Therapy-associated Side Effects Research Articles

Protoporphyrin IX in serum of high-grade glioma patients: A novel target for disease monitoring via liquid biopsy.

High-grade gliomas (HGG) carry a dismal prognosis. Diagnosis comprises MRI followed by histopathological evaluation of tissue; no blood biomarker is available. Patients are subjected to serial MRIs and, if unclear,surgery for monitoring of tumor recurrence, which is laborious. MRI provides only limited diagnostic information regarding the differentiation of true tumor progression from therapy-associated side effects. 5-aminolevulinic acid (5-ALA)is routinely used for induction of protoporphyrin IX (PpIX) accumulation in malignant glioma tissue, enablingimproved tumor visualizationduring fluorescence-guided resection (FGR). We investigated whether PpIX can also serve as a serum HGG marker to monitor relapse. Patients (HGG: n = 23 primary, pHGG; n = 5 recurrent, rHGG) undergoing FGR received 5-ALA following standard clinical procedure. The control group of eight healthy volunteers (HCTR) also received 5-ALA. Serum was collected before and repeatedly up to 72h after drug administration. Significant PpIX accumulation in HGG was observed after 5-ALA administration (ANOVA: p = 0.005, post-hoc: HCTR vs. pHGG p = 0.029, HCTR vs. rHGG p = 0.006). Separation of HCTR from pHGG was possible when maximum serum PpIX levels were reached (CI95% of tMax). ROC analysis of serum PpIX within CI95% of tMax showed successful classification of HCTR and pHGG (AUCROC 0.943, CI95% 0.884-1.000, p < 0.001); the optimal cut-off for diagnosis was 1275pmolPpIX/ml serum, reaching 87.0% accuracy, 90.5% positive predictive and 84.0% negative predictive value. Baseline PpIX level was similar in patient and control groups. Thus, 5-ALA is required for PpIX induction, which is safe at the standard clinical dosage. PpIX is a new target for liquid biopsy in glioma. More extensive clinical studies are required to characterize its full potential.

Abstract A024: Ploidy as a predictive biomarker for gemcitabine sensitivity in triple-negative breast cancers

Abstract The polyploid giant cancer cell (PGCC) state is a common response of cancer cells to various stressors including chemotherapy, irradiation, hypoxia and viral infection. Upon stress, PGCCs adopt an endoreplication in which the genome replicates, mitosis is omitted, and cells grow in size, causing drug resistance. How accessible endoreplication is to a cell, therefore, directly translates to its resistance to therapy. In this study, we hypothesized that endoreplication and PGCC state are more accessible to cancer cells that already have a higher ploidy content prior to therapy. To test this hypothesis, we developed a comprehensive three-tier framework consisting of i) computational, ii) in-vitro and iii) in silico components. First, we designed a set of ordinary differential equations (ODEs) to mathematically model how cells enter and exit the PGCC state in response to a given stressor. We engineered how this in silico approach interacts with in vitro experiments into a broadly applicable software solution called CLONEID. The software uses computer vision to monitor phenotypic changes in cell and nuclear size from standard bright-field microscopy and classify cells into PGCC and non-PGCC states. We used CLONEID to test various therapeutic agents for their ability to select for a stable near-tetraploid (4N) population in a set of near-diploid (2N) cell lines. Through spontaneous cell fusions, we also obtained tetraploid breast cancer cells matched with their parental lines. Altogether, this framework enabled us to i) monitor the PGCC state experimentally in ii) two sets of matched isogenic cell lines with 2N and 4N DNA content to iii) model the successful entry and exit rates to and from the endoreplication state, respectively. As the first application of this framework, we tested the ability of our 2N and 4N TNBC lines (SUM159 and MDA-MB-231) to access the PGCC state upon treatment with 18 chemotherapy agents. Among those drugs, we observed that only gemcitabine caused continued cell growth without cell division in both tetraploid SUM159 and MDA-MB-231 cells whereas near-diploid parental lines were hypersensitive to the treatment. Consequently, tetraploid cancer cells continued to safely grow in the presence of gemcitabine. Furthermore, these PGCCs re-entered the proliferative cell cycle and grew in cell number when treatment is terminated. Gemcitabine-based chemotherapy is a standard treatment for patients with TNBC although its efficacy is limited mainly due to drug resistance. We expect our findings and three-component framework strategy to help stratify the TNBC patient population by their response to gemcitabine. In addition, our mathematical modelling approach has the promising potential to inform personalized dose optimization and to effectively decrease administered gemcitabine dose for a subset of patients, which would alleviate severe therapy-associated side effects and co-morbidities. Citation Format: Vural Tagal, Jackson Cole, Daria Miroshnychenko, Andriy Marusyk, Noemi Andor. Ploidy as a predictive biomarker for gemcitabine sensitivity in triple-negative breast cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr A024.

Influence and Role of the Body Mass Index and Its Development on the Course of Pediatric HSCT - a Retrospective Analysis

T Stetter and M Döring contributed equally to this work. Background Children and adolescents are at increased risk of malnutrition during the course of hematopoietic stem cell transplantation (HSCT). Increased endocrine activity, a catabolic metabolic state and inflammatory processes increase the energy metabolism and therapy-associated side effects impair nutritional intake. Studies have shown that the nutritional status before HSCT in adults has a decisive influence on the time afterwards. The role of nutritional status in children and adolescents before, during, and after HSCT remains poorly understood. Patients and Methods In this monocentric, retrospective study, data from patients who underwent autologous or allogeneic HSCT at the University Children's Hospital Tübingen between November 2012 and November 2021, were analyzed. Exclusion criteria were known gastrointestinal malformations, permanent enteral/parenteral nutrition, and known chronic inflammatory bowel disease before HSCT. On three observation days (baseline: day of in-patient admission, day +30, and day +200 after HSCT) data on age-adjusted BMI percentiles, incidence of transplant-associated adverse events (TRAE; e.g., graft-versus-host disease (GvHD), veno-occlusive disease (VOD), mucositis, infection), and survival (up to 10 years after HSCT; last note in file). were collected. Patients were categorized into alloHSCT and autoHSCT Patients as well as BMI-percentile groups depending on baseline BMI percentile: &amp;lt;3rd percentile, 3rd-&amp;lt;10th percentile, 10th-&amp;lt;25th percentile, 25th-&amp;lt;50th percentile, 50th-&amp;lt;75th percentile, 75th-97th percentile, and &amp;gt;97th percentile. Results A total of 365 patients with a median age of 9 years (0-23 years), 56% of whom were female, were studied. Of these, 307 (84%) underwent allogeneic and 58 (16%) autologous HSCT. The underlying disease was malignant in 262 cases (72%) and non-malignant in 103 cases (28%). The proportions of patients fell into the corresponding BMI percentile groups at the respective observation days (see Table). During the course of time until day +200 after HSCT, the BMI percentile category remained the same in 28% of the cases, in 17%, 10%, and 3% of cases, respectively, patients moved up one, two, and &amp;gt;2 categories, respectively; in 20%, 12%, and 9% of cases, patients dropped one, two, and &amp;gt;2 categories, respectively, compared to baseline. However, comparing the alloHSCT and autoHSCT patients, a different distribution in the development until day +200 is noticeable. Overall, 27% of the alloHSCT and 44% of autoHSCT patients ascend one or more percentile groups, whereas 46% of the alloHSCT and 22% of the autoHSCT patients descend one or more BMI percentile categories. Higher-grade intestinal GvHD stage 3-4 occurred statistically more frequently in the percentile group &amp;gt;75th-97th ( p=0.0028), but when all grades were considered together, no significant clustering in any group was observed. A significant accumulation ( p=0.0413) of VOD, BKV cystitis ( p=0.0021), and Viremia ( p=0.0081) was found in the group &amp;gt;75th-97th percentile. A total of 115 patients (32%) died during the observation period. In the alloHSCT group, 35 deaths (12% of alloHSCT patients) fell under TRM. Here, of the 35 deceased, 12 (34% of deceased, 4% of total alloHSCT patients) were ascribed to the &amp;gt;75th-97th percentile group; the median proportion of deceased patients was 9% (1% of alloHSCT group) in the other percentile groups. In the autoHSCT group, a total of 23 patients (41%) died; of these, all were due to progression or recurrence of the underlying disease. The &amp;lt;3rd percentile and &amp;gt;25th-50th percentile groups each recorded the most deaths, with 26% of those who died and 11% of patients in the autoHSCT group, respectively. Conclusions Contrary to the expectation that particularly underweight pediatric HSCT patients might be more affected by complications, this data collection showed statistically clustered complications and TRM in the group of patients between the 75th-97th BMI percentiles. Although this is only a status description of body weight and length during follow-up, and not a specific survey of nutritional status, the data analysis suggests that HSCT patients in the overweight range should be focused on more closely. A prospective survey of differential nutritional status in pediatric HSCT patients is currently being conducted at our study center.

Assessment of Fertility Outcomes Following Combined Clomiphene and Letrozole Versus Letrozole Therapy for the Treatment of Polycystic Ovarian Syndrome Subfertility.

Poly Cystic Ovarian Syndrome (PCOS) affects 8-13%of women in their reproductive age and is one of the foremost causes of female subfertility. Traditionally, clomiphene citrate has been the first-line treatment for ovulation induction in PCOS. However, the European Society ofHuman Reproduction and Embryology (ESHRE) international evidence-based guidelines in 2018 recommended the use of letrozole as first-line therapy for ovulation induction in anovulatory PCOS women, due to better pregnancy and live birth rates. Here we aimed to evaluate the effect of combined - clomiphene and letrozole versus letrozole for the treatment of PCOS subfertility. It was a retrospective cohort studyconducted on reproductive-age women fulfilling Rotterdam Criteria for PCOS with a history of subfertility. All participants receiving at least one cycle of letrozole and clomiphene combination were recruited as cases. However, women receiving letrozole only for ovulation induction were taken as controls.Hospital records were abstracted for data on baseline characteristics such as age, duration of infertility, PCOS phenotype, body mass index (BMI), past medical and fertility history, treatment with ovulation induction agents, and metformin use. The mean size of the largest follicle, number of dominant follicles of size greater than 15 mm and endometrial thickness on Days 12-14 or on the day of the luteinizing hormone (LH) surge were recorded.A cycle was termed ovulatory if serum progesterone levels were > 5.0 ng/ml on the seventh day after the LH surge or day 22 in the absence of the LH surge. Data pertaining to therapy-associated side effects were also abstracted from the clinical records. Amongst the ovulatory cycles in both groups, there was no significant difference in the day of the LH surge. Serumprogesterone levels on the seventh day post-ovulation were higher with combination therapy (19.35v/s 26.71, p=0.004). The number of ovulatory cycles was also greater with combination therapy, but the difference was just short of significant (25 vs 18, p=0.08). The mean diameter of the largest follicle, incidence of multi-follicular ovulation, and thin endometrium were similar in both groups. The adverse effect profile was similar in both groups. Combination treatment of clomiphene citrate with letrozole may potentially improve fertility outcomes in PCOS subfertility in terms of the likelihood of ovulation and higher post-ovulatory progesterone levels, however, larger studies are required.

Abstract LB175: Ploidy as a predictive biomarker for gemcitabine sensitivity in triple-negative breast cancers

Abstract Polyploid giant cancer (PGCC) state is a common response of cancer cells to various stressors including chemotherapy, irradiation, hypoxia and viral infection. Upon stress, PGCCs adopt an endoreplication in which the genome replicates, mitosis is omitted, and cells grow in size, leading to resistance. How accessible endoreplication is to a cell, therefore, directly translates to its resistance to therapy. In this study, we hypothesized that endoreplication and PGCC state are more plausible to cancer cells that already have a higher ploidy content prior to therapy. To test this hypothesis, we developed a comprehensive three-tier framework consisting of i) computational, ii) in vitro and iii) in silico components. We designed a set of ordinary differential equations (ODEs) to model how cells enter and exit the PGCC state in response to a given stressor. We engineered how this in silico approach interacts with in vitro experiments into a broadly applicable software solution called CLONEID. The software uses computer vision to monitor phenotypic changes in cell and nuclear size from standard bright-field microscopy and classify cells into PGCC and non-PGCC states. We used CLONEID to test various therapeutic agents for their ability to select for a stable near-tetraploid population in a set of near-diploid cell lines. Through spontaneous cell fusions, we also obtained tetraploid breast cancer cells matched with their parental lines. Altogether, this framework, now, enables us i) to monitor the PGCC state experimentally ii) in matched cell lines with differential DNA content iii) to model the successful entrance and exit rates to and from the endoreplication state, respectively. As the first application of this framework, we tested the ability of our matched triple-negative breast cancer (TNBC) lines (SUM-159 and MDA-MB-231) to access the PGCC state upon treatment with 18 commonly-used chemotherapy agents. We observed that gemcitabine caused continued cell growth without cell division in both tetraploid SUM-159 and MDA-MB-231 cells whereas near-diploid parental cells were hypersensitive to the treatment. Consequently, tetraploid cancer cells continued to safely grow in the presence of gemcitabine. Furthermore, these PGCCs re-entered the proliferative cell cycle and grew in cell number when treatment is terminated. Gemcitabine (GEM)-based chemotherapy is a standard treatment for patients with TNBC although its efficacy is limited mainly due to drug resistance. Moreover, such poor response rate is coupled with severe side effects that frequently leads to the failure of vital organs, serious secondary diseases, and co-morbidities. Our findings suggest that ploidy is a predictive biomarker for gemcitabine sensitivity. Thus, we expect our findings and three-component framework strategy to help stratify the TNBC patient population by their response to gemcitabine. In addition, our mathematical modelling approach has the promising potential to inform personalized dose optimization and to effectively decrease administered gemcitabine dose for a subset of patients, which would alleviate therapy-associated side effects and lethalities. Citation Format: Vural Tagal, Jackson P. Cole, Daria Miroshnychenko, Andriy Marusyk, Noemi Andor. Ploidy as a predictive biomarker for gemcitabine sensitivity in triple-negative breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB175.

Physical activity and exercise therapy in oncology

Optimized and individualized treatment options in oncology significantly improve the prognosis of patients. Accordingly, the management of side effects and the avoidance of long-term consequences is becoming increasingly more important. Numerous studies have shown apositive impact of physical activity and targeted exercise therapy on certain patient-related outcomes. Ideally, patients are introduced to exercise therapy directly after the diagnosis is made in order to enable adequate supportive monitoring and to sustainably reduce therapy-associated side effects. Meanwhile, scientific findings have resulted in concrete recommendations for action to effectively improve the main patient-related outcomes, such as fatigue or depression. A moderate endurance training in combination with individualized strength training seems to be of particular importance. In principle, oncological training and exercise therapy can be recommended to every cancer patient regardless of the form of cancer and the timing of therapy but taking the contraindications into account. Therefore, the aim of communal as well as national efforts should be to implement a comprehensive offer of professional exercise therapy to facilitate access of cancer patients to these services as well as to ensure adequate care during and after treatment.

Zebrafish Models of Paediatric Brain Tumours.

Paediatric brain cancer is the second most common childhood cancer and is the leading cause of cancer-related deaths in children. Despite significant advancements in the treatment modalities and improvements in the 5-year survival rate, it leaves long-term therapy-associated side effects in paediatric patients. Addressing these impairments demands further understanding of the molecularity and heterogeneity of these brain tumours, which can be demonstrated using different animal models of paediatric brain cancer. Here we review the use of zebrafish as potential in vivo models for paediatric brain tumour modelling, as well as catalogue the currently available zebrafish models used to study paediatric brain cancer pathophysiology, and discuss key findings, the unique attributes that these models add, current challenges and therapeutic significance.

Covering of large scalp defects prior to postoperative irradiation.

After R0 resection of extensive cutaneous squamous cell carcinoma of the scalp with indication for postoperative radiotherapy, closure techniques should be chosen that allow rapid initiation of radiotherapy. The aim of this retrospective analysis is to evaluate defect coverage by transverse transposition flap and split skin grafting of the donor site in such a scenario with regard to oncologic safety (recurrence rate) and permanence of wound closure. Eleven patients were identified who had histologic cutaneous squamous cell carcinoma treated by microscopically controlled excision and defect coverage using a transverse transposition flap and split skin grafting of the donor site and who received postoperative radiotherapy. Patients were evaluated for recurrence, wound healing disorders and side effects of radiotherapy. The mean age was 81 years. Follow-up time averaged 1.4 years after the last radiotherapy session. Wound healing disorders of the transposition flap or graft necrosis were not detected. All therapy-associated side effects had resolved at follow-up. Local recurrence or metastasis did not occur. Combined transverse transposition flap plasty with split-skin grafting of the donor site is a safe treatment concept with few side effects for large scalp defects with exposed calvaria requiring postoperative radiotherapy.

Patient Preferences: Results of a German Adaptive Choice-Based Conjoint Analysis (Market Research Study Sponsored by Eli Lilly and Company) in Patients on Palliative Treatment for Advanced Breast Cancer

Introduction: Integration of patient preferences into shared decision making improves disease-related outcomes, but such data from patients with advanced breast cancer (aBC) are limited. The objective of this study was to demonstrate the relative importance of overall survival (OS) and progression-free survival (PFS) in relation to quality of life (QoL) and therapy-associated side effects from the perspective of patients with aBC. Methods: Postmenopausal patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative aBC receiving first- or second-line treatment were recruited throughout Germany. Patient-relevant attributes for aBC therapy assessment were collected using a stepwise multimodal approach. A conjoint matrix was developed, resulting in 2 attributes for therapy goals (OS and PFS), 4 for QoL, and 6 for side effects. An online quantitative survey was then performed using adaptive choice-based conjoint (ACBC) methodology. Results: The quantitative survey included 104 patients: 67 (64.4%) receiving first-line treatment and 37 (35.6%) receiving second-line treatment. The QoL attribute “physical agility and mobility” received the highest utility score (19.4 of 100%), reflecting the greatest importance to patients, followed by treatment goals (OS [15.2%] and PFS [14.4%]). Therapy-related side effects were less important, with nausea/vomiting being the most important (9.3%), followed by infection (6.4%) and hair loss (5.0%). The McFadden pseudo R² (0.805), the root likelihood (0.864), and the χ² test (2,809.041; p < 0.0001) indicated a very good fit of the statistical model. Conclusion: Using ACBC analysis, it appears that QoL, OS, and PFS are most important to postmenopausal patients with aBC in relation to cancer treatment. Side effects seem to be less important if OS or PFS are prolonged and the QoL is maintained. Thus, QoL, OS, and PFS should be considered equally when making treatment decisions in aBC.

Meta-analysis of the efficacy of probiotic-supplemented therapy on the eradication of H. pylori and incidence of therapy-associated side effects

Traditional therapies for Helicobacter pylori (H. pylori) infection remain hindered by the antibiotic resistance of the pathogen and the poor therapeutic compliance of patients. To address these issues, probiotics have been added as an adjunctive therapy. This meta-analysis aimed to evaluate the efficacy of probiotic supplementation during standard therapy on the eradication rate of H. pylori infection and incidence of therapy-related side effects. Four online databases were searched for eligible studies without language restriction. Review Manager (REVMAN, Version 5.3) was used to perform all data analyses. Forty articles including 5792 patients met our criteria and were included in the analysis. Notably, probiotic supplementation improved the eradication rate by approximately 10% relative to the control group [odds ratio (OR), 1.94, 95% confidence interval (CI): 1.70–2.22, P < 0.00001]. The incidence of total side effects (OR, 0.56, 95% CI: 0.45–0.70, P < 0.00001) and individual symptoms (e.g., diarrhea, vomiting and nausea, constipation, epigastric pain, taste disturbance) also decreased significantly with probiotic supplementation. No other differences in side effects were observed between the experimental and control groups. Moreover, a longer duration (≥10 days) of probiotic treatment had positive effects on both eradication rate of H. pylori and incidence of overall side effects.

Abstract P1-17-08: Patient preferences: Results of a German adaptive choice-based conjoint analysis study in patients on palliative treatment for advanced breast cancer (aBC)

Abstract Objective: This study aimed to identify patient preferences in aBC related to cancer treatment characteristics, i.e. to determine the relevance of gained lifetime (OS) and time to progression (PFS) in relation to quality of life (QoL) and therapy-associated side effects. Methods: Post-menopausal women with HR+/HER2-aBC receiving 1st or 2nd line treatment were recruited throughout Germany. Patient relevant attributes to assess aBC therapies were collected in a stepwise multi-methodological approach, consisting of desk research, qualitative interviews with patients (n=12), caregivers (n=3) and aBC treating physicians (n=2) and iterative reviews of the empirical findings in a cross-functional team. A draft conjoint matrix was developed which was refined by means of two pre-tests with aBC patients (n=9). The final conjoint matrix consisted of two attributes for therapy goals (OS and PFS), four for QoL and six for side effects. It represented the basis of the subsequent quantitative survey using adaptive choice-based conjoint methodology. Results: In the qualitative phase, QoL emerged as a multidimensional concept, consisting of several factors such as ability to lead a ‘normal’ life, physical capability to do things like before, mobility, carefreeness (not continuously be reminded of the disease), having goals and being able to go for them, and spend quality time with family and friends. Factors limiting QoL were symptom burden, medical controls and side effects, which were considered particularly disturbing if long-lasting, affecting everyday life and when effective management was not available. The quantitative sample consisted of 104 patients (67% 50-64 yrs/33% &amp;gt;65 yrs). Time from aBC diagnosis to survey participation was ≤5 years and &amp;gt;5 years in 50% of patients each. At the time of the survey, 67 patients (64.4%) were receiving 1st line and 37 (35.6%) 2nd line treatment, i.e. regular oral intake in 80%, regular injections in 29% and regular infusions in 15% of patients; the start of the current treatment was ≤1 year in 43% and &amp;gt;1 year in 57% of patients. QoL parameters (physical mobility and flexibility) received the highest value (19.4%), followed by treatment goals (OS 15.2%, PFS 14.4%). Therapy-related side effects turned out to be less important overall with nausea/vomiting being the most relevant side effect (9.3%), followed by infection risk (6.4%), diarrhea (2.9%) and mucosal dryness (1.2%). No significant differences were found between 1st and 2nd line patients. A relation between having experienced a side effect in the past and a desire to avoid it was identified for nausea, vomiting, and dry mucosa. There was no relation between the desire to avoid a side effect and its severity in the past. McFadden pseudo R2 (0.805), Root-Likelihood (0.864) and Chi-square test (2809.041, highly significant (p&amp;lt;0.0001)) demonstrated excellent statistical quality. Conclusions: This study indicated that QoL, PFS and OS are major drivers for therapy selection. Maximizing lifetime may be not an absolute goal and only desirable if no major loss of QoL occurs. Avoiding specific side effects was less relevant than maintaining QoL Citation Format: Mattea Reinisch, Norbert Marschner, Thorsten Otto, Agnieszka Korfel, Clemens Stoffregen, Achim Wöckel. Patient preferences: Results of a German adaptive choice-based conjoint analysis study in patients on palliative treatment for advanced breast cancer (aBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-17-08.

Radiation-induced astrocyte senescence is rescued by Δ133p53.

Cellular senescence and the senescence-associated secretory phenotype (SASP) may contribute to the development of radiation therapy-associated side effects in the lung and blood vessels by promoting chronic inflammation. In the brain, inflammation contributes to the development of neurologic disease, including Alzheimer's disease. In this study, we investigated the roles of cellular senescence and Δ133p53, an inhibitory isoform of p53, in radiation-induced brain injury. Senescent cell types in irradiated human brain were identified with immunohistochemical labeling of senescence-associated proteins p16INK4A and heterochromatin protein Hp1γ in 13 patient cases, including 7 irradiated samples. To investigate the impact of radiation on astrocytes specifically, primary human astrocytes were irradiated and examined for expression of Δ133p53 and induction of SASP. Lentiviral expression of ∆133p53 was performed to investigate its role in regulating radiation-induced cellular senescence and astrocyte-mediated neuroinflammation. Astrocytes expressing p16INK4A and Hp1γ were identified in all irradiated tissues, were increased in number in irradiated compared with untreated cancer patient tissues, and had higher labeling intensity in irradiated tissues compared with age-matched controls. Human astrocytes irradiated in vitro also experience induction of cellular senescence, have diminished Δ133p53, and adopt a neurotoxic phenotype as demonstrated by increased senescence-associated beta-galactosidase activity, p16INK4A, and interleukin (IL)-6. In human astrocytes, Δ133p53 inhibits radiation-induced senescence, promotes DNA double-strand break repair, and prevents astrocyte-mediated neuroinflammation and neurotoxicity. Restoring expression of the endogenous p53 isoform, ∆133p53, protects astrocytes from radiation-induced senescence, promotes DNA repair, and inhibits astrocyte-mediated neuroinflammation.

Patient Co-Morbidity Profile Should Drive PI3K Inhibitor Selection for Relapsed Follicular Lymphoma

Background: Idelalisib (Zydelig®, IDELA), an oral agent, and copanlisib (Aliqopa®, COPA), an intravenous agent, are the only B-cell receptor pathway targeting agents approved for treatment of follicular lymphoma (FL). Both agents target PI3Kδ while COPA also targets PI3Kα. These drugs received accelerated approvals, and overall response rates in their respective phase 2 trials were comparable. Safety profiles may be impacted by distinct kinase inhibitory profiles, delivery method, and dosing. Given similar response rates with these agents, the administration schedule and safety profile become important considerations. A challenge is the appropriate regimen choice to maximize anti-tumor benefit while limiting treatment-emergent adverse events (TEAEs) or exacerbation of pre-existing co-morbidities. Objective: To compare the safety profiles of IDELA and COPA to determine which drug may be more suitable for select patient populations. Methods: We selected key AEs for analysis based on the "Highlights of Prescribing Information" in each drug9s United States package insert (USPI) to assess the incidence of TEAEs in patients receiving COPA or IDELA. Using the Safety Analysis Set for patients with iNHL treated with IDELA (N=163, median duration of treatment [mDoT] 27 weeks) and TEAEs reported for patients with FL and other hematological malignancies treated with COPA (Aliqopa® USPI [N=168, mDoT 22 weeks], Dreyling et al., J. Clin. Oncol. 2017; 35:3898 [N=142, mDoT 22 weeks], and Dreyling et al., Blood. 2017; 130:2777 [N=142, mDoT 26 weeks]), we ascertained the most common TEAEs, compared the incidence of specific TEAEs (estimate difference in proportions, Fisher9s exact test), and assessed the effect of pre-existing conditions on IDELA- and COPA-mediated AEs. Results: All grade (aGr) and grade 3/4 (Gr3/4) diarrhea and transaminitis were significantly more common in IDELA-treated patients, and aGr and Gr3/4 hyperglycemia (blood glucose >160 mg/dL and >250 mg/dL, respectively) and hypertension (systolic blood pressure [SBP] >120 mmHg; diastolic blood pressure [DBP] > 80 mmHg and SBP > 160 mmHg; DBP > 100 mmHg, respectively) were significantly more common in COPA-treated patients (Figs. 1 and 2). The incidences of aGr and Gr3/4 infection, neutropenia, and pneumonitis were similar in IDELA- and COPA-treated patients. IDELA-treated patients with pre-existing diabetes mellitus or hyperglycemia experienced more Gr3/4 hyperglycemia than IDELA-treated patients without either diagnosis (7.1% vs. 0%, p=0.0286), but at rates lower than in COPA-treated patients (10.7% vs. 53.6%, p Conclusion: Pre-existing co-morbidities and the nature of emergent therapy-associated side effects (including type, severity, and duration [transient vs. chronic]) may impact PI3K inhibitor choice for the treatment of relapsed FL. Findings in this analysis suggest that for patients with pre-existing diabetes mellitus or hypertension, IDELA may be a more appropriate option. For patients at increased risk for diarrhea-related complications, COPA may be a more appropriate option. IDELA-treated patients should be followed closely for diarrhea and should be monitored routinely for hepatotoxicity regardless of hepatic status at treatment initiation. Patients treated with either compound should be followed closely for infection, neutropenia, and pneumonitis. Disclosures Ye:Gilead Sciences, Inc.: Employment, Equity Ownership. Xing:Gilead Sciences: Employment. Roudet:Gilead Sciences, Inc.: Employment. Ruzicka:Gilead Sciences, Inc.: Employment. Dreyling:Bayer: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Acerta: Consultancy; Sandoz: Consultancy. Zinzani:Janssen: Honoraria, Speakers Bureau; Gilead: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Speakers Bureau; Bayer: Membership on an entity9s Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity9s Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity9s Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity9s Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity9s Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Takeda: Membership on an entity9s Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Gopal:Teva: Research Funding; Asana: Consultancy; Incyte: Consultancy; Merck: Research Funding; Aptevo: Consultancy; Janssen: Consultancy, Research Funding; Spectrum: Research Funding; Takeda: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Brim: Consultancy.

Special situations of preconditioning and prehabilitation in oncological visceral surgery

Prehabilitation prior to complex visceral oncological surgery is playing an increasingly important role. The aim of this review article is to present special situations of preconditioning in visceral oncological patient cohorts. The following conditions were defined as special situations with subsequently increased risk profile: cardiopulmonary comorbidities, geriatric patients, neoadjuvant therapy and simultaneous fatigue. Aselective literature review based on asearch in the electronic databases MEDLINE, PubMed, Cochrane Library and the International Standard Randomization Controlled Trial Number (ISRCTN) was performed. The identification of high-risk patients is an essential part of the preoperative evaluation conducted by the anesthesiologist prior to surgery. The cardiovascular and the pulmonary risk profile are determined by means of prediction indices evaluating patient-specific and surgery-related risk factors. The increased use of new oral anticoagulants and dual platelet aggregation inhibition requires individualized treatment strategies. Numerous studies have shown clinically relevant effects of exercise therapy interventions throughout all phases of oncological treatment. In addition to positive effects on therapy-associated side effects, sport can also counteract the effects of sedentary behavior in cancer patients and improve the health-related quality of life. The effectiveness of sport and exercise therapies as well as psychological interventions in oncological patients with fatigue (CRF) is broad, with important components being motivation and compliance. In high-risk patients an interdisciplinary approach to planning and conduction of prehabilitation is essential for the early detection and optimization of perioperative risk factors and potential complications. The aim is faster recovery, reduced morbidity and mortality and the possibility to improve long-term survival and quality of life.

Clinical trials in pediatric neuro-oncology: what is missing and how we can improve.

Brain tumors are the most common solid tumor in childhood, yet outcomes vary dramatically. High-grade gliomas have dismal outcomes with poor survival. By contrast, low-grade gliomas, have high survival rates, but children suffer from morbidity of tumor burden and therapy-associated side effects. In this article, we discuss how current trial designs often miss the opportunity to include end points beyond tumor response and thus fail to offer complete assessments of therapeutic approaches. Quality of life, neurocognitive function and neurofunctional deficits need to be considered when assessing overall success of a therapy. Herein, we identify specific end points that should be included in the interpretation of clinical trial results and accordingly, offer a more comprehensive approach to treatment decision-making.

Classical Hodgkin’s Lymphoma: Pathogenesis and Future Treatment Directions

Classical Hodgkin Lymphoma is a germinal center B cell malignancy. Over the past 40 years, through greater understanding of disease pathogenesis, advancements in treatment have lead to greater than 80% long-term survival rates after standard first line therapy. Currently, first-line management of the disease varies, most commonly involving the use of a standard chemotherapy regime (i.e. ABVD or BEACOPP), with or without the use of additional chemotherapies or involved-field radiation therapy. Treatment selection is influenced by disease staging at diagnosis and the need to maintain therapeutic efficacy, whilst minimising the risk of late and potentially fatal therapy-associated side effects. Consequently, higher than acceptable drug-associated toxicities and patient relapse represent the future challenges of this disease. Novel therapies, targeting the aberrant signalling pathways and phenotypic features of the malignant cell pool, and its associatedinflammatory infiltrate, are the future direction of disease management. Currently, combination therapies targeting the PI3K/Akt/mTOR pathway and transcription modulation have shown the greatest clinical efficacy in improving survival outcomes in previously heavily treated cHL patients, with minimal side effects. Whilst these therapies do not yet achieve the clinical efficacy of first line therapies, preliminary stage I and II trials havedemonstrated a reduction in drug associated toxicities and side effects relative to existing treatments for relapse. This paper will investigate current understanding of the pathogenesis of cHL, and how this has shaped the targets of novel therapies for the disease.

Systematic review with meta-analysis: Saccharomyces boulardii supplementation and eradication of Helicobacter pylori infection.

Unsatisfactory Helicobacter pylori eradication rates and therapy-associated side effects remain a problem. To update our 2010 meta-analysis on the effects of Saccharomyces boulardii as supplementation to a standard eradication regimen on H. pylori eradication rates and therapy-associated side effects. The Cochrane Library, MEDLINE and EMBASE databases were searched from July 2010 (end date of last search) to February 2015, with no language restrictions, for randomised controlled trials (RCTs); additional references were obtained from reviewed articles. Quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) guidelines. Eleven RCTs (2200 participants, among them 330 children) met the inclusion criteria. Of the 853 patients in the S. boulardii group, 679 (80%, 95% CI 77-82) experienced eradication compared with 608 of the 855 patients (71%, 95% CI 68-74) in the control group [relative risk (RR) 1.11, 95% confidence interval (CI) 1.06-1.17; moderate quality evidence]. S. boulardii compared with control reduced the risk of overall H. pylori therapy-related adverse effects (RR 0.44, 95% CI 0.31-0.64; moderate quality evidence), particularly of diarrhoea (RR 0.51, 95% CI 0.42-0.62; high quality evidence) and nausea [RR 0.6, 95% CI 0.44-0.83 (moderate quality of evidence)]. In the populations studied, the effectiveness of standard triple therapy was unsatisfactory. The addition of S. boulardii significantly increased the eradication rate, but it was still below the desired level of success. Saccharomyces boulardii significantly decreased some therapy-related side effects.

&amp;lt;i&amp;gt;Lactobacillus&amp;lt;/i&amp;gt; GG Supplementation on Anti-&amp;lt;i&amp;gt;Helicobacter pylori&amp;lt;/i&amp;gt; Therapy-Related Side Effects and Eradication Rates: A Meta-Analysis

Background: Concerns still exist with respect to unsatisfactory eradication rates and/or therapy-associated side effects for the use of standard triple therapy in the treatment of Helicobacter pylori infection, which prompts considerable interest in new therapy. We systematically reviewed the literature to investigate whether Lactobacillus GG as supplementation to standard triple therapy could improve H. pylori eradication rates and/or reduce therapy-associated side effects. Methods: PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) were systematically searched from their inception to August 4, 2015 for randomized controlled trials (RCTs). The language was restricted to English only. Results: Four RCTs involving a total of 305 participants (including 83 children) were included. Lactobacillus GG given along with triple therapy significantly reduced the risk of overall H. pylori therapy-related adverse effects (three RCTs, n = 221, RR 0.59, 95% CI 0.45 - 0.78), particularly of diarrhea (four RCTs, n = 285, RR 0.23, 95% CI 0.11 - 0.47), bloating (four RCTs, n = 289, RR 0.61, 95% CI 0.41 - 0.90), and taste disturbance (four RCTs, n = 288, RR 0.38, 95% CI 0.23 - 0.62). There were no significant differences between groups in the risk of other adverse effects. No beneficial effects of Lactobacillus GG were observed for H. pylori eradication rates (four RCTs, n = 284, RR 0.99, 95% CI 0.88 - 1.13). Conclusion: Current evidence indicates that Lactobacillus GG administered along with standard triple therapy is a feasible way to reduce therapy-related side effects, particularly diarrhea, bloating, and taste disturbance. However, Lactobacillus GG shows no effects on eradication rates.

Nutritional support in the treatment of patients with gastrointestinal cancer

Patients with gastrointestinal(GI) tract neoplasms usually suffer from malnutrition, which is associated with increased morbidity and mortality, reduction of treatment efficacy, increased risk of therapy-associated side-effects, increased length of hospital stay, and reduced quality of life. Proposing an adaptive nutritional support at each step of a multidisciplinary treatment approach for GI cancer is essential.

In vivo assessment of antiretroviral therapy-associated side effects

Antiretroviral therapy has been associated with side effects, either from the drug itself or in conjunction with the effects of human immunodeficiency virus infection. Here, we evaluated the side effects of the protease inhibitor (PI) indinavir in hamsters consuming a normal or high-fat diet. Indinavir treatment increased the hamster death rate and resulted in an increase in triglyceride, cholesterol and glucose serum levels and a reduction in anti-oxLDL auto-antibodies. The treatment led to histopathological alterations of the kidney and the heart. These results suggest that hamsters are an interesting model for the study of the side effects of antiretroviral drugs, such as PIs.