Summary Background Until now, only imatinib and sunitinib have proven clinical benefit in patients with gastrointestinal stromal tumours (GIST), but almost all metastatic GIST eventually develop ...resistance to these agents, resulting in fatal disease progression. We aimed to assess efficacy and safety of regorafenib in patients with metastatic or unresectable GIST progressing after failure of at least imatinib and sunitinib. Methods We did this phase 3 trial at 57 hospitals in 17 countries. Patients with histologically confirmed, metastatic or unresectable GIST, with failure of at least previous imatinib and sunitinib were randomised in a 2:1 ratio (by computer-generated randomisation list and interactive voice response system; preallocated block design (block size 12); stratified by treatment line and geographical region) to receive either oral regorafenib 160 mg daily or placebo, plus best supportive care in both groups, for the first 3 weeks of each 4 week cycle. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was progression-free survival (PFS). At disease progression, patients assigned placebo could crossover to open-label regorafenib. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT01271712. Results From Jan 4, to Aug 18, 2011, 240 patients were screened and 199 were randomised to receive regorafenib (n=133) or matching placebo (n=66). Data cutoff was Jan 26, 2012. Median PFS per independent blinded central review was 4·8 months (IQR 1·4–9·2) for regorafenib and 0·9 months (0·9–1·8) for placebo (hazard ratio HR 0·27, 95% CI 0·19–0·39; p<0·0001). After progression, 56 patients (85%) assigned placebo crossed over to regorafenib. Drug-related adverse events were reported in 130 (98%) patients assigned regorafenib and 45 (68%) patients assigned placebo. The most common regorafenib-related adverse events of grade 3 or higher were hypertension (31 of 132, 23%), hand-foot skin reaction (26 of 132, 20%), and diarrhoea (seven of 132, 5%). Interpretation The results of this study show that oral regorafenib can provide a significant improvement in progression-free survival compared with placebo in patients with metastatic GIST after progression on standard treatments. As far as we are aware, this is the first clinical trial to show benefit from a kinase inhibitor in this highly refractory population of patients. Funding Bayer HealthCare Pharmaceuticals.
Summary Background The risk of recurrence of gastrointestinal stromal tumour (GIST) after surgery needs to be estimated when considering adjuvant systemic therapy. We assessed prognostic factors of ...patients with operable GIST, to compare widely used risk-stratification schemes and to develop a new method for risk estimation. Methods Population-based cohorts of patients diagnosed with operable GIST, who were not given adjuvant therapy, were identified from the literature. Data from ten series and 2560 patients were pooled. Risk of tumour recurrence was stratified using the National Institute of Health (NIH) consensus criteria, the modified consensus criteria, and the Armed Forces Institute of Pathology (AFIP) criteria. Prognostic factors were examined using proportional hazards and non-linear models. The results were validated in an independent centre-based cohort consisting of 920 patients with GIST. Findings Estimated 15-year recurrence-free survival (RFS) after surgery was 59·9% (95% CI 56·2–63·6); few recurrences occurred after the first 10 years of follow-up. Large tumour size, high mitosis count, non-gastric location, presence of rupture, and male sex were independent adverse prognostic factors. In receiver operating characteristics curve analysis of 10-year RFS, the NIH consensus criteria, modified consensus criteria, and AFIP criteria resulted in an area under the curve (AUC) of 0·79 (95% CI 0·76–0·81), 0·78 (0·75–0·80), and 0·82 (0·80–0·85), respectively. The modified consensus criteria identified a single high-risk group. Since tumour size and mitosis count had a non-linear association with the risk of GIST recurrence, novel prognostic contour maps were generated using non-linear modelling of tumour size and mitosis count, and taking into account tumour site and rupture. The non-linear model accurately predicted the risk of recurrence (AUC 0·88, 0·86–0·90). Interpretation The risk-stratification schemes assessed identify patients who are likely to be cured by surgery alone. Although the modified NIH classification is the best criteria to identify a single high-risk group for consideration of adjuvant therapy, the prognostic contour maps resulting from non-linear modelling are appropriate for estimation of individualised outcomes. Funding Academy of Finland, Cancer Society of Finland, Sigrid Juselius Foundation and Helsinki University Research Funds.
Radical surgery is the mainstay of therapy for primary resectable, localized gastrointestinal stromal tumors (GIST). Nevertheless, approximately 40% to 50% of patients with potentially curative ...resections develop recurrent or metastatic disease. The introduction of imatinib mesylate has revolutionized the therapy of advanced (inoperable and/or metastatic) GIST and has become the standard of care in treatment of patients with advanced GIST. This article discusses the proper selection of candidates for adjuvant and neoadjuvant treatment in locally advanced GIST, exploring the available evidence behind the combination of preoperative imatinib and surgery.
Abstract Background Worldwide, sentinel node biopsy (SNB) is the recommended staging procedure for stage I/II melanoma. Most melanoma guidelines recommend re-excision plus SNB as soon as possible ...after primary excision. To date, there is no evidence to support this timeframe. Aim: To determine melanoma specific survival (MSS) for time intervals between excisional biopsy and SNB in SNB positive patients. Methods Between 1993-2008, 1 080 patients were diagnosed with a positive SNB in nine Melanoma Group centers. We selected 1 015 patients (94%) with known excisional biopsy date. Time interval was calculated from primary excision until SNB. Kaplan-Meier estimated MSS was calculated for different cutoff values. Multivariable analysis was performed to correct for known prognostic factors. Results Median age was 51 years (Inter Quartile Range (IQR) 40-62 years), 535 (53%) were men, 603 (59%) primary tumors were located on extremities. Median Breslow thickness was 3.00mm (IQR 1.90-4.80mm), 442 (44%) were ulcerated. Median follow-up was 36 months (IQR 20-62 months). Median time interval was 47 days (IQR 32-63 days). Median Breslow thickness was equal for both <47 days and ≥47 days interval: 3.00mm (1.90-5.00mm) vs 3.00mm (1.90-4.43mm) (p=0.402). Sentinel node tumor burden was significantly higher in patients operated ≥47 days (p=0.005). Univariate survival was not significantly different for median time interval. Multivariable analysis confirmed that time interval was no independent prognostic factor for MSS. Conclusions Time interval from primary melanoma excision until SNB was no prognostic factor for MSS in this SNB positive cohort. This information can be used to counsel patients.
Highlights • CD28-positive CMV-specific CTL have been demonstrated as the most useful marker for CMV viremia prediction. • According to ROC analysis, value of 3 cells/μl was found to be most suitable ...for CMV activation assessment with acceptable sensitivity and specificity. • There was a relationship between values below 3 cells/μl of CD28-positive CMV-specific CTL and CMV viremia development.
Abstract Background Myxoid liposarcoma (MLPS) has been reported to be more radiosensitive compared with other soft tissue sarcomas(STS). The use of preoperative hypofractionated radiotherapy 5x5 Gy ...for five consecutive days, and then immediate surgery in patients with locally advanced STS showed a good local control rate. The main objective of our work was to assess the efficacy of hypofractionated radiotherapy in preoperative setting in patients with locally advanced primary MLPS. Methods From February 1999 till March 2014 32 patients with primary MLPS were treated with preoperative hypofractionated radiotherapy for 5 consecutive days followed by immediate surgery (median dose 5x5Gy). Median size of the tumor 10.5 cm. In one patient the tumor was located on the upper extremity, the other (31 patients) had their tumors located on the lower extremity. Results In 90% patients histologically negative surgical margins (R0) were obtained. 34% patients had distant recurrence of the disease, local recurrence was found in 9,3% of the patients. 5-year local relapse-free survival rate was 90% and overall survival was 68% In all analyzed surgical specimens the radiotherapy response features (hyalinization, fibrosis, paucicelularity, hemorrhages, dilatation of vessels) were detected. We have not found statistically significant differences in terms of OS and LRFS for RCC component, tumor grade, BCL-2, TP-53, postsurgery necrosis and tumor size. In postradiotherapy specimens significantly higher positivity of TP53 expression was detected as compared to primary biopsies. Conclusion Combined therapy with hypofractionated radiotherapy followed by immediate surgery seems to be effective therapy in MLPS demonstrating good local control and pathological response to therapy.
Background:
There is currently no consensus on optimal management of patients with primary or recurrent non-resectable/residual retroperitoneal sarcomas (RPS). The objective of this study was to ...document the outcomes of patients with primary or recurrent non-resectable/residual RPS treated in our center with definitive radiotherapy (RT) and to perform a systematic review on the topic.
Methods:
A retrospective analysis of consecutive RPS patients treated in our center between 2000 and 2019 was performed. All consecutive patients who underwent definitive conformal RT with image guidance for primary or recurrent non-resectable or macroscopically residual RPS were included. Additionally, a systematic review compliant with the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses was performed.
Results:
The study enrolled 14 patients who met the aforementioned criteria. Data on clinicopathological characteristics, RT and response to treatment were assessed. RT allowed achieving prolonged local control of the disease, i.e. no local progression of the disease for more than 12 months after RT in 10 patients. Local control lasted more than 24 months in 6 cases, with minimal or no toxicity. A systemic review of 11 studies revealed concordance of our results with previous reports of primary or recurrent non-resectable/residual RPS.
Conclusions:
RT provided satisfactory local disease control with acceptable treatment tolerance in patients with primary or recurrent non-resectable/residual RPS and represents a valuable treatment modality in the selected group of patients. Additional RT modalities i.e. BT, particle therapy, MRI-guided RT, or GRID/Lattice RT may be introduced to improve local control and further minimize toxicity.
The study aimed to determine vitamin B6 status in elderly (age ≥ 60 years) and younger (age <60 years) recipients of allogeneic kidney graft and to investigate associations between vitamin B6 status ...and immunity markers.
A retrospective observational study.
The study was conducted at the Medical University of Gdańsk, Poland.
We recruited 34 kidney allograft recipients (17 males and 17 females) and allocated them into 2 groups: patients aged ≥ 60 years (18 patients) and those aged <60 years (16 patients). Exclusion criteria included patients receiving vitamin B6 supplementation or drugs known to influence vitamin B6 metabolism.
Plasma levels of pyridoxal 5'-phosphate (PLP), pyridoxal, pyridoxine, pyridoxamine, pyridoxamine 5'-phosphate, and 4 pyridoxic acid were determined by high-performance liquid chromatography. Measured immunity markers were serum cytokines (interleukin-6, interleukin-10, and transforming growth factor-β), levels of T-lymphocyte subsets, and the proliferative ability of peripheral blood mononuclear cells.
Concentrations of all vitamin B6 vitamers in plasma (PLP, pyridoxal, pyridoxamine 5'-phosphate, pyridoxamine, pyridoxine, 4 pyridoxic acid) were comparable in the 2 studied groups. There were no cases of PLP deficiency in the study population, but 29% of patients had PLP concentrations more than the upper reference limit. Vitamin B6 vitamer concentrations were not influenced by gender, estimated glomerular filtration rate, and circulating phosphate concentration. There was no difference in immunity markers according to age. However, the plasma concentrations of vitamin B6 vitamers were inversely associated with levels of CD28(+) lymphocyte subsets, as well as with the proliferative response of peripheral blood mononuclear cells in both groups.
No cases of vitamin B6 deficiency were found among kidney allograft recipients, and we report inverse links between vitamin B6 vitamer concentrations and markers of cellular immunity, suggesting that bioactive vitamin B6 concentration in kidney allograft recipients merits further investigation.
Hypertension is closely associated with chronic kidney disease (CKD) and is one of the main factors of progression of CKD. Early detection of CKD allows introducing a therapy that slows the ...progression of CKD.
A prevalence of hypertension and effectiveness of its treatment were assessed during the accomplishment of the Program for Early Detection of CKD in Poland (PolNef).
In 456 of a total of 2476 participants of PolNef program (269 females, 187 males), CKD was recognized. Diagnosis of CKD was made according to classification proposed by K/DOQI and KDIGO. Estimated glomerular filtration rate (eGFR) from serum creatinine, albuminuria and ultrasound examination were the main diagnostic tools. Hypertension was defined on the basis of actual antihypertensive treatment or on the basis of medium value (> or = 140 and/or > or = 90) of three separate measurements of blood pressure. Frequency of hypertension and effectiveness of its treatment, frequency of overweight and obesity, microalbuminuria, and abnormalities in ultrasound examination of urinary system were studied.
Of the CKD population, 68% were hypertensive, 21% remained without antihypertensive medication, and 22% on medication were effectively treated. Kidney insufficiency with eGFR below 60 ml/min/1.73 m2 was recognized in 9% of CKD population. Also, 63% of women and 39% of men without hypertension had normal body mass compared to 19% of people with CKD and hypertension. Microalbuminuria was found in 51% of women and 66% of men with CKD and hypertension. Increased echogenicity of kidney and simple cysts were detected significantly more often in hypertensive patients.
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