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- Stoop, Thomas F., et al.
(författare)
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Pathological complete response in patients with resected pancreatic adenocarcinoma after preoperative chemotherapy
- 2024
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Ingår i: JAMA Network Open. - : American Medical Association (AMA). - 2574-3805. ; 7:6
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Preoperative chemo(radio)therapy is increasingly used in patients with localized pancreatic adenocarcinoma, leading to pathological complete response (pCR) in a small subset of patients. However, multicenter studies with in-depth data about pCR are lacking.Objective: To investigate the incidence, outcome, and risk factors of pCR after preoperative chemo(radio)therapy.Design, Setting, and Participants: This observational, international, multicenter cohort study assessed all consecutive patients with pathology-proven localized pancreatic adenocarcinoma who underwent resection after 2 or more cycles of chemotherapy (with or without radiotherapy) in 19 centers from 8 countries (January 1, 2010, to December 31, 2018). Data collection was performed from February 1, 2020, to April 30, 2022, and analyses from January 1, 2022, to December 31, 2023. Median follow-up was 19 months.Exposures: Preoperative chemotherapy (with or without radiotherapy) followed by resection.Main Outcomes and Measures: The incidence of pCR (defined as absence of vital tumor cells in the sampled pancreas specimen after resection), its association with OS from surgery, and factors associated with pCR. Factors associated with overall survival (OS) and pCR were investigated with Cox proportional hazards and logistic regression models, respectively.Results: Overall, 1758 patients (mean [SD] age, 64 [9] years; 879 [50.0%] male) were studied. The rate of pCR was 4.8% (n = 85), and pCR was associated with OS (hazard ratio, 0.46; 95% CI, 0.26-0.83). The 1-, 3-, and 5-year OS rates were 95%, 82%, and 63% in patients with pCR vs 80%, 46%, and 30% in patients without pCR, respectively (P < .001). Factors associated with pCR included preoperative multiagent chemotherapy other than (m)FOLFIRINOX ([modified] leucovorin calcium [folinic acid], fluorouracil, irinotecan hydrochloride, and oxaliplatin) (odds ratio [OR], 0.48; 95% CI, 0.26-0.87), preoperative conventional radiotherapy (OR, 2.03; 95% CI, 1.00-4.10), preoperative stereotactic body radiotherapy (OR, 8.91; 95% CI, 4.17-19.05), radiologic response (OR, 13.00; 95% CI, 7.02-24.08), and normal(ized) serum carbohydrate antigen 19-9 after preoperative therapy (OR, 3.76; 95% CI, 1.79-7.89).Conclusions and Relevance: This international, retrospective cohort study found that pCR occurred in 4.8% of patients with resected localized pancreatic adenocarcinoma after preoperative chemo(radio)therapy. Although pCR does not reflect cure, it is associated with improved OS, with a doubled 5-year OS of 63% compared with 30% in patients without pCR. Factors associated with pCR related to preoperative chemo(radio)therapy regimens and anatomical and biological disease response features may have implications for treatment strategies that require validation in prospective studies because they may not universally apply to all patients with pancreatic adenocarcinoma.
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| 2. |
- Stoop, Thomas F., et al.
(författare)
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Surgical Outcomes After Total Pancreatectomy : A High-Volume Center Experience
- 2021
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Ingår i: Annals of Surgical Oncology. - : Springer. - 1068-9265 .- 1534-4681. ; 28:3, s. 1543-1551
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Tidskriftsartikel (refereegranskat)abstract
- Background: The impact of high-volume care in total pancreatectomy (TP) is barely explored since annual numbers are mostly low. This study evaluated surgical outcomes after TP over time in a high-volume center.Methods: All adult patients (age >= 18 years) who underwent an elective single-stage TP at Karolinska University Hospital were retrospectively analysed (2008-2017). High volume was defined as > 20 TPs/year.Results: Overall, 145 patients after TP were included, including 86 (59.3%) extended resections. Major morbidity was 34.5% (50/145) and 90-day mortality 5.5% (8/145). The relative use of TP within all pancreatectomies increased from 5.4% (63/1175) in 2008-2015 to 17.3% (82/473) in 2016-2017 (p < 0.001). Over time, TP was more often performed to achieve radicality (n = 11, 17.5% ton = 31, 37.8%;p = 0.007). In multivariable logistic regression analysis, an annual TP-volume of > 20 was associated with reduced major morbidity (odds ratio [OR] = 0.225, 95% confidence interval [CI], 0.097-0.521;p < 0.001). In the high-volume years (2016-2017), major morbidity (n = 31, 49.2% ton = 19, 23.2%;p = 0.001) and relaparotomy rate (n = 13, 20.6% ton = 5, 6.1%;p = 0.009) improved. Improvements occurred mainly after extended TP, including lower major morbidity (n = 22, 57.9% ton = 12, 25.0%;p = 0.002) and in-hospital mortality (n = 3, 7.9% ton = 0, 0%;p = 0.082).Conclusions: In a single, high-volume center study, an increase in surgical volume of TP was associated with improved perioperative outcomes, especially for extended resections.
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| 3. |
- Tannous, Bakhos A., et al.
(författare)
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Effects of the Selective MPS1 Inhibitor MPS1-IN-3 on Glioblastoma Sensitivity to Antimitotic Drugs
- 2013
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 105:17, s. 1322-1331
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Tidskriftsartikel (refereegranskat)abstract
- Background Glioblastomas exhibit a high level of chemotherapeutic resistance, including to the antimitotic agents vincristine and taxol. During the mitotic agent-induced arrest, glioblastoma cells are able to perform damage-control and self-repair to continue proliferation. Monopolar spindle 1 (MPS1/TTK) is a checkpoint kinase and a gatekeeper of the mitotic arrest.Methods We used glioblastoma cells to determine the expression of MPS1 and to determine the effects of MPS1 inhibition on mitotic errors and cell viability in combination with vincristine and taxol. The effect of MPS1 inhibition was assessed in different orthotopic glioblastoma mouse models (n = 3-7 mice/group). MPS1 expression levels were examined in relation to patient survival.Results Using publicly available gene expression data, we determined that MPS1 overexpression corresponds positively with tumor grade and negatively with patient survival (two-sided t test, P < .001). Patients with high MPS1 expression (n = 203) had a median and mean survival of 487 and 913 days (95% confidence intervals [CI] = 751 to 1075), respectively, and a 2-year survival rate of 35%, whereas patients with intermediate MPS1 expression (n = 140) had a median and mean survival of 858 and 1183 days (95% CI = 1177 to 1189), respectively, and a 2-year survival rate of 56%. We demonstrate that MPS1 inhibition by RNAi results in sensitization to antimitotic agents. We developed a selective small-molecule inhibitor of MPS1, MPS1-IN-3, which caused mitotic aberrancies in glioblastoma cells and, in combination with vincristine, induced mitotic checkpoint override, increased aneuploidy, and augmented cell death. MPS1-IN-3 sensitizes glioblastoma cells to vincristine in orthotopic mouse models (two-sided log-rank test, P < .01), resulting in prolonged survival without toxicity.Conclusions Our results collectively demonstrate that MPS1, a putative therapeutic target in glioblastoma, can be selectively inhibited by MPS1-IN-3 sensitizing glioblastoma cells to antimitotic drugs.
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