Orally Administered Probiotics in the Prevention of Chemotherapy (± Radiotherapy)-Induced Gastrointestinal Toxicity: A Systematic Review With Meta-Analysis of Randomized Trials.

BACKGROUND: Chemoradiotherapy-induced gastrointestinal toxicity may lead to a significant impairment of the oncological patient's quality of life, as well as to reduced adherence to the treatment, which may have a negative impact on survival and mortality rates. OBJECTIVE: The aim of this review was to investigate whether oral probiotic administration prevents chemotherapy (± radiotherapy)-induced gastrointestinal toxicity, particularly diarrhea. METHODS: We searched the MEDLINE, Web of Science, and SCOPUS databases for randomized controlled trials in English published between 1990 and 2020. We conducted statistical data analyses expressing the treatment effect size as a risk ratio (RR) together with a 95% confidence interval (CI). Implications are based on trials rated as having a low risk of bias (RoB). RESULTS: We included 8 trials (n = 697 participants), from which 3 studies rated as low RoB contained primary endpoint data; the risk of developing grade 3/4 diarrhea in patients receiving probiotics was reduced by 78% compared to the control group (RR = 0.22 [95% CI 0.05-1.08]; P = .06; n = 114 participants). Probiotics showed preventive effects in patients treated with chemotherapy alone (RR = 0.34 [0.12-0.94]; P = .04, n = 121 participants) and in patients with colorectal cancer (RR = 0.56 [0.34-0.92]; P = .02; n = 208 participants). The reduction in the incidence of overall diarrhea was not significant. CONCLUSIONS: Probiotics failed to prove a preventive effect of statistical significance against the development of severe and overall diarrhea in cancer patients treated with chemotherapy (± radiotherapy). However, we cannot rule out that the effects of probiotics are clinically relevant, especially in certain subgroups of patients. This needs to be clarified in further well-performed studies.

Preoperative Chemoradiotherapy for Gastroesophageal Junction Adenocarcinoma Modified by PET/CT: Results of Virtual Planning Study.

Background and Objectives: The treatment of gastroesophageal junction (GEJ) adenocarcinoma consists of either perioperative chemotherapy or preoperative chemoradiotherapy. Radiotherapy (RT) in the neoadjuvant setting is associated with a higher probability of resections with negative margins (R0) and better tumor regression rate, which might be enhanced by incrementing RT dose with potential impact on treatment results. This virtual planning study demonstrates the feasibility of increasing the dose to GEJ tumor and involved nodes using PET/CT imaging. Materials and Methods: 16 patients from the chemoradiotherapy arm of the phase II GastroPET study were treated by a prescribed dose of 45.0 Gray (Gy) in 25 fractions. PET/CT was performed before treatment. The prescribed dose was virtually boosted on PET/CT-positive areas to 54.0 Gy by 9 Gy in 5 fractions. Dose-volume histograms (DVH) were compared, and normal tissue complication (NTCP) modeling was performed for both dose schedules. Results: DVHs were exceeded in mean heart dose in one case for 45.0 Gy and two cases for 54.0 Gy, peritoneal space volume criterion V45Gy < 195 ccm in three cases for 54.0 Gy and V15Gy < 825 ccm in one case for both dose schedules. The left lung volume of 25 Gy isodose exceeded 10% in most cases for both schedules. The NTCP values for the heart, spine, liver, kidneys and intestines were zero for both schemes. An increase in NTCP value was for lungs (median 3.15% vs. 4.05% for 25 × 1.8 Gy and 25 + 5 × 1.8 Gy, respectively, p = 0.013) and peritoneal space (median values for 25 × 1.8 Gy and 25 + 5 × 1.8 Gy were 3.3% and 14.25%, respectively, p < 0.001). Conclusion: Boosting PET/CT-positive areas in RT of GEJ tumors is feasible, but prospective trials are needed.

N-of-1 Trials in Pediatric Oncology: From a Population-Based Approach to Personalized Medicine-A Review.

Pediatric oncology is a critical area where the more efficient development of new treatments is urgently needed. The speed of approval of new drugs is still limited by regulatory requirements and a lack of innovative designs appropriate for trials in children. Childhood cancers meet the criteria of rare diseases. Personalized medicine brings it even closer to the horizon of individual cases. Thus, not all the traditional research tools, such as large-scale RCTs, are always suitable or even applicable, mainly due to limited sample sizes. Small samples and traditional versus subject-specific evidence are both distinctive issues in personalized pediatric oncology. Modern analytical approaches and adaptations of the paradigms of evidence are warranted. We have reviewed innovative trial designs and analytical methods developed for small populations, together with individualized approaches, given their applicability to pediatric oncology. We discuss traditional population-based and individualized perspectives of inferences and evidence, and explain the possibilities of using various methods in pediatric personalized oncology. We find that specific derivatives of the original N-of-1 trial design adapted for pediatric personalized oncology may represent an optimal analytical tool for this area of medicine. We conclude that no particular N-of-1 strategy can provide a solution. Rather, a whole range of approaches is needed to satisfy the new inferential and analytical paradigms of modern medicine. We reveal a new view of cancer as continuum model and discuss the "evidence puzzle".

PET/CT-tailored treatment of locally advanced oesophago-gastric junction adenocarcinoma: a report on the feasibility of the multicenter GastroPET study.

BACKGROUND: Perioperative chemotherapy is a recommended treatment approach for localised oesophago-gastric junction adenocarcinoma, but not all patients respond to neoadjuvant chemotherapy. Early identification of non-responders and treatment adaptation in the preoperative period could improve outcomes. GastroPET is a national, multicentre phase II trial evaluating a 18FDG-PET/CT-guided preoperative treatment strategy with the R0 resection rate as a primary endpoint. Here, we report on the accuracy of the methodology, the feasibility of the study design and patient safety data after enrolment of the first 63 patients. METHODS: Patients with locally advanced oesophago-gastric junction adenocarcinoma (Siewert I - III) stage Ib-IIIc underwent baseline 18FDG-PET/CT scanning and re-evaluation after 14 days of oxaliplatinum-5FU-(docetaxel) chemotherapy. Responders were defined by a ⩾ 35% decrease in tumour FDG standardised uptake value (SUV)average from baseline. Responders continued with the same chemotherapy for 2 to 3 months prior to surgery. PET-non-responders switched to preoperative chemoradiotherapy [weekly carboplatin and paclitaxel with concurrent radiotherapy (45 Gy in 25 fractions)]. Here, we aim to confirm the feasibility of FDG-PET-based response assessment in a multicenter setting and to compare local versus central reading. In addition, we report on the feasibility of the study conduct and patient safety data. RESULTS: A total of 64 patients received baseline and sequential 14-day 18FDG-PET/CT scanning. And, 63 were allocated to the respective treatment arm according to PET-response [35 (56%) responders and 28 (44%) non-responders]. The concordance of local versus central reading of SUV changes was 100%. Until the date of this analysis, 47 patients (28 responders and 19 non-responders) completed surgery. Postoperative complications of grade ⩾ 3 (Common Terminology Criteria for Adverse Events, CTCAE Version 5.0) were reported in five responders (18%; 95% CI: 7.9-36%) and two non-responders (11%; 95% CI: 2.9-31%), with no statistical difference (p = 0.685). One patient in each arm died after surgery, leading to a postoperative in-hospital mortality rate of 4.3% (2/47 patients; 95% CI: 1.2-14%). CONCLUSION: Local and central FDG-SUV quantification and PET-response assessment showed high concordance. This confirms the accuracy of a PET-response-guided treatment algorithm for locally advanced oesophago-gastric junction cancer in a multicenter setting. Preoperative treatment adaptation revealed feasible and safe for patients.

Decrease in abundance of apurinic/apyrimidinic endonuclease causes failure of base excision repair in culture-adapted human embryonic stem cells.

The inevitable accumulation of chromosomal abnormalities in human embryonic stem cells (hESCs) during in vitro expansion represents a considerable obstacle for cell replacement therapies. To determine the source of chromosomal abnormalities, we examined hESCs maintained in culture for over 55 months for defects in telomere maintenance and DNA repair. Although prolonged culture affected neither telomerase activity nor nonhomologous end joining, the efficiency of base excision repair (BER) was significantly decreased and correlated with reduced expression of apurinic/apyrimidinic endonuclease 1 (APE1), the major nuclease required for BER. Interestingly, the expression of other BER enzymes was unchanged. Addition of human recombinant APE1 protein to nuclear extracts from late passage hESCs increased BER efficiency to the level typical of early passage hESCs. The link between BER and double-strand breaks (DSB) was demonstrated by decreased DSB release after downregulation of APE1 in early passage hESCs via siRNA. Correspondingly lower APE1 level in late passage hESC resulted in slower and less intensive but long lasting DSB release upon ionizing radiation (IR). Downregulation of APE1 in early passage hESCs also led to approximately 30% decrease in γ-H2AX signaling following IR, similar to that in late passage hESCs. We suggest that downregulation of APE1 significantly contributes to the failure of BER during long-term culture of hESCs, and further that BER failure is one of the factors affecting the genomic instability of hESCs by altering BER-dependent DSB release and cell cycle/checkpoint signaling.