| 1. |
- Ekman, Simon, et al.
(författare)
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Hsp90 as a therapeutic target in patients with oesophageal carcinoma
- 2010
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Ingår i: Expert opinion on therapeutic targets. - : Informa Healthcare. - 1472-8222 .- 1744-7631. ; 14:3, s. 317-328
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Forskningsöversikt (refereegranskat)abstract
- Importance of the field: Oesophageal carcinoma has a poor prognosis with a 5-year overall survival rate of only 10 - 20%. The disease is often diagnosed at a late stage, when dissemination may already have occurred, contributing to the poor prognosis. However, recent developments in targeted therapy now offer new possibilities in the treatment arsenal. Heat shock protein 90 (Hsp90) has been demonstrated to protect oncogenic variants of signalling molecules from degradation, thus promoting cell growth and survival. Hsp90 has been found to be abundantly expressed in oesophageal cancer and may serve as a therapeutic target in the treatment of this disease. Areas covered in this review: We have summarised available data concerning the role of Hsp90 in oesophageal carcinoma as well as available information on other tumour types. What the reader will gain: To be able to elaborate on the molecular mechanisms of action of Hsp90 and discuss state-of-the-art of clinical trials involving Hsp90 inhibitors in malignancies, with a special emphasis on oesophageal cancer. Take home message: Preclinical studies on Hsp90 inhibition in oesophageal cancer are promising and it is anticipated that in the near future clinical trials with Hsp90 inhibitors will be initiated also for oesophageal cancer, using the experience from other trials.
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| 2. |
- Lövgren, Tanja, et al.
(författare)
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Complete and long-lasting clinical responses in immune checkpoint inhibitor-resistant, metastasized melanoma treated with adoptive T cell transfer combined with DC vaccination
- 2020
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Ingår i: Oncoimmunology. - : TAYLOR & FRANCIS INC. - 2162-4011 .- 2162-402X. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Development of T cell-directed immune checkpoint inhibitors (ICI) has revolutionized metastatic melanoma (MM) therapy, but <50% of treated patients experience durable responses. This phase I trial (NCT01946373) investigates the safety/feasibility of tumor-infiltrating lymphocyte (TIL) adoptive cell therapy (ACT) combined with dendritic cell (DC) vaccination in MM patients progressing on ICI. An initial cohort (5 patients) received TIL therapy alone to evaluate safety and allow for optimization of TIL expansion protocols. A second cohort (first-in-man, 5 patients) received TIL combined with autologous tumor lysate-loaded DC vaccination. All patients received cyclophosphamide/fludarabine preconditioning prior to, and intravenous (i.v.) IL-2 after, TIL transfer. The DC vaccine was given as five intradermal injections after TIL and IL-2 administration. [F-18]-FDG PET/CT radiology was performed to evaluate clinical response, according to RECIST 1.1 (on the CT part). Immunological monitoring was performed by flow cytometry and T-cell receptor (TCR) sequencing. In the safety/optimization cohort, all patients had a mixed response or stable disease, but none durable. In the combination cohort, two patients experienced complete responses (CR) that are still ongoing (>36 and >18 months, respectively). In addition, two patients had partial responses (PR), one still ongoing (>42 months) with only a small bone-lesion remaining, and one of short duration (<4 months). One patient died early during treatment and did not receive DC. Long-lasting persistency of the injected TILs was demonstrated in blood. In summary, we report clinical responses by TIL therapy combined with DC vaccination in 4 out of 4 treated MM patients who previously failed ICI.
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| 3. |
- Tabernero, Josep, et al.
(författare)
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A Randomized Phase III Study of Arfolitixorin versus Leucovorin with 5-Fluorouracil, Oxaliplatin, and Bevacizumab for First-Line Treatment of Metastatic Colorectal Cancer : The AGENT Trial
- 2024
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Ingår i: Cancer Research Communications. - : American Association For Cancer Research (AACR). - 2767-9764. ; 4:1, s. 28-37
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Tidskriftsartikel (refereegranskat)abstract
- Purpose:Suboptimal treatment outcomes with 5-fluorouracil (5-FU)/folate, the standard of care for metastatic colorectal cancer (mCRC), have generated interest in optimizing the folate. Arfolitixorin ([6R]-5,10-methylene-tetrahydrofolate) is an immediately active folate and may improve outcomes over the existing standard of care (leucovorin).Experimental Design:AGENT was a randomized, phase III study (NCT03750786). Patients with mCRC were randomized to arfolitixorin (120 mg/m2 given as two intravenous bolus doses of 60 mg/m2) or leucovorin (400 mg/m2 given as a single intravenous infusion) plus 5-FU, oxaliplatin, and bevacizumab. Assessments were performed every 8 weeks. The primary endpoint was the superiority of arfolitixorin for overall response rate (ORR).Results:Between February 2019 and April 2021, 490 patients were randomized (245 to each arm). After a median follow-up of 266 days, the primary endpoint of superiority for ORR was not achieved (48.2% for arfolitixorin vs. 49.4% for leucovorin, Psuperiority = 0.57). Outcomes were not achieved for median progression-free survival (PFS; 12.8 and 11.6 months, P = 0.38), median duration of response (12.2 and 12.9 months, P = 0.40), and median overall survival (23.8 and 28.0 months, P = 0.78). The proportion of patients with an adverse event of grade ≥3 severity was similar between arms (68.7% and 67.2%, respectively), as was quality of life. BRAF mutations and MTHFD2 expression were both associated with a lower PFS with arfolitixorin.Conclusions:The study failed to demonstrate clinical benefit of arfolitixorin (120 mg/m2) over leucovorin. However, it provides some useful insights from the first-line treatment setting, including the effect of gene expression on outcomes.Significance:This phase III study compared arfolitixorin, a direct-acting folate, with leucovorin in FOLFOX plus bevacizumab in mCRC. Arfolitixorin (120 mg/m2) did not improve the ORR, potentially indicating a suboptimal dose.
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| 4. |
- Tell, Roger
(författare)
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Description and prediction of clinical radiosensitivity : emphasis on normal tissue reactions
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There is a range in the severity of normal tissue reactions observed when cancer patients receive radiotherapy (RT). The limits of dosage in RT have empirically been set by doses that have caused severe reactions in the most sensitive patients. The understanding of factors governing variations of radiosensitivity is therefore very important in RT. This thesis describes specific normal tissue effects after irradiation and explores factors behind this. In this work special emphasis has been put on sensitivity of the thyroid and the lung to RT. RT of head and neck cancer frequently involves the thyroid gland and can cause thyroid dysfunction. The thyroid function was prospectively studied in a cohort of 391 patients with head and neck cancer admitted for external RT. The median follow-up was 19 months. Seventeen of 264 evaluable patients (6%) developed clinical hypothyroidism (increased TSH/decreased FT4) whereas chemical hypothyroidism (increased TSH/normal FT4) developed in 57 patients (22%). At 3 years after treatment, the actuarial risk of hypothyroidism was 15% (clinical) and 40% (chemical), respectively. The thyroid fraction included in the treatment volume was a significant risk factor (p = 0.041). Using the cohort described above, we further studied the long-term incidence of clinical hypothyroidism in 308 evaluable patients. The median follow-up in this study was 4.2 years. The incidence of clinical hypothyroidism was 17%, and the median time to development of hypothyroidism was 1.8 years. The 5 and 10 years Kaplan-Meier actuarial risk of hypothyroidism was 20% and 27%, respectively. Multivariate analysis of data showed that bilateral neck irradiation (relative hazard [RH] 0.37, p = 0.02), pre-TSH value (RH 1.58, p < 0.001), addition of surgery (p < 0.001), and if surgery involved the thyroid gland (RH 4.74. p < 0.001) were significant risk factors. If surgery did not involve the thyroid gland, there was, however, no increased risk compared with no surgery (RH 1.44, p = 0.305). Individual sensitivity of the thyroid to radiation may also be investigated in cohorts that have received radioiodine (131I). Several studies have attempted to determine factors that may predict response to 131I, but none have been adopted widely. We have examined if clinical features, thyroid 24-h 131I uptake test before and 12 weeks after 131I therapy and treatment factors may predict the response of 1290 patients with thyrotoxicosis. Multivariate logistic regression of pre-treatment factors showed that a low 131I uptake was a statistically significant covariate for remission after one 131I treatment (odds ratio 0.61,p < 0.001). Clinical type was also a significant variable in the multivariate assessment (overall, p = 0.001). The post-treatment 131I uptake test data suggest that an uptake of 20% or less is related to a favourable outcome after 131I therapy for thyrotoxicosis. A well-known effect of exposure to RT is a cell cycle arrest in proliferating cells with a very characteristic accumulation of cells in G2 phase. In a study on 49 head and neck cancer patients admitted for RT, we evaluated radiation-induced cell cycle delay in lymphocytes and related it to treatment outcome. Cell cycle changes were measured in mitogen-stimulated peripheral blood lymphocytes before and after irradiation. Non-responding patients had a high level of S-phase cells compared with partial (p < 0.001) and complete responders (p = 0.016). An inverse relationship was found when analysing the fraction of cells in G2 (p = 0.009 and p = 0.034, respectively). Responding patients thus had an increased G2 phase accumulation in comparison with non-responders. From a cohort of 177 breast cancer patients, 16 patients (9%) developed severe early lung reactions after RT. In these patients we measured radiation-induced cell cycle delays of lymphocytes and analysed them together with matched control patients. Cells from the control patients responded to a higher extent to mitogen stimulation than cells from the cases (p < 0.05). Analysis of S and G2 phase accumulation showed a significant dose-response effect (p < 0.001) but no significant difference between the two groups. We also studied whether there is a correlation with serum factors known to be involved in the pathogenesis of lung injuries. There was no difference between patients who did and did not develop pulmonary injury after RT with respect to plasma levels of TGF-01 or GSH as has been suggested by other authors. When using the thyroid and the lungs for the analysis of side-effects of RT, we found factors like initial-TSH and 24-h 1311 thyroid uptake tests to be of significant importance for the outcome. It is likely that the background of the variations in sensitivity should be explored in the genetic polymorphism of individuals probably involving several genes.
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| 5. |
- Tell, Roger, et al.
(författare)
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Multicentre Phase II Trial of Paclitaxel and Carboplatin with Concurrent Radiotherapy in Locally Advanced Non-small Cell Lung Cancer
- 2008
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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 28:5B, s. 2851-2857
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To evaluate weekly, induction chemotherapy followed by weekly concomitant chemoradiotherapy in a multicentre phase II study of patients with wiresectable stage III non-small cell lung cancer (NSCLC; stage wet IIIB excluded). Patients (aid Methods: Eligible patients received three weekly cycles of paclitaxel 100 mg/m(2) and carboplatin AUC2 followed by six weekly cycles of paclitaxel 60 mg/m(2) and carboplatin AUC2 in combination with thoracic radiotherapy (2 Gy per fraction and day to a total (lose of 60 Gy), Results: Sixty-four patients (40 males and 24 females) with a median age of 63 Years (range, 43-79 years) entered the study. T and N stage were distributed as follows: T1 2 patients (3.2%). T2 10 patients (15.6%), T3 15 patients (23.4%). T4 37 patients (57.8%), N0 10 patients (15.6%). N1 1 patient (1.6%), N2 26 patients (40.6%), N3 26 patients (40.6%), and N missing I patient (1.6%). Seven patients (10.9%) suffered from grade 314 oesophagitis. Grade 112 oesophagitis occurred in 36 patients (56.3%) and pneumonitis grade 112 occurred in 10 patients (15.6%). Sixty-three patients were evaluated on an intent-to-treat basis. The overall response rate was 74.6%. The median time to progression was 247 days and median overall survival was 461 days. According to subgroup analyses, no statistically signicant differences were noted according to gender, age (<65 vs. >= 65 years), perfromance status, histology, or study centre. Conclusion: Induction chemotherapy followed by concurrent chemoradiotherapy with weekly cycles of paclitaxel and carboplatin is feasible and generates moderate toxicity. Efficacy is comparable to other recently published regimens. However, prognosis remains, ill general, poor for this group of patients and further work to develop better therapy is required.
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