bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and efficacy of pressurized intraperitoneal aerosolized chemotherapy in appendiceal and colorectal cancer patients with peritoneal carcinomatosis: A first-in-US phase I study.
Authors: Raoof Mustafa , Frankel Paul Henry , Fakih Marwan , Chao Joseph , Lim Dean , Woo Yanghee , Paz Isaac Benjamin , Lew Michael , Cristea Mihaela C. , Rodriguez-Rodriguez Lorna , Fong Yuman , Solass Wiebke , Thomas Rebecca Meera , Chang Sue , Blakely Andrew M. , Whelan Richard L. , Deperalta Danielle , Reymond Marc A. , Merchea Amit , Dellinger Thanh Hue 
Published: January 2022

125 Background: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is being evaluated as a novel minimally invasive palliative treatment of peritoneal metastases (PM). Prior studies have established the feasibility and safety of repeated PIPAC treatments in gastrointestinal and gynecologic cancers. The goal of the present phase 1 trial was to establish the safety and feasibility of PIPAC oxaliplatin in a highly chemotherapy refractory colorectal and appendiceal cancer patient population. Methods: Patients with biopsy-proven peritoneal metastases from colorectal or appendiceal cancer underwent up to three PIPAC treatments using oxaliplatin (92 mg/m2) with a six-week interval at two academic centers. Patients with bowel obstruction, extra-peritoneal metastases, or poor performance status (ECOG>2) were excluded. PIPAC was nebulized over 5 min with a 30 min aerosol dwell time. Apart from the first PIPAC cycle, the patients also received a sensitizing dose of 5FU/LV (400mg/m2) within 24 hours of the procedure. Primary end point was safety as assessed by dose limiting toxicities within 6 weeks of the first PIPAC. Secondary endpoints included safety with the addition of 5FU/LV, efficacy, surgical morbidity, technical failure rate, progression-free and overall survival, pharmacokinetics (PK), and quality of life assessment. Results: A total of 8 patients were included: 5 colorectal; and 3 appendiceal. Median number of prior chemotherapy cycles was 2 (Interquartile range – IQR; 1.5-3.5). All patients were refractory to systemic oxaliplatin-based chemotherapy. Median time from diagnosis to PIPAC was 16 months (IQR; 5.6, 17.5) and Peritoneal Carcinomatosis Index was 29 (IQR; 20.5, 31.5). Five (62.5%) patients completed 3 PIPAC cycles while in 3 (37.5%) patients PIPAC was discontinued due to disease progression within the peritoneal cavity. No surgical complication or dose limiting toxicity was observed. Only one patient developed grade 3 treatment-related toxicity after first PIPAC (anemia), and another patient after second PIPAC (abdominal pain and anemia). At the completion of PIPAC treatment 5 patients had stable disease and 3 had disease progression. Pharmacokinetic, histologic response and preliminary survival data will be presented at the meeting. Conclusions: PIPAC with oxaliplatin is safe and feasible in a highly chemotherapy refractory cohort of appendiceal and colorectal carcinomatosis patients with or without sensitizing 5-FU/ LV. Clinical trial information: NCT04329494.
Intensification of local therapy with high-dose rate intraoperative radiation therapy (HDR-IORT) and extended resection for locally advanced and recurrent colorectal cancer.
Authors: Agas Ryan Anthony Francisco , Tan Jennifer , Xie Sophia , Van Dyk Sylvia , Heriot Alexander Graham , Ngan Samuel Y 
Published: January 2022

126 Background: This study reports our long-term experience with high dose rate intraoperative radiotherapy (HDR-IORT) in a single, quaternary institution. Methods: From 2004-2020, 138 consecutive patients with 141 total resections for locally advanced rectal cancer (LARC) (n=60, 43%) defined as T4Nx or T3N+ or locally recurrent rectal cancer (LRRC) (n=81, 57%) were retrospectively reviewed. The median age was 61 years (range 31-83) with 30 patients aged >70 years during surgery. Most patients had preoperative radiotherapy (RT) +/- concurrent chemotherapy (n=125). Thirty-two recurrent cancers received preoperative pelvic reirradiation to a median dose of 36 Gy (range 34.2 – 41.4). HDR-IORT was delivered using isotope iridium-192 in a remote afterloader, and a Freiburg applicator, after macroscopic resection of the tumour. A single 10 Gy fraction was delivered. Fifty-eight of 84 patients who underwent pelvic exenterations had >3 en bloc organs resected, and 96 patients underwent pelvic sidewall dissections. IORT sites included the primary tumour bed (33%), nodal regions (28%) and wider pelvic areas (70%). Resection margin status were R0 in 76 patients (54%) and R1 in 65 (46%). R1 resection was defined as positive (n=53) or close (n=12). R1 resection patients accounted for 61% of pelvic relapses. Results: With a median follow-up time of 4 years, 3-, 5-, and 7- year, overall survival (OS) rates were 75%, 48%, and 45%, respectively (84%,58%, 58% for LARC and 68%,39%, 35% for LRRC). Local progression-free survival (LPFS) of all patients were 88%, 85%, and 85%, respectively (97%, 93%, 93% for LARC and 80%, 80%, 80% for LRRC). On multivariable analysis, an R1 resection was associated with a trend toward poorer OS (p=0.05), while a trend towards worse LPFS (p=0.07) was noted for those without preoperative RT. The most common severe (grade ≥3) adverse events were postoperative abscess (n=25) and bowel obstruction (n=11). Overall, there were 49 (34%) grade 3-4 and no grade 5 adverse events. No intraoperative complications were attributed to IORT. The 30-day mortality rate was 0%. Conclusions: Favorable OS and LPFS can be achieved with intensive local therapy. As R1 resection may be associated with worse survival, optimisation of IORT, surgical resection, and systemic therapy are required. [Table: see text]
BREAKWATER safety lead-in (SLI): Encorafenib + cetuximab (EC) ± chemotherapy for first-line (1L) treatment (tx) of BRAF V600E-mutant (BRAFV600E) metastatic colorectal cancer (mCRC).
Authors: Kopetz Scott , Yoshino Takayuki , Kim Tae Won , Desai Jayesh , Yaeger Rona , Van Cutsem Eric , Ciardiello Fortunato , Wasan Harpreet Singh , Maughan Tim , Zhang Yuanyuan , Usari Tiziana , Chung Chin-Hee , Zhang Xiaosong , Tabernero Josep 
Published: January 2022

134 Background: Currently, there are no 1L tx options indicated specifically for patients (pts) with BRAFV600E mCRC. Based on results of BEACON CRC (NCT02928224), BRAF inhibitor encorafenib + EGFR inhibitor cetuximab was approved for tx of previously treated pts with BRAFV600E mCRC. BREAKWATER (NCT04607421), an ongoing, open-label, global, multicenter, randomized phase 3 study, evaluates 1L EC ± chemotherapy for tx of pts with BRAFV600E mCRC. Here we present preliminary data on safety and pharmacokinetics (PK) from the BREAKWATER SLI, which aimed to identify the chemotherapy backbone for EC for the phase 3 portion of BREAKWATER. Methods: SLI inclusion criteria were BRAFV600E mCRC (determined using tumor tissue or blood); evaluable disease (RECIST v1.1); ≤1 prior systemic tx for mCRC; European Cooperative Oncology Group performance status (ECOG PS) 0/1; and adequate bone marrow, hepatic, and renal function. Pts previously treated with BRAF/EGFR inhibitors or both oxaliplatin and irinotecan were excluded. Pts received encorafenib 300 mg daily + cetuximab 500 mg/m2 every 2 weeks (Q2W) + either FOLFIRI Q2W or mFOLFOX6 Q2W in 28-day cycles. The primary endpoint was frequency of dose-limiting toxicities (DLTs). PK were a secondary endpoint. Data cutoff date: Sep 13, 2021. Results: 57 pts were enrolled (EC + FOLFIRI, n = 30; EC + mFOLFOX6, n = 27). Median (range) age was 57 (28–78) years; 25% were Asian; 65% had ECOG PS 0; 37% had ≥3 organs involved; 58% were treatment naive. At cutoff date, tx was ongoing in 45 (79%) pts. Median (range) duration of tx for encorafenib in EC + FOLFIRI and EC + mFOLFOX6 was 15 (0–31) and 14 (0–27) weeks, respectively. One DLT was observed: grade 4 neutropenia in 1 pt in EC + FOLFIRI. Tx-emergent all-cause serious adverse events (AEs) occurred in 20% and 19% and grade ≥3 AEs in 33% and 56% of pts in EC + FOLFIRI and EC + mFOLFOX6, respectively. The table shows frequent (all grade in ≥30% pts or grade ≥3 in ≥10% with either tx) tx-emergent all-cause AEs. One pt died due to disease progression. In EC + FOLFIRI, in the presence of steady-state encorafenib, AUCinf of irinotecan and its active metabolite, SN-38, significantly decreased ̃25% and ̃40%, respectively, compared with values in the absence of encorafenib. In EC + mFOLFOX6, oxaliplatin PK was not significantly altered by steady-state encorafenib. Conclusions: Based on these data, BREAKWATER phase 3 will compare EC ± mFOLFOX6 with mFOLFOX6/FOLFOXIRI/CAPOX ± bevacizumab. Clinical trial information: NCT04607421. [Table: see text]
A pilot study to reliably measure the tissue concentration of mitomycin C after hyperthermic intraperitoneal chemotherapy in patients with gastrointestinal malignancies.
Authors: Kriley Isaac , Rozich Noah , Bellini Geoffrey , Papenfuss Wesley Allan , Anshus Emily , Schwind Analeah , Hribar Austin , Rehrauer Kyle , Castillo Uvidelio , Weese James L. , FACS Aaron Chevinsky 
Published: January 2022

138 Background: HIPEC with MMC is a treatment for gastrointestinal cancers metastatic to the peritoneal cavity. The pharmacokinetics of MMC in plasma, peritoneal fluid, and urine are described. The amount of MMC in intraabdominal tissues after HIPEC are not well described. The aim of this study is to evaluate if MMC concentrated in tissue samples after HIPEC by high performance liquid chromatography (HPLC) from patients with gastrointestinal neoplasms. Methods: HIPEC was performed at 40°C with 40mg of MMC for 90 minutes, after which the peritoneal cavity was flushed, anastomoses created as needed, and the wound closed. Eligible patients were treated at a single institution, ≥18 years old, and underwent HIPEC with MMC. Samples were taken of the omentum, peritoneum, liver core biopsy, tumor, and mesenteric fat before and after HIPEC. All patients signed informed consent. Samples were frozen in liquid nitrogen, minced, and sonicated in 500µL of phosphate buffered saline. The homogenized samples were centrifuged, and the supernatant was analyzed by HPLC for MMC. The HPLC was performed using a Dionex Ultimate 3000. Analysis was performed with a Kinetex - 5µm Biphenyl 100A  150 x 4.6mm column. MMC was detected with a Diode Array Detector 3000 with fixed UV at 365nm, 280nm, 254nm, and 210nm. The mobile phase used isocratic 40% acetonitrile and 60% water at 0.5 ml/min. The analysis volume was 10µL. Samples were blinded prior to analysis and analyzed in triplicate. Results: Thirteen patients were enrolled, 11 were female, the average age was 57 years (range: 30  85). Diagnoses were low-grade appendiceal mucinous neoplasm (7), high-grade appendiceal mucinous neoplasm (1), appendiceal adenocarcinoma (1), colon adenocarcinoma (1), colon mucinous adenocarcinoma (1), peritoneal mesothelioma (1), and small bowel mucinous adenocarcinoma (1). Complete tissue samples were available for 10 patients. Two patients had complete cytoreduction and did not have tumor for analysis after HIPEC. One patient refused liver biopsy. MMC was not detected in any sample prior to HIPEC. After HIPEC, MMC was most often detected in peritoneum (12 of 13 cases) and tumor (9 of 11). MMC was less often detected in omentum (5 of 13), mesenteric fat (2 of 13), or liver (1 of 12). Conclusions: MMC concentrated in 92% of peritoneal samples, 82% of tumor samples, and less often in liver tissue. MMC is hydrophilic which may contribute to the low detection rates in omentum and mesenteric fat. A reliable method to measure MMC concentration in normal and malignant tissues is novel and may have clinical implications. Our next steps are to expand the cohort of patients and evaluate whether tissue concentration is associated with clinical outcomes.
The immune impact of PI3K-AKT pathway inhibition in colorectal cancer.
Authors: Nusrat Maliha , Syed Muddassir Ali , Katkhuda Riham , Parra Edwin R. , Wistuba Ignacio Ivan , Kong Paul , Koehne Amanda , Dasari Arvind , Overman Michael J. , Menter David , Kopetz Scott 
Published: January 2022

154 Background: Our prior work has shown that PI3K-altered colorectal cancer (CRC), with PIK3CA mutation or PTEN loss, has increased expression of key immune checkpoints (including PD-L1) resulting in immune evasion, despite increased immune engagement. Here, we investigated the impact of PI3K-AKT inhibition on the immune repertoire of CRC. Methods: Multiplex immunofluorescence was performed using two Vectra panels [1: AE1/AE3, CD3, CD8, PD-1, PD-L1, CD68; and 2: AE1/AE3, CD3, CD8, Granzyme B (GzB), CD45RO, FoxP3] on paired biopsies (baseline and cycle 1 day 15) from 6 patients with PI3K-altered metastatic CRC (mCRC) treated with AKT inhibitor, MK2206 (200 mg oral weekly), on a phase 2 clinical trial. Separately, one million CT26 CRC cells were implanted in BALB/C-e mice. After 48 hours, 10 mice/group were randomized for treatment with pan-PI3K inhibitor copanlisib (C, 10 mg/Kg IV 2x/week), anti-PD-1 (P, 200 µg IP 2x/week), copanlisib + anti-PD-1 (C+P), or control (Ct), for 21 days. Mouse tumors were stained with 6-plex immunohistochemistry (CD3, CD8, PD-L1, Ki67, GzB, AE1/AE3). Data were analyzed using related-samples Wilcoxon Signed-Rank test, Mann-Whitney U test, Kruskal-Wallis test, and Student’s t-test, as appropriate. Results: In PI3K-altered mCRC patients, AKT inhibition resulted in a trend towards increased median densities of intratumoral CD8+ T cells (0.8 vs 4.8 density/mm2, P = 0.14) and memory T cells (0 vs 10.3, P = 0.07), and decreased density of macrophages (12.4 vs 0, P = 0.07). No antigen experienced T cells were seen and activated CD8+ T cells were present in 1 patient only. In CT26 mice, PI3K and PD-1 co-inhibition resulted in the smallest mean tumor volumes (C+P 12% of Ct vs C 40% and P 42% of Ct, P < 0.05 for both), and the highest median % of intratumoral CD8+Ki67+ T cells as compared to all other treatment arms (C+P 1.6% vs C 0.5%, P 0.4%, Ct 0.6%, P < 0.05 for each pairwise comparison). C+P also increased the % of total CD3+ and CD8+ cells as compared to Ct and C (P < 0.05 for all). C alone did not increase immune infiltration in this non-PI3K activated model. Conclusions: PI3K-AKT pathway inhibition has the potential to improve effector T cell infiltration in PI3K-altered CRC. PI3K inhibitor synergizes with anti-PD-1 to improve treatment efficacy and CD8+ T cell proliferation. The mechanisms behind this immune repertoire shift are yet to be elucidated, such as via cytokine modulation. Therapeutic approaches to activate the proliferating CD8+ cells would be useful, and may require PI3Kα/β specific inhibitors to allow early T cell activation through PI3Kδ/γ isoforms.
Association of circulating nucleosomes levels with FIT performance for advanced adenomas in a symptomatic population.
Authors: Chang Li-Chun , Herzog Marielle , Hardat Nathalie , Pamart Dorian , Chiu Han Mo 
Published: January 2022

170 Background: The effectiveness of screening using either fecal immunochemical testing (FIT) or colonoscopy in reducing colorectal cancer (CRC) mortality has been demonstrated in previous studies. Nevertheless, the single test sensitivity of FIT for relevant precursor lesions, especially high-risk neoplasms like invasive cancer or advanced adenomas (AA), is a concern. Improving the sensitivity for high-risk neoplasm is critical to improving the effectiveness of screening in reducing CRC incidence and mortality. Dysregulation of histone post-translational modifications (PTMs) has been linked with several cancers including CRC. We investigated the clinical performance of circulating nucleosome levels containing specific histone PTMs in blood, in combination with FIT from symptomatic subjects referred to colonoscopy to evaluate their discriminant power towards CRC and AA. Methods: 10mls whole blood was obtained prior to colonoscopy from 476 patients referred to colonoscopy in National Taiwan University Hospital for surveillance or secondary to bowel symptoms. Patients were classified into 5 groups based on their colonoscopy reports: (i) patient with CRC (n = 67), (ii) patients with AA (n = 60, including 22 with AA≥2cm); (iii) patients with non-AA (n = 123); (iv) patients with non-neoplastic polyps (n = 29); (vi) healthy controls with no endoscopic lesion (n = 197). Plasma samples were analyzed for nucleosome levels using 7 different quantitative immunoassays (Nu.Q assays; Belgian Volition SRL, Belgium) targeting H3.1-nucleosomes or different histone modifications (H3K27Me3-, H3K36Me3-, H3K9Me3-, H3K14Ac-, H3K27Ac- or H3R8Cit-nucleosomes). All study subjects were asked to collect a stool sample at home within 48-hours before the colonoscopy. The fecal samples were assayed with the OC-SENSOR FIT kit (Eiken Chemical Co., Ltd., Tokyo, Japan) for all subjects. Results: At a cut-off of 20µg/g feces, the FIT test showed a sensitivity of 83.5% at 82.1% specificity for CRC +AA vs. Controls. All the CRC patients were detected but 35% of AA were missed, and 7 of which were high-risk adenomas (AA≥2cm). A combination of 2 Nu.Q biomarkers: H3K36Me3 and H3K9Me3 with FIT in a decision tree model showed an improved sensitivity of 98.4% allowing the detection of all CRC patients and 97% of the patients with AA including all high-risk adenomas. The 2 missed AA were one AA below 1cm and one between 1 and 2cm. Unnecessary colonoscopies could be reduced by 28.9% of the control and 20.7% of the non-neoplastic polyps subgroups as both are found negative with this panel of assays. Conclusions: At present, all the symptomatic patients are sent to colonoscopy in clinical practice. Our results indicate that H3K36Me3- and H3K9Me3-nucleosome levels, in combination with FIT in a decision tree model, could detect all CRC patients and all high-risk adenomas and help reduce unnecessary colonoscopies.
Circulating microRNA: Searching for new players in assessment of therapy response in colorectal cancer patients.
Authors: Vymetalkova Veronika , Cervena Klara , Vodicka Pavel , Filip Stanislav 
Published: January 2022

183 Background: The identification of clinicopathological and molecular predictive and/or prognostic factors represents currently one the most challenging tasks in oncology. Significant efforts are currently being dedicated to identify patients who will or will not benefit from chemotherapy. In fact, drug resistance is a limiting factor of the efficacy of chemotherapy in colorectal cancer (CRC) treatment. However, despite modern surgical techniques and adjuvant systemic therapy, only 20% of patients with distant metastasis achieve long-term remission, while 60–70% of patients develop local or distant recurrence. Methods: Recently, we have identified by high-throughput approach that circulating microRNAs (miRNAs), namely, miR-122-5p and miR-142-5p show a high potential for CRC screening and early detection as well as for the assessment of patients’ outcomes and the effectiveness of treatment schedule. Results: In detail, the expression levels of these miRNAs were significantly different between CRC patients and controls. A year after diagnosis, miRNA expression profiles were significantly modified in patients responding to treatment and were no longer different from those measured in controls. On the other hand, patients not responding to therapy maintained low expression levels in their second sampling. As selection during metastasizing may shift molecular patterns by which CRC liver metastases retain their unique molecular profile, we thus elaborated our results on CRC patients with liver metastasis and measured these circulating miRNAs repeatedly over two years. The first sampling was performed at the time of post therapy developed liver metastasis (i.e., recurrence), and every 3 months depending on patients` conditions (i.e., covering the liver resection, administration of chemotherapy etc). Detailed results of the study will be presented during the meeting. Conclusions: The present study aimed to explain why patients with the same cancer stage may differ in treatment susceptibility and long-term outcomes.
Evaluation of SN-38 PK profile in patients with RAS wild-type metastatic colorectal cancer treated with a combination of SCO-101 and FOLFIRI.
Authors: Schou Jakob Hagen Vasehus , Roest Nicklas , Ladekarl Morten , Hansen Jens Bo Rode , Hedtjaern Maj , Vestlev Peter Michael 
Published: January 2022

185 Background: The FOLFIRI regimen (5-fluorouracil, leucovorin and irinotecan) is a predominant treatment regimen for metastatic colorectal cancer. To optimize the benefit for the patients, it would be desirable to increase the efficacy of irinotecan by increasing the exposure of SN-38 (the active metabolite of irinotecan) to the cancer cells, while maintaining a good safety profile. The oral drug SCO-101, that is currently being developed by Scandion Oncology A/S, was tested in an early clinical trial (CORIST-trial, ClinicalTrials.gov identifier: NCT04247256). SCO-101 is an inhibitor of ABCG2, UGT1A1 and SRPK1. The CORIST trial was set up to address the safety, tolerability, and efficacy of SCO-101 given orally for 6 days followed by FOLFIRI at varying doses from day 5 to 7, in a biweekly schedule, in patients with metastatic colorectal cancer who have formerly been treated with FOLFIRI and afterwards progressed. The first part of the study was a dose-finding study, where the impact of SCO-101 on the pharmacokinetics (PK) of SN-38 was studied. Methods: 12 patients from the dose-finding part of the CORIST study received 150 mg SCO-101 for 6 days and 45 – 80% of the recommended dose of FOLFIRI. 6 of the patients had RAS wild-type tumors and these patients are the subject of the current analysis. Blood for PK analysis was sampled from the patients at 1, 2, 4, 8, 24, 48, and 96 hours after treatment with FOLFIRI and SCO-101. The blood samples were analyzed for Cmax, T½ and AUC (0-24h) of SCO-101, irinotecan and SN-38. Results: The PK of SN-38 from the patients in the study, normalized to a dose of irinotecan of 90 mg/m2 showed a T½ day 5 of 19 hours (SD 5,7) a Cmax of 60 ng/ml (SD 20,6) and an AUC_0-24h of 1415 hxng/ml (SD: 670). The results were compared to SN-38 data from treatment with irinotecan at 180 mg/m2, which is used in standard doses of FOLFIRI and the data is presented in the table. The data analysis showed an increased T½, increased Cmax and increased AUC of SN-38 when combining SCO-101 with 90 mg/m2 irinotecan, compared to SN-38 PK data from standard irinotecan treatment of 180 mg/m2. The toxicity profile of the patients treated with 90 mg irinotecan/m2 (50% FOLFIRI) showed only grade 1 and 2 adverse events. Conclusions: SCO-101 in combination with FOLFIRI has demonstrated the ability to modulate the PK profile of SN-38 in mCRC patients with RAS wild-type tumors, by significantly increasing the half-life, the peak plasma concentration, and area under the curve of SN-38. The combined treatment was well tolerated, and the drug is now being tested for efficacy in the CORIST trial.[Table: see text]