Leucovorin Research Articles

Proteomic profiling of FOLFOX-resistant colorectal cancer cells.

e15588 Background: Chemoresistance is a major cause of colorectal cancer (CRC) mortality. Although multidrug regimen has been established as the backbone of CRC chemotherapy for better treatment efficacy, chemoresistance is common among late-stage CRC. Proteomic profiling of both the chemoresistant and wild-type CRC cells may provide hints for the mechanisms of chemoresistance and suggest targets for improving chemotherapy efficacy. Methods: Human CRC cell lines (DLD-1 and HCT-116) were treated with progressively increased dosage of FOLFOX (5-flurouracil (5-FU), folinic acid (LEU) and oxaliplatin (OXA)) to develop chemoresistance as DLD-1-R and HCT-116-R respectively. After confirmation of the successful development of chemoresistance by Cell Counting Kit-8 test (CCK-8), the comparison of cell samples between chemoresistant and wild-type cell lines were conducted by proteomic profiling using quantitative mass spectrometry (MS)-based techniques. MS and MS/ MS peptides spectra were analysed by Progenesis QI for proteomics software compared with Swiss-Prot dataset. Differentially expressed proteins (DEP) are defined as -1 > log2FC > 1, p < 0.05. Gene-list enrichment by Enrichr (https://maayanlab.cloud/Enrichr/) was employed for identifying the hallmark gene sets of the significantly enriched molecular processes and pathways of each group. All experiments were performed with at least 3 replications. Results: The development of FOLFOX-resistance took one year. The highest drug concentrations achieved were 0.5mM 5-FU, 50µM LEU, and 50µM OXA for DLD-1-R, and 5µM 5-FU, 0.5µM LEU, and 0.5µM OXA for HCT-116-R. The chemoresistance was found to be 14.73 (DLD-1-R) and 1.61 (HCT-116-R) times of the wild-type DLD-1 and HCT-116 respectively from CCK-8 tests. A total of 345 DEP with 154 up-regulated and 191 down-regulated proteins were found in DLD-1-R. While a total of 95 DEP with 66 up-regulated and 29 down-regulated proteins were found in HCT-116-R. Gene ontology molecular process (2021) analyses found that cadherin binding were significantly enriched in both DLD-1-R and HCT-116-R (Adjusted p-value < 0.05). KEGG pathway (2021) analysis found that oxidative phosphorylation, regulation of actin cytoskeleton and HIF-1 signalling pathway are among the significantly enriched pathways in DLD-1-R (Adjusted p value < 0.05). There was no significantly enriched pathway found in HCT-116-R in the same analysis. Conclusions: Our study has successfully established CRC cells with chemoresistance to the FOLFOX regimen. Proteomic profiling has found the cadherin binding as the significantly altered molecular process along with several important signalling pathways in chemoresistant CRC cells. These findings could suggest new directions in the development of anti-chemoresistance strategies of CRC.

FOLINIC ACID OR L-METHYLFOLATE SUPPLEMENTATION FOR THE TREATMENT OF HYPERHOMOCYSTEINEMIA

Objective: Hyperhomocysteinemia (HHcy) is recognized as a risk factor for for cardiovascular disease. The aim of this study was to investigate and compare the efficacy of two tHcy-lowering treatments including FNA or L-methylfolate in healthy Greek adults. Design and method: Two hundred and seventy two (272) health Greek adults (143 men; mean age±SD: 43.0±15.3 years), with elevated serum tHcy levels (>10 mmol/L) received randomized folinic acid (Group 1) or L-methylfolate (Group 2) orally both with hydroxycobalamine im for three months. Serum folate, Cbl and tHcy levels were determined using immunoassays methods at the beginning and the end of the study period. The MTHFR C677T and A1298C gene polymorphisms were genotyped using polymerase chain reaction and reverse hybridization. Results: At the end of the 3-month intervention period the levels of serum folate and Cbl were significantly increased, whereas serum tHcy concentrations were significantly decreased in both groups. The individuals with 677TT genotype had significantly higher reduction of serum tHcy levels than individuals with the 677CC or 677CT genotypes. Although the individuals of Group 1 had significantly greater increase of their serum folate levels than those of Group 2, the reduction of serum tHcy concentrations between the two groups did not differ significantly. The individuals with 677CT genotype had statistically significant greater reduction of serum tHcy levels when received folinic acid than methylfolate supplementation. Conclusions: The tHcy-lowering treatment which included FNA supplementation compared to treatment which included L-methylfolate supplementation caused a greater increase of serum folate levels but no difference in reduction of serum tHcy levels. The reduction of serum tHcy levels was influenced by the existence of MTHFR C677T and not A1298C gene polymorphisms. The individuals with 677CT genotype appear to benefit more by the treatment which included FNA than L-methylfolate supplementation.

NET-02: a randomised, non-comparative, phase II trial of nal-IRI/5-FU or docetaxel as second-line therapy in patients with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma.

The prognosis for patients with poorly-differentiated extra-pulmonary neuroendocrine carcinoma (PD-EP-NEC) is poor. A recognised first-line (1L) treatment for advanced disease is etoposide/platinum-based chemotherapy with no standard second-line (2L) treatment. Patients with histologically-confirmed PD-EP-NEC (Ki-67>20%; Grade 3) received IV liposomal irinotecan (nal-IRI) (70mg/m2 free base)/5-FU (2400mg/m2)/folinic acid, Q14 days (ARM A), or IV docetaxel (75mg/m2), Q21 days (ARM B), as 2L therapy. Primary endpoint was 6-month progression-free survival (PFS) rate (80% power to demonstrate one-sided 95% lower confidence interval excluded 15% (target level of efficacy: 30%)). Secondary endpoints: objective response rate (ORR), median PFS, overall survival (OS), toxicity and patient-reported quality-of-life (QoL) (ClinicalTrials.gov: NCT03837977). Of 58 patients (29 each arm); 57% male, 90% ECOG PS 0/1, 10% PS 2, 89.7% Ki-67≥55%, primary site: 70.7%-gastrointestinal, 18.9%-other, 10.3%-unknown, 91.4%/6.9%/1.7% were resistant/sensitive/intolerant to 1L platinum-based treatment, respectively. The primary end-point of 6-month PFS rate was met by ARM A: 29.6% (lower 95% Confidence-Limit (CL) 15.7), but not by ARM B: 13.8% (lower 95%CL:4.9). ORR, median PFS and OS were 11.1% (95%CI:2.4-29.2) and 10.3% (95%CI:2.2-27.4%); 3 months (95%CI:2-6) and 2 months (95%CI:2-2); and 6 months (95%CI:3-10) and 6 months (95%CI:3-9) in ARMS A and B, respectively. Adverse events≥grade 3 occurred in 51.7% and 55.2% (1 and 6 discontinuations due to toxicity in ARMS A and B), respectively. QoL was maintained in ARM A, but not ARM B. nal-IRI/5-FU/folinic acid, but not docetaxel, met the primary endpoint, with manageable toxicity and maintained QoL, with no difference in OS. ORR and median PFS were similar in both arms. This study provides prospective efficacy, toxicity and QoL data in the 2L setting in a disease group of unmet need, and represents some of the strongest evidence available to recommend systemic treatment to these patients. Servier.

FOOTPATH: A randomized, open-label phase-2 study of liposomal irinotecan + 5-FU and folinic acid (NAPOLI) versus sequential NAPOLI and mFOLFOX6 versus gemcitabine/nab-paclitaxel in treatment-naïve metastatic pancreatic cancer (mPDAC).

4021 Background: The optimal first-line regimen in the treatment of mPDAC remains unknown. Recent data demonstrated superiority of 5-FU/liposomal irinotecan/oxaliplatin (NALIRIFOX) over gemcitabine/nab-paclitaxel. However, the question remains open if both irinotecan and oxaliplatin are required in first-line treatment and whether these agents can be given sequentially. Methods: Eligible patients with histologically confirmed diagnosis of mPDAC were randomized 1:1:1 to receive in Arm A standard treatment (gemcitabine 1000 mg/m2 + nab-paclitaxel 125 mg/m2) or investigational therapy applying in Arm B the NAPOLI regimen (liposomal irinotecan 80 mg/m2 + folinic acid 400 mg/m2 + 5-FU 2400 mg/m2) or in Arm C a sequence of NAPOLI and mFOLFOX6 (oxaliplatin 85mg/m2 + folinic acid 400mg/m2 + 5-FU 2400 mg/m2). Overall, 274 patients were enrolled at 48 sites in Germany. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate, disease control rate, duration of study treatment and safety. Results: In the full analysis set (n=265), neither treatment with NAPOLI (3.1 months, HR 1.224, p= 0.2123) nor the sequence of NAPOLI and mFOLFOX6 (6.0 months, HR 0.864 p= 0.0720) lead to a statistically significant improvement of PFS over gemcitabine/nab-paclitaxel (4.3 months). Median duration of treatment was 3.5 months in Arm A, 2.0 months in Arm B and 3.7 months in Arm C, respectively. In a first analysis of overall survival, OS in Arm A was 8.7 months (95% CI, 7.1-11.9 months) versus 7.9 months in Arm B (95% CI, 6.6-12.3 months; HR 1.178, P= 0.348) and 11.0 months in Arm C (95% CI, 8.4-13.6 months; HR 0.879, P=0.154). Overall, safety was comparable with published data, with higher rates of neutropenia and peripheral neuropathy in Arm A, while diarrhea was more frequent in Arms B and C. Conclusions: The study did not show superiority of either NAPOLI or the sequence of NAPOLI/mFOLFOX6 over standard therapy with gemcitabine/nab-paclitaxel. In view of the published evidence, the present data supports the hypothesis that sequential NAPOLI/mFOLFOX6 may be equally effective with regard to OS, but less toxic, compared to mFOLFIRINOX. Clinical trial information: NCT03487016 . [Table: see text]

The effect of adding a selective FAK inhibitor AMP945 to FOLFIRINOX in a model of pancreatic cancer.

e15128 Background: Pancreatic Cancer (PC) is a one of the leading causes of cancer-related death in the world, with a five-year survival rate of ~11%. The majority of patients present with advanced metastatic disease and are treated with chemotherapy. FOLFIRINOX is the standard-of-care treatment for patients in many countries and has been shown to result in a median overall survival of 11.1 months. Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase which transduces signaling from integrin receptors, activated through interactions with the extracellular matrix, to regulate cell survival, proliferation and migration, and is often highly expressed in PC. Inhibition of FAK in preclinical models of PC has been shown to sensitize cells to radiotherapy, immunotherapy and chemotherapy. AMP945 is a potent and selective FAK inhibitor currently undergoing a Phase Ib/IIa trial in PC in combination with gemcitabine and nab-paclitaxel (NCT05355298). We now demonstrate that AMP945, in combination with FOLFIRINOX, can significantly improve survival in mouse models of PC, providing strong rationale for clinical testing of this novel treatment combination. Methods: Patient Derived Xenograft (PDX) models of PC in NOGIL2 mice using TKCC10lo patient derived cells were conducted in both subcutaneous and orthotopic formats. Once the tumor was palpable, AMP945 (10 mg/kg, b.i.d.) was administered for four days. On day 8 oxaliplatin (5 mg/kg) and irinotecan (25 mg/kg) were administered, with leucovorin calcium (100 mg/kg) and fluorouracil (25 mg/kg) being dosed on day 9. The mice were monitored until day 12 and the treatment regimen was repeated for up to 20 cycles, or until the experimental endpoint was reached. At the experimental endpoint the mice were sacrificed, the tumor harvested and analyzed. Results: In the subcutaneous model the combination of AMP945 and FOLFIRINOX increased survival by ~35% compared to FOLFIRINOX alone. In the orthotopic model, median survival was extended by ~30% when using the AMP945/FOLFIRINOX combination, compared to FOLFIRINOX alone. In both models there was a significant reduction in tumor size and clear evidence of on-target FAK inhibition in tumors (reduction in pY397FAK levels) in the combination therapy groups. Notably, a significant increase in cleaved caspase-3, a marker of apoptosis, was also apparent in the combination therapy groups. Conclusions: The FAK inhibitor AMP945, given in a pulsed-dosing regimen in combination with FOLFIRINOX, significantly enhances survival in a mouse model of pancreatic cancer by increasing apoptosis and reducing tumor burden, highlighting the potential of this combination in clinical treatment of PC. A clinical study of the combination of AMP945 with FOLFIRINOX is now in planning.

Toripalimab combined with fluorouracil, leucovorin calcium, oxaliplatin and irinotecan (FOLFIRINOX) regimen or combined with oxaliplatin and tegafur (SOX) regimen in perioperative treatment of locally advanced resectable gastric or gastroesophageal junction adenocarcinoma (G/GEJ): An open-label, randomized, phase II study.

e16090 Background: Currently, NCCN guidelines recommend PD-1 inhibitors for the first-line therapy in gastric cancer patients (pts). However, the role of PD-1 inhibitor treatment in the perioperative setting remains unclear. This phase 2 study aimed to evaluate toripalimab plus FOLFIRINOX or SOX as perioperative treatment regimens in pts with locally advanced resectable G/GEJ. Methods: Pts were 1:1 ratio randomized to A or B groups. Pts in A group received four cycles of toripalimab (240mg, D1, q2w) and FOLFIRINOX regimen (oxaliplatin, 65 mg/m², d1; irinotecan, 150 mg/m², d1; leucovorin, 200 mg/m², d1; and fluorouracil, 2400 mg/m², d1-2, q2w) prior to surgery. Then D2 radical gastrectomy was performed, and another 4 cycles of toripalimab and FOLFIRINOX regimen were given within 2 months after surgery. In B group, chemo was changed to SOX regimen (oxaliplatin, 130 mg/m², d1; S-1, 40-60 mg/m2, d1-14, q3w) and toripalimab (240mg, D1) was administered every 3 weeks. The rest treatments were the same as A group. The primary endpoint was tumor regression grade (TRG, TRG 0-1). Key secondary endpoints included pathologic complete response (pCR) rate, 3-year disease-free survival (DFS), 5-year overall survival (OS) and safty. Results: Up to Jan 28, 2023, 54 eligible pts were enrolled (A 21, B 33) with baseline characteristics as follows: The median (range) age was 67 (23-71) years; 6/54 (11.1%) pts had signet ring cell carcinoma component; 40/54 (74.1%) pts had cT4 tumors and 18/54 (33.3%) had lymph node positive disease. 32/54 (59.3%) pts underwent successful resection. R0 resection rate was 100%. The TRG 0-1 rate was higher but not significant in the B group than in the A group (31.58% vs. 23.08%, P = 0.703). 4 pts (A 2, 15.4%; B 2, 10.5%) had a pCR. 23 (A 8, B 15, 71.9%) pts had tumor downstaged after surgery. Treatment-related adverse events (TRAEs) of any grade occurred in 25/54 (46.3%) pts. Grade ≥3 TRAEs occurred in 10/54 (18.5%) pts: 7 with grade 3-4 neutropenia, 2 with grade 3 thrombocytopenia and 1 with grade 3 myelosuppression. No new safety signals were observed and no TRAEs leading to death in either group. Conclusions: Toripalimab plus FOLFIRINOX or SOX regimens is tolerable and effective for pts with locally advanced resectable G/GEJ in the perioperative treatment setting. There were no significant differences in efficacy and safety between the two groups. Whether intensive or simplified treatment is more suitable for neoadjuvant therapy needs to be further explored. The low pCR rate in both groups may be due to the small sample size and the pts with more advanced primary tumors. This study is ongoing and more data will be released. Clinical trial information: NCT04908566 . [Table: see text]

P-231 Interim results of a phase II study of fluorouracil (FU), leucovorin (LV), and nanoliposomal irinotecan (nal-IRI) in previously treated advanced biliary tract cancer (NAPOLI-2)

P-231 Interim results of a phase II study of fluorouracil (FU), leucovorin (LV), and nanoliposomal irinotecan (nal-IRI) in previously treated advanced biliary tract cancer (NAPOLI-2)

Alternating short-course oxaliplatin-based chemotherapy and nivolumab as first-line treatment of patients with abdominal metastases from microsatellite-stable (MSS) colorectal cancer (CRC): A randomized phase 2 trial.

3552 Background: The CRC incidence increases sharply from the age of 60. Most patients harbor primarily non-immunogenic MSS disease and abdominal metastases are in particular considered unresponsive to immune checkpoint blockade (ICB). The METIMMOX trial explored if MSS-CRC can be transformed into an immunogenic malignancy by short-course oxaliplatin-based therapy and if followed by ICB (without concomitant chemotherapy that might compromise an invoked tumor-defeating immunity) may result in durable clinical response for patients with abdominal metastases. Methods: Patients had MSS-CRC with infradiaphragmatic metastases deemed unresectable, ECOG performance status 0-1, and were eligible for first-line oxaliplatin-based therapy. They were randomly assigned to FLOX (oxaliplatin 85 mg/m2 day 1, bolus 5-fluorouracil 500 mg/m2 and folinic acid 100 mg days 1-2) Q2W (control arm) or alternating cycles of 2 FLOX Q2W and 2 nivolumab (240 mg) Q2W (experimental (exp) arm) with break periods at prespecified intervals. Response assessment per i/RECIST by blinded central review was done every 8 weeks with progression-free survival (PFS) as primary endpoint. Sample size of 40 in each arm with 1:1 randomization would detect exp arm doubling of median PFS. Associations between PFS and relevant patient and disease variables were estimated by Cox proportional-hazards regression models. Prespecified correlative analyses included circulating tumor DNA (ctDNA) by droplet digital PCR and circulating immune cell composition by high-dimensional single-cell mass cytometry. Results: Of 80 enrolled subjects (05/2018-10/2021), 76 intention-to-treat (ITT) cases were equally allocated to the study arms and followed to censoring at 10/2022 with identical median PFS of 9.3 months (95% CI, 6.4-12.9 (control arm) and 4.6-15.2 (exp arm)). The adjusted Cox model revealed interaction between age and study arm, as patients ≥60 years had significantly lowered risk of progression when receiving exp therapy (median PFS 13.6 months (95% CI, 8.5-18.8); p = 0.022). No unexpected adverse events were recorded; specifically, no grade ≥4 immune-mediated adverse event occurred. Of note, 17% of exp arm patients had durable complete response, among whom all BRAF-mutant cases ( n = 3) with PFS 21-35 months and rapid clearance of baseline BRAF-mutant ctDNA (control arm BRAF-mutant cases ( n = 10), median PFS 3.6 months). Responding exp arm patients showed distinct subsets of circulating immune cells with more homogenous profiles than ICB-unresponsive subjects. Conclusions: With equal primary endpoint for the ITT cases, alternating short-course oxaliplatin-based therapy and nivolumab significantly improved PFS compared to standard first-line chemotherapy in MSS-CRC patients ≥60 years with abdominal metastases. Clinical trial information: NCT03388190 .

The prognostic impact of NKA dynamics in first-line treatment of metastatic colorectal cancer.

e15514 Background: Metastatic colorectal cancer (mCRC) remains a therapeutic challenge and new markers hold high priority. Natural Killer (NK) cells are immune cells with potent antitumor properties. The association between neoplastic development and level of effector functions of this cell type is well known. Moreover, it is recognized that NK cells are subject to tumor-mediated immune suppression. The present study aimed at elucidating a potential relationship between NK cell activity (NKA) and response to folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) in mCRC. Methods: NKA was analyzed in patients enrolled in a randomized trial of mCRC receiving FOLFOXIRI and either tocotrienol or placebo as first-line treatment. Blood (1 mL) was sampled into NK Vue tubes at baseline and before treatment cycles 2-3, placed at 37°C for 24 hours, and after incubation, the level of interferon-γ (IFNγ) in the plasma was a surrogate measure for NKA. A cutoff of 250 pg/mL IFNγ distinguished normal and low NKA. The endpoints were response rate (RR), progression-free survival (PFS), and overall survival (OS). Results: A total of 70 patients were enrolled in the randomized clinical trial. The results showed that tocotrienol had no effect on either RR (p = 0.62), PFS (p = 0.52), or OS (p = 0.80). Patients were classified into two groups according to the dynamics of NKA measured at the available time points. Patients that dropped from a normal to a low level of NKA in samples taken between baseline and before cycle 3 and patients with continuous low NKA (IFNγ < 250 pg/mL) were categorized as NKA-low. The NKA-high group included patients that increased from an abnormal to a normal level of NKA and patients that remained within the normal range (IFNγ > 250pg/mL) in all available samples. The RR in the two groups were 38% (8/21) and 69% (24/35), respectively (p = 0.0496). The median PFS was 186 days (95% confidence interval (CI) 136-225 days, n = 23) for the NKA-low group and 252 days (95% CI 223-305 days, n = 37) for NKA-high (p = 0.0005). The hazard ratio (HR) was 2.65 (95% CI 1.28-5.50). After adjusting for age, performance status (PS), and tumor location, NKA remained an independent prognostic factor for PFS (HR = 3.32, 95% CI 1.67-6.61, p = 0.001). Median OS was 408 days (95% CI 219-679 days, n = 23) and 1051 days (95% CI 645-1225 days, n = 37), respectively (p = 0.0034). For OS, the NKA-low group also showed a poor prognosis, HR 2.23 (95% CI 1.17-4.25). NKA dynamics remained an independent prognostic marker for OS after adjusting for age, PS, and tumor location (HR = 2.74, 95% CI 1.50-5.03, p = 0.001). Conclusions: The results suggest that NKA dynamics within the first two cycles of treatment may hold relevant prognostic information in first-line treatment of mCRC. The possible causative relationship between NKA and treatment effect needs further elucidation, but calls for experimental trials combining chemotherapy with NK cell therapy in mCRC.

Impact of prior bevacizumab therapy on the incidence of ramucirumab-induced proteinuria in colorectal cancer: a multi-institutional cohort study.

The association between prior bevacizumab (BEV) therapy and ramucirumab (RAM)-induced proteinuria is not known. We aimed to investigate this association in patients with metastatic colorectal cancer (mCRC). mCRC patients who received folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus RAM were divided into with and without prior BEV treatment groups. The cumulative incidence of grade 2-3 proteinuria and rate of RAM discontinuation within 6months (6M) after RAM initiation were compared between the two groups. We evaluated 245 patients. In the Fine-Gray subdistribution hazard model including prior BEV, age, sex, comorbidities, eGFR, proteinuria ≥ 2 + at baseline, and later line of RAM, prior BEV treatment contributed to proteinuria onset (P < 0.01). A shorter interval between final BEV and initial RAM increased the proteinuria risk; the adjusted odds ratios (95% confidence intervals) for the intervals of < 28days, 28-55days, and > 55days (referring to prior BEV absence) were 2.60 (1.23-5.51), 1.51 (1.01-2.27), and 1.04 (0.76-1.44), respectively. The rate of RAM discontinuation for ≤ 6M due to anti-VEGF toxicities was significantly higher in the prior BEV treatment group compared with that in the no prior BEV treatment group (18% vs. 6%, P = 0.02). Second-line RAM discontinuation for ≤ 6M without progression resulted in shorter overall survival of 132 patients with prior BEV treatment (P < 0.01). Sequential FOLFIRI plus RAM after BEV failure, especially within 55days, may exacerbate proteinuria. Its escalated anti-VEGF toxicity may negatively impact the overall survival.

RWD20 Analysis of US Real World Evidence Data to Assess and Compare the Effectiveness of Two Chemotherapy Regimens: FOLFIRINOX Vs Gemcitabine/Nab-paclitaxel for First Line Metastatic Pancreatic Cancer

To demonstrate the validity of our analysis techniques utilizing real-world data to assess and compare the effectiveness of two chemotherapy regimens that have not been directly compared in randomized clinical trials: FOLFIRINOX (combined leucovorin calcium, fluorouracil, irinotecan and oxaliplatin) and gemcitabine plus nab-paclitaxel for first line metastatic pancreatic cancer.

Tetrahydrobenzo[h]quinoline derivatives as a novel chemotype for dual antileishmanial-antimalarial activity graced with antitubercular activity: Design, synthesis and biological evaluation

Derivatives with tetrahydrobenzo[h]quinoline chemotype were synthesized via one-pot reactions and evaluated for their antileishmanial, antimalarial and antitubercular activities. Based on a structure-guided approach, they were designed to possess antileishmanial activity through antifolate mechanism, via targeting Leishmania major pteridine reductase 1 (Lm-PTR1). The in vitro antipromastigote and antiamastigote activity are promising for all candidates and superior to the reference miltefosine, in a low or sub micromolar range of activity. Their antifolate mechanism was confirmed via the ability of folic and folinic acids to reverse the antileishmanial activity of these compounds, comparably to Lm-PTR1 inhibitor trimethoprim. Molecular dynamics simulations confirmed a stable and high potential binding of the most active candidates against leishmanial PTR1. For the antimalarial activity, most of the compounds exhibited promising antiplasmodial effect against P. berghei with suppression percentage of up to 97.78%. The most active compounds were further screened in vitro against the chloroquine resistant strain P. falciparum, (RKL9) and showed IC50 value range of 0.0198–0.096 μM, compared to IC50 value of 0.19420 μM for chloroquine sulphate. Molecular docking of the most active compounds against the wild-type and quadruple mutant pf DHFR-TS structures rationalized the in vitro antimalarial activity. Some candidates showed good antitubercular activity against sensitive Mycobacterium tuberculosis in a low micromolar range of MIC, compared to 0.875 μM of isoniazid. The top active ones were further tested against a multidrug-resistant strain (MDR) and extensively drug-resistant strain (XDR) of Mycobacterium tuberculosis. Interestingly, the in vitro cytotoxicity test of the best candidates displayed high selectivity indices emphasizing their safety on mammalian cells. Generally, this work introduces a fruitful matrix for new dual acting antileishmanial-antimalarial chemotype graced with antitubercular activity. This would help in tackling drug-resistance issues in treating some Neglected Tropical Diseases.

Review of Current Systemic Therapy and Novel Systemic Therapy for Pancreatic Ductal Adenocarcinoma.

This review aims to describe the systemic treatment options for pancreatic ductal adenocarcinoma and includes a summary of the current treatments as well as the ongoing clinical trials which may be efficacious in the treatment of this aggressive malignancy. A literature review was performed using MEDLINE/PubMed between August 1996 and February 2023. The reviewed studies are categorized into these categories: current standard of care treatments, targeted therapies, immunotherapy and clinical trials. The current treatment modality for the treatment of advanced pancreatic cancer is mainly systemic chemotherapy. The introduction of polychemotherapy regimens including gemcitabine/nab-paclitaxel and FOLFIRINOX (oxaliplatin, irinotecan, folinic acid and fluorouracil) has improved the clinical outcome of advanced pancreatic cancer. For further improvement in clinical outcomes, several novel approaches have been extensively studied in pancreatic cancer. The review discusses the current standard chemotherapy regimen and the novel treatment options in the field. While there are novel treatments being explored for metastatic pancreatic, it remains a debilitating and aggressive disease with high mortality that warrants continued efforts to advance therapeutic options.

Combined expression of HIF1α, VEGF and HER2 predicts metastasis, relapse and response to combination chemotherapy in colorectal cancer patients

Addressing a single target is the frequent development of drug resistance followed by cancer relapse and treatment failure. Therefore, assessment of simultaneous expression of target molecules is essential to choose the optimal combination therapy for each colorectal cancer patient.This study aims to evaluate the immunohistochemical expression of HIF1α, HER2 and VEGF and to clarify their clinical significance as prognostic factors and predictive markers of FOLFOX (combination chemotherapy inclusive of Leucovorin calcium, Fluorouracil and Oxaliplatin response).Marker expression was retrospectively evaluated by immunohistochemistry in 111 patients with colorectal adenocarcinomas from south Tunisia, followed by statistical analysis.The immunohistochemical staining revealed that 45 %, 80.2 %, 86.5 % and 25.5 % of specimen were positive for nuclear, cytoplasmic HIF1α expression, VEGF and HER2 respectively. Nuclear HIF1α and VEGF were associated with worst prognosis while cytoplasmic HIF1α and HER2 were correlated with favourable prognosis. Multivariate analysis confirms the association between nuclear HIF1α, distant metastasis, relapse, FOLFOX response and 5 years overall survival. HIF1α positivity and HER2 negativity were significantly associated to short survival. Combined immunoprofiles HIF1α+/VEGF+, HIF1α+/HER2-, HIF1α+/VEGF+/HER2- were associated to distant metastasis, cancer relapse and short survival. Interestingly, our findings confirmed that patients bearing a HIF1α positive tumor were significantly more resistant to FOLFOX compared to negative ones (p = 0.002, p ≤ 0.001). Positive expression of HIF1α and VEGF, or decreased expression of HER2 was each associated with poor prognosis and short overall survival. In summary, we found that expression of nuclear HIF1α, alone or combined with VEGF and HER2 serves as a predictive marker of poor prognosis and FOLFOX response in colorectal cancer from south Tunisia.

Economic evaluations of radioembolization with yttrium-90 microspheres in liver metastases of colorectal cancer: a systematic review

BackgroundTransarterial radioembolization with yttrium-90 (Y-90 TARE) microspheres therapy has demonstrated positive clinical benefits for the treatment of liver metastases from colorectal cancer (lmCRC). This study aims to conduct a systematic review of the available economic evaluations of Y-90 TARE for lmCRC.MethodsEnglish and Spanish publications were identified from PubMed, Embase, Cochrane, MEDES health technology assessment agencies, and scientific congress databases published up to May 2021. The inclusion criteria considered only economic evaluations; thus, other types of studies were excluded. Purchasing-power-parity exchange rates for the year 2020 ($US PPP) were applied for cost harmonisation.ResultsFrom 423 records screened, seven economic evaluations (2 cost-analyses [CA] and 5 cost-utility-analyses [CUA]) were included (6 European and 1 USA). All included studies (n = 7) were evaluated from a payer and the social perspective (n = 1). Included studies evaluated patients with unresectable liver-predominant metastases of CRC, refractory to chemotherapy (n = 6), or chemotherapy-naïve (n = 1). Y-90 TARE was compared to best supportive care (BSC) (n = 4), an association of folinic acid, fluorouracil and oxaliplatin (FOLFOX) (n = 1), and hepatic artery infusion (HAI) (n = 2). Y-90 TARE increased life-years gained (LYG) versus BSC (1.12 and 1.35 LYG) and versus HAI (0.37 LYG). Y-90 TARE increased the quality-adjusted-life-year (QALY) versus BSC (0.81 and 0.83 QALY) and versus HAI (0.35 QALY). When considering a lifetime horizon, Y-90 TARE reported incremental cost compared to BSC (range 19,225 to 25,320 $US PPP) and versus HAI (14,307 $US PPP). Y-90 TARE reported incremental cost-utility ratios (ICURs) between 23,875 $US PPP/QALY to 31,185 $US PPP/QALY. The probability of Y-90 TARE being cost-effective at £ 30,000/QALY threshold was between 56% and 57%.ConclusionsOur review highlights that Y-90 TARE could be a cost-effective therapy either as a monotherapy or when combined with systemic therapy for treating ImCRC. However, despite the current clinical evidence on Y-90 TARE in the treatment of ImCRC, the global economic evaluation reported for Y-90 TARE in ImCRC is limited (n = 7), therefore, we recommend future economic evaluations on Y-90 TARE versus alternative options in treating ImCRC from the societal perspective.

Posterior reversible encephalopathy syndrome triggered by FLOT (5-fluorouracil, oxaliplatin, docetaxel, and calcium levofolinate) chemotherapy and thrombocytopenia (docetaxel and cisplatin) chemotherapy.

Posterior reversible encephalopathy syndrome is a clinical and imaging syndrome characterized by endothelial dysfunction, blood-brain barrier disruption, and vasogenic edema. The common clinical symptoms of posterior reversible encephalopathy syndrome include headache, altered consciousness, visual disturbances, and seizures, among which headache and seizures are the most common. The classic imaging patterns usually reveal vasogenic edema. We describe the case of a middle-aged woman with gastric cancer. She was under treatment by fluorouracil, leucovorin, oxaliplatin, and docetaxel regimen and thrombocytopenia regimen after tumor progression, but developed unconsciousness, irritability, and headache shortly after initiation of treatment. Her magnetic resonance imaging in our hospital shows abnormal signals in bilateral frontal parietal occipital lobes with hyperintensities on T2-weighted magnetic resonance imaging and fluid-attenuated inversion recovery imaging, accompanied by the increased value of apparent diffusion coefficient. And T1-weighted images illustrate hypointense foci, with increased diffusion-weighted imaging signals. After admission, she was treated to control blood pressure, reduce brain edema, expand blood vessels, improve consciousness, and symptomatic support treatment. 3 days after the onset of the disease, her headache symptoms and state of consciousness gradually improved, and her blood pressure can be controlled at about 130/80 mmHg. This is the first report that posterior reversible encephalopathy syndrome is caused by a thrombocytopenia regimen, and our case highlights the pathogenic role of a thrombocytopenia regimen in posterior reversible encephalopathy syndrome. However, the association between the thrombocytopenia regimen and previous fluorouracil, leucovorin, oxaliplatin, and docetaxel regimens needs further study.

Fluoropyrimidine usage in cases with hyperammonemia: real-world data study using the Japanese Adverse Drug Event Report (JADER) database.

Fluoropyrimidines are anticancer drugs and can cause hyperammonemia both intravenously and orally. Renal dysfunction may interact with fluoropyrimidine to cause hyperammonemia. We performed quantitative analyses of hyperammonemia using a spontaneous report database to examine the frequency of intravenously and orally administered fluoropyrimidine, the reported frequency of fluoropyrimidine-related regimens, and fluoropyrimidine's interactions with chronic kidney disease (CKD). This study used data collected between April 2004 and March 2020 from the Japanese Adverse Drug Event Report database. The reporting odds ratio (ROR) of hyperammonemia was calculated for each fluoropyrimidine drug and was adjusted for age and sex. Heatmaps depicting the use of anticancer agents in patients with hyperammonemia were drawn. The interactions between CKD and the fluoropyrimidines were also calculated. These analyses were performed using multiple logistic regression. Hyperammonemia was observed in 861 of the 641,736 adverse events reports. Fluorouracil was the most frequent drug associated with hyperammonemia (389 cases). The ROR of hyperammonemia was 32.5 (95% CI 28.3-37.2) for intravenously administered fluorouracil, 4.7 (95% CI 3.3-6.6) for orally administered capecitabine, 1.9 (95% CI 0.87-4.3) for tegafur/uracil, and 2.2 (95% CI 1.5-3.2) for orally administered tegafur/gimeracil/oteracil. Calcium levofolinate, oxaliplatin, bevacizumab, and irinotecan were the most frequently reported agents in cases of hyperammonemia with intravenously administered fluorouracil. The coefficient of the interaction term between CKD and fluoropyrimidines was 1.12 (95% CI 1.09-1.16). Hyperammonemia cases were more likely to be reported with intravenous fluorouracil than orally administered fluoropyrimidines. Fluoropyrimidines might interact with CKD in hyperammonemia cases.

Comparison of two doses of leucovorin in severe low-dose methotrexate toxicity – a randomized controlled trial

BackgroundLeucovorin (folinic acid) is a commonly used antidote for severe toxicity with low-dose methotrexate, but its optimum dose is unclear, varying from 15 to 25 mg every 6-h.MethodsOpen-label RCT included patients with severe low-dose (≤ 50 mg/week) methotrexate toxicity defined as WBC ≤ 2 × 10^9/L or platelet ≤ 50 × 10^9/L and randomized them to receive either usual (15 mg) or high-dose (25 mg) intravenous leucovorin given every 6-h. Primary outcome was mortality at 30-days and secondary outcomes were hematological recovery and mucositis recovery. Trial Registration number: CTRI/2019/09/021152.ResultsThirty-eight patients were included, most with underlying RA who had inadvertently overdosed MTX (taken daily instead of weekly). At randomization, the median white blood and platelet count were 0.8 × 10^9/L and 23.5 × 10^9/L. 19 patients each were randomized to receive either usual or high-dose leucovorin. Number (%) of deaths over 30-days was 8 (42) and 9 (47) in usual and high-dose leucovorin groups (Odds ratio 1.2, 95% CI 0.3 to 4.5, p = 0.74). On Kaplan–Meier, there was no significant difference in survival between the groups (hazard ratio 1.1, 95% CI 0.4 to 2.9, p = 0.84). On multivariable cox-regression, serum albumin was the only predictor of survival (hazard ratio 0.3, 95% CI 0.1 to 0.9, p = 0.02). There was no significant difference in hematological or mucositis recovery between the two groups.ConclusionThere was no significant difference in survival or time-to hematological recovery between the two doses of leucovorin. Severe low-dose methotrexate toxicity carried a significant mortality.

Comparison of Two Chemotherapy Regimens After First-Line Treatment for HER2-Negative Metastatic Gastric Cancer.

Metastatic stage gastric cancer is a disease with a poor prognosis and the likelihood of achieving a cure in these patients is low. Treatment response to subsequent-line treatments is poor. We aimed to investigate the effectiveness of the folinic acid, fluorouracil and irinotecan (FOLFIRI) and paclitaxel+carboplatin regimens, which are used in subsequent lines of therapy in advanced-stage gastric cancer. This study included 40 patients who have metastatic stage gastric cancer and received FOLFIRI or paclitaxel+carboplatin therapy in subsequent lines of therapy between 2017 and 2022. The data of the patients were analyzed retrospectively. At diagnosis median age was 51 (23-88) years. The tumor was localized in the gastroesophageal junction in eight (20%) patients and in other gastric locations in 32 (80%) patients. At diagnosis, 75% (n=30) of the patients presented with the disease in the metastatic stage, while 25% (n=10) presented with stage II-III disease. Regarding the treatments received in the second and further lines of therapy, 18 (45%) patients received paclitaxel+carboplatin and 22 (55%) patients received a FOLFIRI regimen. Of these treatments, 67.5% (n=27) were given as the second line and 32.5% (n=13) were given as third-line therapy. The objective response rate (ORR) was 45.5% in the FOLFIRI arm compared to 16.7% in the paclitaxel+carboplatin arm (p=0.05). Both treatment arms had a median progression-free survival (PFS) of three months (p=0.82). The median overall survival (OS) time was seven months in the FOLFIRI arm compared to eight months in the paclitaxel+carboplatin arm (p=0.71). Side effects were similar between both treatment arms. This study determined that FOLFIRI and paclitaxel+carboplatin treatments have similar OS, PFS, and side effect profiles in subsequentline treatment of gastric cancer. The FOLFIRI treatment regimen yielded a higher ORR.

Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients1, yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3. Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA–lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8+ T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence.