Search

Abstract Background Digitoxin induces apoptosis in different human malignant cell lines in vitro. In this paper we investigated if patients taking digitoxin for cardiac disease have a different cancer incidence compared to the general population. Methods Computer stored data on digitoxin concentrations in plasma from 9271 patients with cardiac disease were used to define a user population. Age and sex matched controls from the Norwegian Cancer Registry were used to calculate the number of expected cancer cases. Results The population on digitoxin showed a higher incidence of cancer compared to the control population. However, an additional analysis showed that the population on digitoxin had a general increased risk of cancer already, before the start on digitoxin. Leukemia/lymphoma were the cancer types which stood out with the highest risk in the digitoxin population before starting on digitoxin. This indicates that yet unknown risk factors exist for cardiovascular disease and lymphoproliferative cancer. An internal dose-response analysis revealed a relationship between high plasma concentration of digitoxin and a lower risk for leukemia/lymphoma and for cancer of the kidney/urinary tract. Conclusion Morbidity and mortality are high in the population on digitoxin, due to high age and cardiac disease.These factors disturb efforts to isolate an eventual anticancer effect of digitoxin in this setting. Still, the results may indicate an anticancer effect of digitoxin for leukemia/lymphoma and kidney/urinary tract cancers. Prospective clinical cancer trials have to be done to find out if digitoxin and other cardiac glycosides are useful as anticancer agents.

Background: Digitoxin induces apoptosis in different human malignant cell lines in vitro. In this paper we investigated if patients taking digitoxin for cardiac disease have a different cancer incidence compared to the general population.Methods: Computer stored data on digitoxin concentrations in plasma from 9271 patients with cardiac disease were used to define a user population. Age and sex matched controls from the Norwegian Cancer Registry were used to calculate the number of expected cancer cases.Results: The population on digitoxin showed a higher incidence of cancer compared to the control population. However, an additional analysis showed that the population on digitoxin had a general increased risk of cancer already, before the start on digitoxin. Leukemia/lymphoma were the cancer types which stood out with the highest risk in the digitoxin population before starting on digitoxin. This indicates that yet unknown risk factors exist for cardiovascular disease and lymphoproliferative cancer. An internal dose-response analysis revealed a relationship between high plasma concentration of digitoxin and a lower risk for leukemia/lymphoma and for cancer of the kidney/urinary tract.Conclusion: Morbidity and mortality are high in the population on digitoxin, due to high age and cardiac disease. These factors disturb efforts to isolate an eventual anticancer effect of digitoxin in this setting. Still, the results may indicate an anticancer effect of digitoxin for leukemia/lymphoma and kidney/urinary tract cancers. Prospective clinical cancer trials have to be done to find out if digitoxin and other cardiac glycosides are useful as anticancer agents. [ABSTRACT FROM AUTHOR]

Background: Total neoadjuvant treatment (TNT) for locally advanced rectal cancer (LARC) increases pathologic complete response (pCR) rate and reduces the risk of systemic recurrences over chemoradiotherapy (CRT) in randomised trials, e.g., the RAPIDO trial. A modified RAPIDO schedule was prospectively explored in Sweden to evaluate TNT in routine health care before the RAPIDO results were published., Methods: Between July 2016 and June 2020, 273 patients with high-risk LARC (clinical tumour stage cT4, clinical nodal stage cN2, extramural vascular invasion, involved mesorectal fascia or enlarged lateral lymph nodes) were treated in a prospective observational cohort study at 16 hospitals (LARCT-US). Another 189 patients at 18 (including the 16) hospitals were similarly treated ( ad modum LARCT-US, AdmL) during the same period. Inclusion and exclusion criteria were identical to the RAPIDO trial. Patients received short-course radiotherapy (5 × 5 Gy for 5 days) followed by four cycles of CAPOX or six FOLFOX-6, followed by total mesorectal excision or, if clinical complete response (cCR), inclusion into a watch-and-wait (W&W) study. The primary endpoint was complete response (CR), i.e., the sum of pCR in specimens and cCR exceeding one year in W&W patients. Safety was assessed in all patients., Findings: Compared to the RAPIDO trial, patients were older, and tumours more advanced. Median follow-up was 4.8 years (IQR 4.2-5.2). In LARCT-US all patients received radiotherapy and 268 (98%) started chemotherapy whereas in AdmL all patients received radiotherapy and chemotherapy. In LARCT-US 34 patients had pCR and 31 sustained cCR resulting in a CR-rate of 24% (95% CI 20-28). In AdmL, results were similar (23%, 95% CI 17-30). Locoregional recurrences were 6% (95% CI 4-10) and 5% (95% CI 2-9), respectively, both at 3 years and at last follow-up. Neurotoxicity, recorded in LARCT-US, was lower than in RAPIDO (EORTC-QLQ-CIPN20 tingling toes or feet mean score 24 (SD 31) vs 43 (SD 37)). One treatment-associated death occurred., Interpretation: Despite older patients and more advanced tumours, results similar to the RAPIDO trial were obtained. Hence, two chemotherapy cycles less do not compromise the results maintaining a high CR-rate. This TNT schedule resulted in favourable outcomes in a nation-wide real-life situation., Funding: Swedish Cancer Society., Competing Interests: BG reports research support from the Swedish Cancer Society and the Foundation Oncology Department in Uppsala Research Fund, EA reports research support from the Swedish Cancer Society, Swedish Research Council and Grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement. All other authors declare no competing interests., (© 2024 The Author(s).)

Background: In patients undergoing resection for pancreatic cancer, adjuvant modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improves overall survival compared with alternative chemotherapy regimens. We aimed to compare the efficacy and safety of neoadjuvant FOLFIRINOX with the standard strategy of upfront surgery in patients with resectable pancreatic ductal adenocarcinoma., Methods: NORPACT-1 was a multicentre, randomised, phase 2 trial done in 12 hospitals in Denmark, Finland, Norway, and Sweden. Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, and had a resectable tumour of the pancreatic head radiologically strongly suspected to be pancreatic adenocarcinoma. Participants were randomly assigned (3:2 before October, 2018, and 1:1 after) to the neoadjuvant FOLFIRINOX group or upfront surgery group. Patients in the neoadjuvant FOLFIRINOX group received four neoadjuvant cycles of FOLFIRINOX (oxaliplatin 85 mg/m 2 , irinotecan 180 mg/m 2 , leucovorin 400 mg/m 2 , and fluorouracil 400 mg/m 2 bolus then 2400 mg/m 2 over 46 h on day 1 of each 14-day cycle), followed by surgery and adjuvant chemotherapy. Patients in the upfront surgery group underwent surgery and then received adjuvant chemotherapy. Initially, adjuvant chemotherapy was gemcitabine plus capecitabine (gemcitabine 1000 mg/m 2 over 30 min on days 1, 8, and 15 of each 28-day cycle and capecitabine 830 mg/m 2 twice daily for 3 weeks with 1 week of rest in each 28-day cycle; four cycles in the neoadjuvant FOLFIRINOX group, six cycles in the upfront surgery group). A protocol amendment was subsequently made to permit use of adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m 2 , irinotecan 150 mg/m 2 , leucovorin 400 mg/m 2 , and fluorouracil 2400 mg/m 2 over 46 h on day 1 of each 14-day cycle; eight cycles in the neoadjuvant FOLFIRINOX group, 12 cycles in the upfront surgery group). Randomisation was performed with a computerised algorithm that stratified for each participating centre and used a concealed block size of two to six. Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was overall survival at 18 months. Analyses were done in the intention-to-treat (ITT) and per-protocol populations. Safety was assessed in all patients who were randomly assigned and received at least one cycle of neoadjuvant or adjuvant therapy. This trial is registered with ClinicalTrials.gov, NCT02919787, and EudraCT, 2015-001635-21, and is ongoing., Findings: Between Feb 8, 2017, and April 21, 2021, 77 patients were randomly assigned to receive neoadjuvant FOLFIRINOX and 63 to undergo upfront surgery. All patients were included in the ITT analysis. For the per-protocol analysis, 17 (22%) patients were excluded from the neoadjuvant FOLFIRINOX group (ten did not receive neoadjuvant therapy, four did not have pancreatic ductal adenocarcinoma, and three received another neoadjuvant regimen), and eight (13%) were excluded from the upfront surgery group (seven did not have pancreatic ductal adenocarcinoma and one did not undergo surgical exploration). 61 (79%) of 77 patients in the neoadjuvant FOLFIRINOX group received neoadjuvant therapy. The proportion of patients alive at 18 months by ITT was 60% (95% CI 49-71) in the neoadjuvant FOLFIRINOX group versus 73% (62-84) in the upfront surgery group (p=0·032), and median overall survival by ITT was 25·1 months (95% CI 17·2-34·9) versus 38·5 months (27·6-not reached; hazard ratio [HR] 1·52 [95% CI 1·00-2·33], log-rank p=0·050). The proportion of patients alive at 18 months in per-protocol analysis was 57% (95% CI 46-67) in the neoadjuvant FOLFIRINOX group versus 70% (55-83) in the upfront surgery group (p=0·14), and median overall survival in per-protocol population was 23·0 months (95% CI 16·2-34·9) versus 34·4 months (19·4-not reached; HR 1·46 [95% CI 0·99-2·17], log-rank p=0·058). In the safety population, 42 (58%) of 73 patients in the neoadjuvant FOLFIRINOX group and 19 (40%) of 47 patients in the upfront surgery group had at least one grade 3 or worse adverse event. 63 (82%) of 77 patients in the neoadjuvant group and 56 (89%) of 63 patients in the upfront surgery group had resection (p=0·24). One sudden death of unknown cause and one COVID-19-related death occurred after the first cycle of neoadjuvant FOLFIRINOX. Adjuvant chemotherapy was initiated in 51 (86%) of 59 patients with resected pancreatic ductal adenocarcinoma in the neoadjuvant FOLFIRINOX group and 44 (90%) of 49 patients with resected pancreatic ductal adenocarcinoma in the upfront surgery group (p=0·56). Adjuvant modified FOLFIRINOX was given to 13 (25%) patients in the neoadjuvant FOLFIRINOX group and 19 (43%) patients in the upfront surgery group. During adjuvant chemotherapy, neutropenia (11 [22%] patients in the neoadjuvant FOLFIRINOX group and five [11%] in the upfront surgery group) was the most common grade 3 or worse adverse event., Interpretation: This phase 2 trial did not show a survival benefit from neoadjuvant FOLFIRINOX in resectable pancreatic ductal adenocarcinoma compared with upfront surgery. Implementation of neoadjuvant FOLFIRINOX was challenging. Future trials on treatment sequencing in resectable pancreatic ductal adenocarcinoma should be biomarker driven., Funding: Norwegian Cancer Society, South Eastern Norwegian Health Authority, The Sjöberg Foundation, and Helsinki University Hospital Research Grants., Competing Interests: Declaration of interests HG has received honoraria from Pfizer, Amgen, and Bristol Myers Squibb. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Around one fourth of patients with colorectal cancer present themselves with distant metastases at the time of diagnosis, and one additional one fifth of the patients will develop distant metastases during the disease, most commonly in the liver. Surgical treatment such as liver resection or ablation, often combined with chemotherapy and targeted therapy, is the only treatment option with curative potential, but only about 20% of the patients with liver metastases are candidates for surgical intervention. Standard treatment for unresectable patients is palliative oncological therapy; however, less than 10% of these patients will achieve a 5-year survival. Non-randomized studies indicate that liver transplantation could be an option for selected patients with colorectal liver metastases (CRLM), which are not suitable for operation or ablation due to surgical technical reasons such as massive tumor burden and small future liver remnant, or oncological reasons, for example, early relapse after liver surgery. Since there is a shortage of donated liver grafts, it is important to select the patient group that benefit most from the treatment. Although some studies present positive results from liver transplantation of CRLM, the results must be validated in a randomized controlled trial before this new indication for liver transplantation can be introduced as a clinical routine., Methods: The SOULMATE study is a randomized study evaluating if liver transplantation with liver grafts, primarily from extended criteria donors, increases overall survival in patients with CRLM, not suitable for resection or ablation, in comparison with best established treatment. Patients will be randomized to liver transplantation (LT)+ best established treatment (BET) or to best established treatment only. In the SOULMATE trial, we will evaluate the use of livers from extended criteria donors to decrease the risk of prolonging waiting time for patients on the waiting list for LT., Discussion: The SOULMATE study has the possibility to confirm the positive results of previous studies in a randomized setting. The use of extended criteria donors will make the results transferable globally, as most countries are struggling with organ shortage., Trial Registration: Clinical Trial number: NCT04161092 registered 13 November 2019., (© 2022. The Author(s).)

The article provides a mathematical description based on the theory of differential equations, for the proliferation of malignant cells (cancer). A model is developed which enables us to describe and predict the dynamics of cell proliferation much better than by using ordinary curve fitting procedures. By using differential equations the ability to foresee the dynamics of cell proliferation is in general much better than by using polynomial extrapolations. Complex time relations can be revealed. The mass of each living cell and the number of living cells are described as functions of time, accounting for each living cell's age since cell-birth. The linkage between micro-dynamics and the population dynamics is furnished by coupling the mass increase of each living cell up against the mitosis rate. A comparison is made by in vitro experiments with cancer cells exposed to digitoxin, a new promising anti-cancer drug. Theoretical results for the total number of cells (living or dead) is found to be in good agreement with experiments for the cell line considered, assuming different concentrations of digitoxin. It is shown that for the chosen cell line, the proliferation is halted by an increased time from birth to mitosis of the cells. The delay is probably connected with changes in the Ca concentration inside the cell. The enhanced time between the birth and mitosis of a cell leads effectively to smaller mitosis rates and thereby smaller proliferation rates. This mechanism is different from the earlier results on digitoxin for different cell lines where an increased rate of apoptosis was reported. But we find it reasonable that cell lines can react differently to digitoxin. A development from enhanced time between birth and mitosis to apoptosis can be furnished, dependent of the sensitivity of the cell lines. This mechanism is in general very different from the mechanism appealed to by standard chemotherapy and radiotherapy where the death ratios of the cells are mainly affected. Thus the analysis supports the view that a quite different mechanism is invoked when using digitoxin. This is important, since by appealing to different types of mechanism in parallel during cancer treatment, more selectivity in the targeting of benign versus malignant cells can be invoked. This increases the probability of successful treatment. The critical digitoxin level concentration, i.e. the concentration level where the number of living cells is not increasing, is approximately 50 ng/ml for the cell line we investigated in this article. Therapeutic plasma concentration of digitoxin when treating cardiac congestion is about 15-33 ng/ml, but individual tolerances are large. The effect of digitoxin during cancer treatment is therefore very promising. The dynamic model constitutes a new powerful tool, supported by empirics, describing the mechanism or process by which the number of malignant cells during anti-cancer treatment can be studied and reduced.

Apo-2L is a new member of the tumour necrosis factor (TNF) family shown to induce apoptosis in a number of tumour cell lines. Apo-2L mRNA is expressed by numerous human tissues. Here we report that Apo-2L is expressed and utilized by human Natural Killer (NK) cells. NK cells were shown to express surface Apo-2L in response to interleukin 2 (IL-2) activation, and this response was restricted to the CD3(-)population of the NK cells. Apo-2L mRNA and intracellular Apo-2L were present in both CD3(-)and CD3(+)NK cells; however, increased expression in response to IL-2 was only observed in CD3(-)CD56(+)cells. Also, IL-2-activated NK cells were shown to utilize membrane-bound Apo-2L in mediating lysis of Jurkat cells. Furthermore, Apo-2L-induced apoptosis of Jurkat cells was more rapid than FasL-induced apoptosis, indicating an important and distinct role for Apo-2L in apoptotic cell destruction. In conclusion, we report that NK cells express Apo-2L and that IL-2 activated CD3(-)NK cells utilize the Apo-2L pathway in mediating target cell lysis., (Copyright 1999 Academic Press.)

The Fas/Fas-ligand (FasL) system seems to play a key role in regulating immunoresponses. Highly purified CD56+CD3- natural killer (NK) cells were found to be resistant to the apoptosis-inducing Fas mAb CH11 in the absence or in the presence of interleukin-2 (IL-2) for up to 3 days. However, NK cells activated with IL-2 for 3 days became apoptotic following combined treatment with CH11 and actinomycin D, suggesting the presence of an intact apoptotic machinery. In contrast, NK cells cultivated in IL-2 for 6 days became sensitive to CH11-induced apoptosis without addition of actinomycin D. At this time, a pronounced up-regulation of the Fas protein on the NK cell membrane was detected. By using reverse transcription/polymerase chain reaction it was found that the anti-apoptotic gene FLIP was strongly expressed in NK cells for up to 6 days of IL-2 stimulation. After day 6, a time-dependent decrease in the expression of FLIP was observed concomitantly with increased sensitivity for Fas-mediated apoptosis. The amount of apoptotic and necrotic NK cells in the presence of IL-2 increased in a time-dependent manner, reaching 40% at day 6 of culture. The amount of apoptotic and necrotic NK cells was reduced in the presence of Fas-Fc protein. In addition, IL-2 stimulated the NK cells to release soluble FasL in a time-dependent manner, whereas membrane FasL did not seem to increase in a similar manner. These results indicate that Fas/FasL interactions are involved in the down-regulation of IL-2-activated human NK cells.

This study demonstrates cytokine-mediated regulation of Fas and Fas-ligand (Fas-L) expression in human NK cells and the involvement of the Fas-L pathway in NK/LAK cytotoxicity. Freshly isolated, high purified human CD56+CD3- NK cells were found to express Fas and Fas-L. Cytokines further increased the Fas expression in the CD56+CD3- NK cells, with interleukin (IL)-2 being the most potent stimulus followed by IL-12, while IL-7 had no effect. IL-2 and IL-7 equally enhanced the Fas expression in the CD56+CD3+ population, while IL-12 had a less pronounced effect. Incubation of the CD56+CD3- NK cells with IL-2, but not with IL-12 and IL-7, led to an upregulation at the Fas-L expression, whereas neither of the cytokines affected the Fas-L expression in the CD56+CD3+ cells. Antagonistic Fas mAb M3 and Fas-IgG1 fusion protein significantly inhibited NK cytotoxicity towards Fas-expressing Jurkat cells, while non-antagonistic Fas mAb M31 and irrelevant CD14-IgG1 fusion protein had no effect. IL-2-generated LAK cells were much more potent than NK cells in exerting the cytotoxic effect on Jurkat cells, which was also partially inhibited to M3 and Fas-IgG1. Thus, human NK and LAK cells express Fas and Fas-L, utilize the Fas-L cytotoxic pathway and enhance the expression of these molecules in response to cytokines.