahim Khamees, Yazan Sallam, Mohammad Adam, Fouad Jaber
Journal: Journal of Clinical Oncology (2024)

e15656 Background: Cancer patients are vulnerable to severe SARS-COVID outcomes due to the immunosuppressive effect by both the inherent nature of cancer and its diverse therapeutic interventions. Although COVID-19 vaccines have shown efficacy, their effectiveness appears to decrease among cancer patients. We hypothesize that colorectal cancer (CRC) patients are at a higher risk of breakthrough COVID-19 infection and severe outcomes. Methods: We conducted a retrospective cohort study using TriNetX, a population-based database that sources data from electronic medical records (EHRs) of 61 health care organizations in the US. Using ICD-10 codes, we created two cohorts of patients with COVID-19: with CRC and without CRC. The primary aim was a composite outcome of hospitalization, emergency department (ED) visits, and mortality. Secondary aims of our study included risk of hospitalization, ED visits, critical care admission, intubation, and mortality, individually. We performed propensity score matching (PSM) of 44 variables to control for confounding. Odds ratio (OR) and 95% confidence interval (CI) were used to report associations for the propensity-matched cohorts. Results: In CRC patients, the composite outcome (ED visits, hospitalization, death) was 51.6% with breakthrough infections, higher than 44.3% in matched patients without CRC (aOR = 1.39; [95%CI: 1.17 - 1.53]). CRC patients had a significantly elevated cumulative event probability within 180 days (log-rank test, p &lt; 0.0001). Though mortality and critical care stay were similar, CRC patients had a higher risk of hospitalization (aOR = 1.3; [95%CI: 1.12 – 1.50]) and intubation (aOR = 1.79; [95%CI: 1.06 – 3.03]). In subgroup analysis, CRC patients had a higher composite outcome after 2 doses (aOR = 1.39; [95%CI: 1.17 - 1.53]) and 3 doses (aOR = 1.56; [95%CI: 1.26 - 1.95]). Those with 3 doses faced a higher risk of critical stay (aOR = 1.74; [95%CI: 1.06 – 2.86]). Younger CRC patients (16-64 years) with breakthrough infections were at higher risk of all-cause ED visits (aOR = 2.61; [95%CI: 1.73 - 3.94]). No significant differences were observed based on sex. Conclusions: Our retrospective study provides real-world evidence that CRC patients are at a higher risk of more severe outcomes after breakthrough COVID-19 infections. This may warrant a reevaluation of current preventive measures and the possible need for frequent booster vaccine doses for this patient population. [Table: see text]
AI-assisted colonoscopy in gastroenterology fellowship training: An interim analysis of a randomized controlled trial.
Authors: Niwen Kong, Patrick Chang, Denis Nguyen, Sarah Wang, Nisha Sharma, Maziar Amini, Justin Ong, Daniel Wang, Jennifer Dodge, Dara Bruce, Aileen Bui, Omar Bakr, John Kim, James Buxbaum
Journal: Journal of Clinical Oncology (2024)

e15642 Background: Artificial intelligence (AI) assisted colonoscopy may increase adenoma detection rates (ADR) for endoscopists, but its role for trainees in learning endoscopy has not been delineated. This randomized control trial explores the impact of AI on ADR by year of fellowship and anatomical location. Methods: In a registered randomized controlled trial (NCT05423964), gastroenterology fellows were assigned to AI (GI Genius, Medtronic; Minneapolis, MN) vs. conventional colonoscopy(CC). We included all symptomatic or screening colonoscopies with adequate bowel prep by trainees (postgraduate year 4-6). Baseline demographics, polyp pathology, size in 5mm increments, and location, and ADR was collected and compared for AI versus CC arms. A multivariate regression was used to identify factors influencing ADR of the right colon. Results: Of 685 colonoscopies between March 15 th to July 28 th , 2023, a total of 381 procedures performed by 17 fellows met criteria. Patient characteristics were similar between arms. In the CC arm, there was no difference in ADR among fellow years (1 st 39% vs. 2 nd 33% vs. 3 rd 36%, p = 0.63; Right colon: 1 st 31% vs 2 nd 21% vs 3 rd 30%, P = 0.21). Within 2 nd year fellows, there was higher ADR using AI vs. CC for screening colonoscopies (52% vs 17%, p = 0.025). In the right colon, ADR was significantly higher using AI vs. CC for screening alone colonoscopies within 1st and 2nd year fellows (1 st 50% vs 13%, p = 0.04; 2 nd 57% vs 9%, p &lt; 0.001). 2nd year fellows also increased ADR in the right colon using AI vs CC for symptomatic and screening colonoscopies (44% vs 21%, p = 0.001). There was no difference in procedural time with addition of AI, but a trend to longer withdrawal time. Multivariable logistic regression analysis also showed AI assisted colonoscopies was associated with enhanced ADR in right colon for trainees performing colonoscopy for symptomatic and screening (OR [95%CI]: 2 [1.3-3.3]) and screening alone (OR [95%CI]: 8.3 [2.5-26.6]). Conclusions: This randomized control trial shows AI assisted colonoscopies improve ADR, particularly in the right colon for postgraduate trainees. We propose a use case for AI assisted colonoscopy guiding targeted improvement of ADR in in the right colon which has been highlighted by the American Gastroenterology Association as an area of need. Clinical trial information: NCT05423964 . [Table: see text]
Stereotactic ablative radiotherapy combined with fruquintinib and tislelizumab in metastatic colorectal cancer: Updated findings from a single-arm, prospective phase II trial (RIFLE).
Authors: Yajie Chen, Kun Wang, Zhang Zhiyuan, Hui Zhang, Wang Yang, Ruiyan Wu, Menglong Zhou, Zhen Zhang, Fan Xia
Journal: Journal of Clinical Oncology (2024)

e15570 Background: Stereotactic ablative radiotherapy (SABR) has been shown to sensitize immunotherapy through inducing immunogenic death and remodeling the tumor immune microenvironment. In addition, anti-angiogenic therapy exhibits synergistic antitumor effects with PD-1/PD-L1 antibodies through its immunomodulatory effects for metastatic colorectal cancer (mCRC) patients. Here, we report the updated results from RIFLE trial: the efficacy and safety of the combination of fruquintinib, PD-1 inhibitor tislelizumab and SABR in mCRC patients. Methods: This is a single-center, single-arm, prospective phase II clinical trial (NCT04948034). mCRC patients with at least 2 measurable lesions (≥1 of which can be targeted with radiation and ≥1 lesion outside the radiation field) who have failed ≥ 1L standard therapy will receive SABR followed by fruquintinib (5 mg, d1-14, qd) and tislelizumab (200 mg, d1, q3w) within two weeks from completion of radiation. The percentage change from baseline in the sum of longest diameter of target lesions, consist of specified radiated and non-radiated lesions, will be assessed after at least 2 cycles’ drug treatment. Primary endpoint is best objective response rate (ORR) of target lesions. Secondary endpoints include disease control rate (DCR), duration of response (DoR), progression-free survival (PFS) rate, overall survival (OS) rate and toxicity. Results: From August 2021 to February 2024, 34 patients were included in the trial and 31 in the efficacy analysis. Median age was 62 years, 24 (77.4%) patients were male, 26 (83.9%) had ≥ 3 metastases, and 14 (45.2%) had received ≥ 3 prior lines of systemic therapy. The biological effective dose (BED) for irradiated lesions ranged from 37.5 to 105 Gy. Median study follow-up was 17.3 months (95%CI:13.841-20.759), 24 patients were alive and 13 remained on treatment. 1 patient achieved complete response (CR) for target lesions, 8 partial response (PR), 14 stable disease (SD), illustrating an ORR of 29% and a DCR of 74.2%. Median PFS was 8.8 months (95%CI:5.868-11.732). The most common treatment-related adverse events (TRAEs) were proteinuria (35.5%), hypertension (22.6%) and rash (19.4%). Grade 3-4 AEs occurred in 9 patients, including proteinuria and hypertension, and there were no treatment-related deaths. Conclusions: SABR combined with tislelizumab and fruquintinib shows promising effects and good safety in the treatment of metastatic colorectal cancer, which is expected to provide new therapeutic strategies and improve the prognosis for mCRC patients. Clinical trial information: NCT04948034 . [Table: see text]