tbuckley/cabot-search huggingface dataset:
Therapeutic potential of immune-cold solid tumors through homologous recombination deficiency.
Authors: Gowhar Shafi, Aarthi Ramesh, Alain D'Souza, Sangeeta Prajapati, Bhagwat Jadhav, Kanchan Hariramani, Madhura Basavalingegowda, Vikas Leelavati Balasaheb Jadhav, Hrishita Kothavade, Fauzul Mobeen, Atul Bharde, Jayant Khandare
Journal: Journal of Clinical Oncology (2024)

e14585 Background: Genome-wide homologous recombination deficiency (HRD) score is an important parameter to select patients for HRR pathway inhibitors. HRD scores are independent therapeutic predictors unlike tumor mutation burden (TMB), and microsatellite instability (MSI) values to stratify tumors for predicting immunogenicity. Since solid tumors often choose the hallmark of immune evasion to disseminate to distant tissues, their identification and treatment through genomic signatures for immunotherapy is essential. Low TMB and MSI values are often associated with immune evasion and immune cold tumors. For such patients HRD scores can be important determinants to inform on the therapeutic potential of HRR pathway inhibitors and immune checkpoint inhibitors (ICI). In this study, we retrospectively investigated solid tumors with metastatic phenotypes exhibiting microsatellite stable (MSS), MSI-Low and TMB low phenotypes. The presence of HRR pathway deficiency in these patients may lead to chromosomal instabilities and cell surface neo-antigens thereby offering potential therapeutic benefit to PARP inhibitors and ICI. Methods: 53 metastatic cancer patients were retrospectively analysed for genome-wide HRD, TMB and MSI scores based on OncoIndx comprehensive gene panel (CGP). OncoIndx CGP targets 1080 cancer related genes along with 47 HRR genes and 1600 MSI signature sites. HRD, TMB and MSI scores were determined by sequencing the individual sample libraries in pair end mode on Illumina Nextseq platform (depth 5500X). Cutoff scores HRD high (≥50), TMB high (≥10 Mutations/MB), MSI high (≥20). Results: A cohort of 53 solid tumor patients were evaluated retrospectively of which 71.6% (n=38) patients showed metastasis (brain, Popliteal fossa, skeletal, and nodal metastasis). Of these, 9.4% (n=5) patients were detected with MSI-high, 56.6% (n=30) were MSI-Low and 1.8% (n=1) were MSS. 13.2% (n=7) patients were TMB-High, 3.7% (n=2) were TMB intermediate and 41.0% (n=22) were TMB-Low. Most importantly, 41.0% (n=22) patients were both MSI and TMB low thus transforming the tumor suggestively immune-cold. Only 22.7% (n=5) patients showed PD-L1 expression on IHC with scores ranging from TPS: 2% to 20%. In this dominantly immune-cold patient cohort, 40.9% (n=9) patients showed high/intermediate HRD (22.7% high (n=5); 18.18% Intermediate (n=4)). Conclusions: The presence of HRD in 40.9% patients in the dominant immune-cold patients was observed with increased chromosomal instability and cell surface neo-antigens. Thus, HRD could potentially transform tumors to become immune-hot to benefit from PARP inhibitors and ICI.
Prediction of immune-related adverse events in urological cancer during checkpoint inhibitor immunotherapy through immunohistochemical analysis of tumorous LCP1/ADPGK.
Authors: Liqing Xu, Yicen Ying, Kaiwei Yang, Qi Tang, Xuesong Li
Journal: Journal of Clinical Oncology (2024)

e14699 Background: The expanded utilization of immune checkpoint inhibitors (ICIs) have successfully improved the outcome of cancer patients, yet the concomitant immune-related adverse events (irAEs) can lead to fulminant unfavorable consequences. Currently, a comprehensive approach to predict irAEs is lacking. Some relevant biomarkers derived from database analyses are still in the early stages of investigation and lack robust validation in clinical samples, including LCP1/ADPGK. Herein, we validated the performance of LCP1 and ADPGK in a retrospective patient cohort with advanced urological cancers undergoing ICIs treatment, while comparing the predictive efficacy between different algorithmic models. Methods: We retrospectively collected clinical data of patients with renal cell carcinoma (RCC), upper urinary tract epithelial carcinoma (UTUC), bladder cancer (BC) receiving anti-PD-1/PD-L1 treatment from 2020 to 2023 in Peking University First Hospital. Patients were categorized into irAEs and non-irAEs groups, with irAE assessments conducted by two expert urological oncologists. Immunohistochemistry (IHC) was performed on 5-µm-thick pre-treated FFPE tumor tissue sections. Results: A total of 112 patients were included in the study, comprising 60 with RCC, 21 with UTUC, and 31 with BC. Among them, 51 (45.5%) patients experienced irAEs, with 9 exhibiting severe irAEs of grade III-IV. Immunohistochemical analysis revealed higher expression levels of LCP1 and ADPGK in patients with irAEs compared to those without irAEs. The area under the receiver-operating characteristic curve (AUC) for predicting irAEs using LCP1 and ADPGK individually was 0.82 (p &lt; 0.0001, 95%CI = 0.74-0.90) and 0.86 (p &lt; 0.0001, 95%CI = 0.80-0.93), respectively. The combination of LCP1 and ADPGK demonstrated an improved AUC of 0.89 (p &lt; 0.0001, 95%CI = 0.83-0.95). Among different algorithms, the bivariate linear-regression and the geometric mean model show similar prediction effects. Notably, the combined LCP1+ADPGK model successfully predicted irAEs in RCC (AUC = 0.89, p &lt; 0.0001, 95%CI = 0.81-0.98), UTUC (AUC = 0.81, p = 0.0063, 95%CI = 0.63-0.99), and BC (AUC = 0.88, p = 0.0004, 95%CI = 0.75-1.00). The expression of LCP1/ADPGK was not associated with the type of cancers. Conclusions: The bivariate linear-regression model of LCP1 and ADPGK could accurately predict irAEs in patients with urological cancers, which may allow us to improve the risk-benefit balance for individuals considered for ICIs therapy.
The effect of energy from reiki treatments on sleep quality for patients with breast and prostate cancer on hormone therapy.
Authors: Jeremy McGuire, Umang Gada, Chunkit Fung, Nikesha Gilmore, Michelle Christine Janelsins, Luke Joseph Peppone
Journal: Journal of Clinical Oncology (2024)

e24076 Background: Manypatients with cancer receiving hormone therapy experience difficulty with sleeping and insomnia. Reiki is a technique where therapy is delivered to the patient with either no or very light physical touch whereas traditional massage therapy uses pressure and movement by the therapist to manipulate soft tissue. Both Reiki and traditional massage therapy have been shown by others to be effective in providing benefits in sleep quality. This study is the first to compare changes in sleep quality after massage and Reiki treatments in patients with prostate and breast cancer receiving hormone therapy. Methods: Eighty-seven, breast (n = 56) and prostate cancer (n = 31), patients receiving hormone therapy experiencing self-reported fatigue ≥4/10were included in this randomized controlled trial (RCT). Patients were randomized into one of three treatment arms for 4-weeks: Arm 1 received two massage treatments, Arm 2 received two Reiki treatments and Arm 3 received four Reiki treatments. Each treatment session was approximately 75 minutes. . Participants with a baseline score of ( ≥8) on the ISI were included in this analysis. Results: 75% of all enrolled participants (n = 65) met the inclusion criteria for baseline clinically meaningful insomnia. Both Reiki and massage provided improvement in sleep quality from pre to post intervention and there was no difference between 2 and 4 Reiki sessions. Reiki significantly increased sleep quality (p &gt; .01) with a mean decrease in total ISI score of 2.96. Massage therapy showed a trend towards improved sleep quality (p = 0.06) with a mean decrease in ISI score of 1.95. There was a clinically meaningful decrease in total ISI score (≥6) in 15% of those who received massage therapy compared to 25% in the reiki therapy group. Conclusions: Four weeks of Reiki significantly improved sleep quality in patients with breast and prostate cancer receiving hormone therapy. Reiki may be a better non-pharmacologic therapeutic for improving sleep quality. Clinical trial information: NCT02758756 .
Effect of common medications on immune checkpoint inhibitor efficacy.
Authors: Virginia Falvello, Daria Brinzevich, Alex Bryant, Michael D Green
Journal: Journal of Clinical Oncology (2024)

e14710 Background: Previous studies have suggested that certain common medications could impact immune checkpoint inhibitor (ICI) efficacy and survival. These studies lacked non-ICI control groups, raising the possibility that survival differences could be explained by confounding. Methods: We developed a pan-cancer cohort of 27,998 patients who received ICIs in the national Veterans Health Administration (VHA) from 2010 to 2023. ICI patients were matched to 66,488 historical control patients treated with chemotherapy or targeted therapy before initial ICI regulatory approval in each cancer. We ascertained baseline use of drugs from 15 common medication classes within 1 year before therapy start and performed propensity-weighted Cox regression analyses to assess the impact of each medication class on overall survival (OS) and time to next treatment (TTNT). Interaction tests measured whether the impact of each medication class was significantly different in ICI versus historical control patients. Results: In the ICI cohort, the most common cancer types were NSCLC (46%) and melanoma (10%). After adjustment for multiple comparisons, only statins (adjusted hazard ratio [aHR] 0.93), PPIs (aHR 1.06), and loop diuretics (aHR 1.19) were associated with overall survival differences among ICI patients; nearly identical associations were observed in historical control patients (interaction p-values &gt; 0.4 for all; Table). Similar results were seen for TTNT and in sensitivity analyses limiting to more recent medication users. Conclusions: Common medications do not appear to impact ICI efficacy. Previously described survival effects are likely the result of confounding. [Table: see text]
Examination of in vitro and in vivo antitumor activity of PARP1 selective inhibitor D0112-005.
Authors: Li Li
Journal: Journal of Clinical Oncology (2024)

e15115 Background: The approved PARP inhibitors have demonstrated efficacy in ovarian, breast, prostate, and pancreatic cancers, particularly in homologous recombination repair (HRR)-deficient tumors, including BRCA mutant tumors. The severe hematological toxicity of first-generation PARPi in combination with chemotherapy is due to the lack of selectivity for PARP2. So, we developed selective PARP1 inhibitor D0112-005 with the aim to improve safety and efficacy. Methods: The selectivity of D0112-005 on PARP1, PARP2 was measured by chemiluminescent assay kit and PARP trap™ assay kit. The anti-proliferative ability of D0112-005 was evaluated by CCK-8 in BRCA mutant cell lines. In vivo anti-tumor effect of D0112-005 was evaluated in MDA-MB-436 BRCA1 mutant xenograft model. The potential for hematologic toxicity was evaluated in rats for 28 days repeat-dose and dogs for 14 days repeat-dose. Results: D0112-005 is a highly potent and selective inhibitor of PARP1 with 2000-fold selectivity for PARP1 over PARP2 and PARP3. D0112-005 trapped PARP1-DNA with an EC 50 value of 6.49 nM. In contrast, the EC 50 of PARP2-DNA trapping was 430μM. These data demonstrate that D0112-005 is a potent and selective PARP1 trapper. D0112-005 showed high anti-proliferation activity against BRCA mutant MDA-MB-436 and HCC1395 cell lines, with IC 50 values of 2.06 nM and 2.446 nM, respectively. In the MDA-MB-436 BRCA1m xenograft model, a dose-dependent anti-tumor effect was observed after 21 days administration, with TGIs of 38.77%, 106.7% and 111.73% at the dose of 0.1, 0.3 or 1 mg/kg once daily by oral, respectively. In the 1 mg/kg group, the anti-tumor efficacy was maintained after 14 days of drug withdrawal. D0112-005 showed well tolerance without bodyweight loss. In rat 28 days repeat dose study, D0112-005 100mg/kg had less changes on hematologic parameters compared with Olaparib. The main toxic reaction of D0112-005 (10mg/kg) was reversible thrombocytopenia in dog 14 days repeated toxicity study. Conclusions: D0112-005 potently and selectively inhibits PARP1 resulting in excellent anti-tumor activity in vivo and in vitro, which also good safety profile in the repeated toxicity study in rats and dogs.
<scp>STING</scp>/<scp>RANTES</scp> pathway in airway epithelium enhances <i>Der p1</i>‐induced airway inflammation
Authors: Mayoko Tsuji, Mitsuko Kondo, Akira Nishiyama, Tomohiko Tamura, Ayako Nakamura‐Ishizu, Miho Koizumi, Hiroaki Honda, Etsuko Tagaya
Journal: Allergy (2024)

Data sharing not applicable to this article as no datasets were generated or analysed during the current study. Appendix S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Addition of IL-6 and phosphate to the m-EASIX score and detection of ICANS and CRS progression.
Authors: Kenneth Barker, Tom Marco, Muhammad Husnain, Emmanuel Katsanis
Journal: Journal of Clinical Oncology (2024)

e14511 Background: Cytokine release syndrome (CRS) and immune cell associated neurotoxicity syndrome (ICANS) can be severe complications of CAR-T infusion. Both syndromes have been associated with endothelial dysfunction which prompted prior use of a modified version of the Endothelial Activation and Stress Index (m-EASIX) to predict the occurrence of severe grades of ICANS and CRS. Recent studies have linked low phosphorous (P) levels to both syndromes, and IL-6 is a known mediator of both. Our study aimed to enhance early prediction of CRS and ICANS by integrating both P and IL-6 into the m-EASIX score. Methods: This retrospective study included 44 patients (26 male and 18 female) ranging from 42 to 86 years old with non-Hodgkin's lymphoma presenting to the University of Arizona Cancer Center for CAR-T treatment. P, CRP, IL-6, and LDH were recorded up to 7 days before and 14 days after CAR-T infusion. All platelet levels were recorded the day of infusion. Variations of the m-EASIX score as outlined in table 1 were then calculated. The values of P were cubed to ensure relative differences in P had proportional consistency to differences in other values. The scores were then used to generate ROC curves for the occurrence of CRS, ICANS, and the progression of CRS to grade ≥2 with CI generated through the Wilson/Brown method. Results: Of the 44 patients, 21 developed CRS alone, 12 developed ICANS+CRS, and 11 developed neither. 18 patients had progression of CRS to grade ≥2. The median day of onset for CRS, ICANS, and progression of CRS to grade ≥2 was 2, 5, and 4 days respectively. Day 3 post infusion yielded the highest values of area under the curve (AUC) with each variation of the m-EASIX score statistically significant with a p&lt;0.001 as represented in table 1. The addition of P and IL-6 to the m-EASIX score increased AUC, sensitivity, and specificity for the occurrence of CRS, ICANS, and progression of CRS to grade ≥2. Conclusions: The inclusion of P and IL-6 in the m-EASIX score improved the sensitivity and specificity of detecting CRS, CRS progression, and the development of ICANS on the 3rd day post infusion. Larger scale studies investigating the efficacy of inclusion of P and IL-6 in the m-EASIX score in guiding early interventions to mitigate complications associated with CAR-T therapy are necessary. [Table: see text]
Interpectoral nodal dissection for invasive breast cancer: A retrospective single institution study from India.
Authors: Varadharajan Vijayakumar, Balasubramanian Venkitaraman, Suhaildeen Kajamohideen
Journal: Journal of Clinical Oncology (2024)

e12585 Background: Interpectoral lymph nodes are one of the axillary lymphatic drainage sites in breast carcinoma. Usually dissection of Interpectoral nodes (IPN) avoided during axillary dissection as they are not the primary lymphatic drainage site. Our study aims to identify the rate of positivity of Interpectoral nodes in invasive breast cancer, predictors of IPN positivity in relation to tumour location, size, grade and hormone receptor status and to evaluate the need for IPN clearance during axillary dissection. Methods: A retrospective analysis of histopathology reports of 367 patients who underwent Axillary dissection in a single centre from Jan 2017-Dec 2022 for breast cancer was analysed. Inclusion criteria: Female Patients with operable Invasive Breast cancer with node positive axilla who underwent axillary dissection (upfront and post chemotherapy). Exclusion criteria: metastatic breast cancer, node-negative patients/sentinel lymph node biopsy, inadequate nodal dissection, and incomplete clinicopathological information. Data was analysed looking for presence of nodes in interpectoral tissue in Axillary dissection and to identify the positivity of interpectoral lymph nodes in specimens. Results: Interpectoral nodal dissection was done in n=216 of the 367 patients. The clinicopathological characters are described in Table. IPN were identified in 35% (n=77) of the 216 Axillary dissection specimens. IPN were positive in 7.8% (17 of 216) of patients who had interpectoral nodal dissection. 22% of the interpectoral lymph nodes removed were positive. As regards tumour size, Rotter's nodes were identified commonly in T3 and T4 tumours and positive in people with N2 and N3 disease. By multivariate analysis, T stage and N stage were the most important determinants of IPN yield and positivity. Site of tumour, neoadjuvant therapy, molecular subtype or Ki 67 were not found to be associated with either presence or positivity of interpectoral nodes. In 5 cases IPN positivity upstaged the nodal stage and in 1 patient it was the only positive node. Conclusions: As IPN is positive in most LABC, whenever axillary dissection is done in such cases Interpectoral nodes can be safely removed while dissecting level III nodes. Nodal recurrence is the most common site of recurrence post mastectomy and hence Interpectoral nodes need to be routinely removed in patients undergoing Axillary dissection for operable breast cancer to enable accurate staging and to prevent local or systemic failure. [Table: see text]
Development of custom amplicon-based test systems for detecting KRAS, NRAS, and BRAF gene mutations in colorectal cancer using next-generation sequencing (NGS).
Authors: Julia Zhusina, Elena Aksenova, Kristina Larionova, Anastasiia Nikolaeva, Olesya Sluchanko, Andrey Vvedensky, Julia Bazhenova, Denis Pyankov, Sergey Korostelev
Journal: Journal of Clinical Oncology (2024)

e15061 Background: Polymerase chain reaction (PCR)-based mutation diagnostics in colorectal cancer is widely available. However, PCR has limitations in identifying rare mutations and precise mutation coordinates. Targeted sequencing, though promising, often incurs high costs and longer research durations, demanding higher DNA sample quality. Our study demonstrates the benefits of using a customized amplicon test system for diagnosing somatic mutations in tumor tissue, including detecting rare mutations not captured by PCR, requiring less input biomaterial, and similar research costs. Methods: A targeted NGS assay system was developed using region-specific primers for KRAS (exons 2, 3, and 4), NRAS (exons 2, 3, and 4), and BRAF (exon 15). Library preparation involved a three-step PCR process: Target PCR incorporating Illumina overhang adapter sequences, Index PCR introducing multiplexing indices and sequencing adapters, and PCR cleanup using magnetic beads. Sequencing utilized MiSeq v2 reagents with paired 300‐bp reads, generating high-quality, full-length reads. Validation included re-testing known samples. Tumor cell percentages in FFPE specimens were determined, and DNA was extracted using the QIAamp DNA FFPE Tissue Kit. Data analysis utilized proprietary software. Results: Out of 1234 samples, 1133 were tested, with mutations detected in 685 samples (60.45%). KRAS mutations were found in 548 (48.36%), NRAS mutations in 40 (3.5%), and BRAF mutations in 88 (7.7%) samples. Double mutations were observed in 9 samples (0.79%). Data on rare and double mutations are presented in the table. Conclusions: The developed test system accurately identifies essential mutations in colorectal cancer, including rare and potentially clinically significant variants. The required DNA amount ranged from 10 to 30 ng in 5 μl, nearly ten times less than well-known commercial PCR test systems like COBAS (Roche) and therascreen (QIAGEN). The cost of the study is comparable to PCR with a minimum study duration of 4 days. [Table: see text]
Transcriptome-based response predictor to identify potential responders among patients with negative standard markers for response to immune checkpoint blockers.
Authors: Gal Dinstag, Efrat Elis, Doreen S. Ben-Zvi, Anna Elia, Padma Sheila Rajagopal, Kenneth D. Aldape, Eytan Ruppin, Eli Pikarsky, Aron Popovtzer, Johnathan Arnon, Tuvik Beker, Ranit Aharonov
Journal: Journal of Clinical Oncology (2024)

2666 Background: Immune checkpoint blockers (ICB) are revolutionizing cancer treatment, and are being approved for an increasingly wide range of cancer types. The most common biomarkers currently in use to select patients for ICB are PD-L1 expression on tumor cells, as measured by IHC, and tumor mutational burden (TMB) and microsatellite instability (MSI), both measured by NGS. However, some patients that are negative for these markers still respond to ICB. This calls for complementary biomarkers to better identify responders to ICB, especially in patients that are negative to current biomarkers. Here, we focus on predicting response to anti-PD1 in patients with negative PD-L1, TMB or MSI. Methods: We employ ENLIGHT, our transcriptome-based precision oncology platform, which identifies and utilizes clinically relevant genetic interactions to predict a patient’s response to a wide range of targeted drugs, including ICB. ENLIGHT generates an individual ICB response score calculated from a 10-gene expression signature - the ENLIGHT Matching Score (EMS). Patients with EMS above a predetermined threshold are considered matched by ENLIGHT to anti-PD-1 treatments. We have previously shown, based on more than 1000 cases analyzed retrospectively, that this signature can identify responders to anti-PD-1 with high accuracy. Here, we use ENLIGHT to perform a retrospective analysis of 125 cases from three different datasets, who had low PD-L1 presentation (&lt;1%), low TMB (&lt; 10) or microsatellite stable tumors (MSS), and were treated with anti-PD-1, to specifically assess ENLIGHT’s performance in this biomarker-negative sub-population. Results: Patients who responded to anti-PD-1 treatments had significantly higher EMS in all three datasets. Correspondingly, ENLIGHT is highly predictive of response to anti-PD-1 in patients with negative ICB markers in the three datasets (ROC AUCs of 0.80, 0.84, 0.77, respectively, for low PDL1, low TMB and MSS). It is important to note that ENLIGHT was not trained on any of these datasets, and is applied as-is using previously published parameters. Overall, we find that patients who are ENLIGHT-Matched to anti-PD1 in this biomarker-negative cohort are almost 3 times more likely to respond than patients who are not (31% vs. 11%, p=5e-13). Conclusions: ENLIGHT is a powerful tool for predicting response to anti-PD-1 treatment in patients with negative standard biomarkers for ICB, a currently unmet need with considerable clinical importance.
Antibody drug conjugate, a level-up version of monoclonal antibody?
Authors: Yuqi Yang, Yue Zheng, Xu Sun, Ailin Zhao, Yijun Wu
Journal: International Journal of Surgery (2024)

Yang, Yuqi MBBS; Zheng, Yue MD; Sun, Xu MD; Zhao, Ailin MD; Wu, Yijun MD Author Information