Factors That Influence Physical Activity Behavior in Children and Adolescents During and After Cancer Treatment: A Qualitative Systematic Review of the Literature.

PURPOSE: The aim of this systematic review is to reveal the social, personal, and contextual factors that influence physical activity (PA) in children and adolescents during and after cancer treatment. METHOD: SPORTDiscus, Cochrane, Web of Science, PubMed, and FIS Education electronic database were systematically searched. RESULTS: The 13 included studies show that social support (parents, siblings, and friends) in particular is rated as important by cancer survivors; for example, doing PA together. Depending on the treatment status and state of health, particularities arise. During the acute treatment phase, parents issued more prohibitions regarding PA than after treatment. The state of health and concern about infections are described as inhibiting factors. Not all hospitals generally offer special exercise programs for cancer patients, and in some cases, only sporadic exercise sessions were conducted by specialized staff. In addition, the hospital atmosphere, such as cramped rooms, tends to be associated with demotivating effects. CONCLUSIONS: Both inhibiting and promoting factors in the area of social, personal, and contextual factors could be identified. The most fundamental factor for PA is the physical condition. Social factors, such as parents or friends, often have a motivating effect and can promote PA. Inhibiting factors are mainly context-related, such as an environment unsuitable for PA. Although the review highlights interesting aspects, further treatment-related and longitudinal studies could provide deeper insights.

Eyelid and conjunctival mast cell tumors: A retrospective study of 26 dogs and 8 cats.

OBJECTIVE: The objective of the study was to describe clinical and histologic characteristics of eyelid (LMCT) and conjunctival (CMCT) mast cell tumors in dogs and cats presented to a referral clinic in Germany. ANIMAL STUDIED: Medical records were reviewed to identify dogs and cats diagnosed with LMCTs or CMCTs between 2006 and 2020. RESULTS: LMCT were diagnosed in 31 patients and were cutaneous (n = 28; 20 dogs and 8 cats) or subcutaneous (three dogs). Five cases involved the mucocutaneous junction (four dogs, one cat). CMCTs occurred only in dogs (n = 3). At the time of presentation two of the four canine LMCT cases involving the mucocutaneous junction had metastasized to a mandibular lymph node. When applying the Kiupel system, both these cases were categorized as high grade. 85.7% (18/21) of the canine (19 cutaneous and 2 subcutaneous) LMCT and all CMCT cases were categorized as Kiupel low grade. No local recurrences occurred in all LMCT cases in which clean surgical margins were obtained (n = 18, mean surgical margin width: dogs 9.4 mm, cats 3.8 mm). Two cats (2/4) and four dogs (4/7) with questionable or incomplete surgical margins experienced local recurrences (mean time to recurrence of 180 and 637 days in dogs and cats, respectively). CONCLUSION: Recurrence of low-grade LMCTs and CMCTs following excision with clean margins is rare. Tumors involving the mucocutaneous junction may be of higher grade and prone to lymphatic metastasis.

Clinical Outcome for Patients Managed with Low-Dose Cisplatin and Doxorubicin Delivered as Pressurized Intraperitoneal Aerosol Chemotherapy for Unresectable Peritoneal Metastases of Gastric Cancer.

BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is increasingly used to manage gastric cancer peritoneal metastasis (GCPM). METHODS: This study analyzed a prospective database of GCPM patients treated with cisplatin and doxorubicin PIPAC (PIPAC-C/D). The outcome criteria were adverse events, pathologic response [peritoneal regression grading score (PRGS)], and overall survival (OS). RESULTS: The PIPAC-C/D procedure was scheduled for 144 patients with a median age of 57 years (range 22-88 years). Access to the abdominal cavity for the first PIPAC failed in 11 patients (7.7 %). A total of 296 procedures were performed for 131 patients. Of the 144 patients, 52 (36.1%) underwent one PIPAC, 32 (22.2%) underwent two PIPACs, 24 (16.7%) underwent three PIPACs, and 21 (14.6%) underwent four or more PIPACs. The overall morbidity/mortality was grade 1 for 22 patients (15.3%), grade 2 for 32 patients (22.2%), grade 3 for 7 patients (4.9%), grade 4 for no patients (0%), and grade 5 for 2 patients (1.4%). Of the 37 patients who had three or more PIPACs eligible for histopathologic response analysis, 27 (73%) had major or complete regression (PRGS 1/2). A median OS of 11 months (range 0-61 months) for the total study population and 16 months (range 2-61 months) for the patients with three or more PIPACs was observed. For 10 patients (7%) who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, the median OS was 15 months (minimum, 4 months; maximum, 27 months). Multivariate analysis showed three or more PIPACs to be an independent prognostic factor for improved OS (hazard ratio, 0.36; p < 0.0001). CONCLUSIONS: Repetitive PIPAC-C/D ± systemic chemotherapy is associated with low morbidity and mortality rates. Prospective randomized trials are needed to confirm whether three or more PIPAC-C/Ds improve clinical outcome.

Pressurized Intraperitoneal Aerosol Chemotherapy for Colorectal Peritoneal Metastases.

BACKGROUND: The benefit of repetitive PIPAC specifically in CPM patients has yet to be demonstrated in terms of oncological and functional outcomes. OBJECTIVE: The aim of this study was to evaluate the outcome of patients with non-resectable colorectal peritoneal metastases (CPM) treated with pressurized intraperitoneal aerosol chemotherapy (PIPAC). METHODS: We conducted an analysis of a prospective single-center database of all CPM patients who underwent PIPAC with oxaliplatin 92 mg/m2 body surface (PIPAC-Ox). The outcome criteria were adverse events (Common Terminology Criteria for Adverse Events version 4.0), Peritoneal Regression Grading Score (PRGS), and survival. RESULTS: Overall, 102 patients with a median age of 64 years (33-88) were scheduled for PIPAC-Ox. Access to the abdominal cavity for the first application failed in 22/102 (21.6%) patients. A total of 185 PIPACs were performed, with 26/102 (25.5%), 20/102 (19.6%), 17/102 (16.7%), and 17/102 (16.7%) patients undergoing one, two, three, and four or more PIPACs, respectively. Perioperative overall morbidity/mortality Grade I-V occurred in 14 (7.6%), 29 (15.8%), 6 (3.2%), 1 (0.5%), and 1 (0.5%) patient without significant differences between each cycle. Of 27 patients who underwent three or more PIPACs, 20/102 (19.6%) had major/complete CPM regression (PRGS 1-2). In a multivariate analysis, independent predictive factors for > 12 months' survival following the first PIPAC-Ox administration were three or more PIPACs (odds ratio [OR] 4.5, 95% confidence interval [CI] 1.35-15.2; p = 0.014) and younger patient age (OR 1.058, 95% CI 1.00-1.12; p = 0.039). CONCLUSIONS: Repetitive PIPAC-Ox for CPM patients, alone or combined with perioperative systemic chemotherapy, is feasible. Our data suggest that three or more consecutive PIPAC-Ox cycles for advanced CPM can improve survival.

Sustained-release voriconazole-thermogel for subconjunctival injection in horses: ocular toxicity and in-vivo studies.

BACKGROUND: Keratomycosis is a relatively common, sight threatening condition in horses, where treatment is often prolonged and costly. Subconjunctival (SCo) injections offer less resistance to drug diffusion than the topical route, resulting in better penetration to the ocular anterior segment. Voriconazole, a second generation triazole antifungal, is effective against common fungal organisms causing keratomycosis. If combined with a thermogel biomaterial, voriconazole can be easily injected in the SCo space to provide sustained drug release. The purpose of this study was to evaluate the drug concentrations in the anterior segment and clinical effects after SCo injections of voriconazole-containing thermogel: poly (DL-lactide-co-glycolide-b-ethylene glycol-b-DL-lactide-co-glycolide) (PLGA-PEG-PLGA) in healthy equine eyes. RESULTS: Voriconazole aqueous humor (AH) and tear concentrations were compared between 6 horses, receiving 1% voriconazole applied topically (0.2 mL, q4h) (Vori-Top) or 1.7% voriconazole-thermogel (0.3 mL) injected SCo (Vori-Gel). For the Vori-Gel group, voriconazole concentrations were measured in AH and tears at day 2 and then weekly for 23 days, and at day 2 only for the Vori-Top group. Ocular inflammation was assessed weekly (Vori-Gel) using the modified Hackett-McDonald scoring system. Ocular tissue concentrations of voriconazole following SCo 1.7% voriconazole-thermogel (0.3 mL) injections were evaluated post euthanasia in 6 additional horses at 3 different time points. Three horses received bilateral injections at 2 h (n = 3, right eye (OD)) and 48 h (n = 3, left eye (OS)) prior to euthanasia, and 3 horses were injected unilaterally (OS), 7 days prior to euthanasia. Voriconazole-thermogel was easily injected and well tolerated in all cases, with no major adverse effects. On day 2, drug concentrations in tears were higher in the Vori-Top, but not statistically different from Vori-Gel groups. For the Vori-Gel group, voriconazole was non-quantifiable in the AH at any time point. Total voriconazole concentrations in the cornea were above 0.5 µg/g (the target minimum inhibitory concentration (MIC) for Aspergillus sp.) for up to 48 h; however, concentrations were below this MIC at 7 days post treatment. CONCLUSIONS: Voriconazole-thermogel was easily and safely administered to horses, and provided 48 h of sustained release of voriconazole into the cornea. This drug delivery system warrants further clinical evaluation.

Intravitreal injection of low-dose gentamicin for the treatment of recurrent or persistent uveitis in horses: Preliminary results.

BACKGROUND: Despite appropriate medical therapy, many horses with equine recurrent uveitis continue to suffer from recurrent bouts of inflammation. Surgical intervention via the pars plana vitrectomy or suprachoroidal cyclosporine implant placement may control and/or prevent recurrences, however, these procedures may be contraindicated, unavailable, or declined by an owner. Thus, an effective adjunctive treatment option may help to improve the clinical outcomes in those situations. There are several anecdotal reports on the use of intravitreal gentamicin injections, but to date, no data evaluating the complication rate and/or treatment effect following this treatment have been published. Thus, the aim of this prospective study was to describe the intravitreal gentamicin injection technique, describe the associated peri-injection (within 24 h) and post-injection (30 to 780 days) complications, and to report the effects of the injection on the clinical signs of uveitis. Additionally, evaluation of the systemic and ocular Leptospira-status, and its effect on the treatment outcome was performed. A total of 86 horses of various ages, breeds, and gender presenting with recurrent or persistent uveitis were treated via intravitreal injection of 4 mg of undiluted gentamicin (0.04 ml, Genta 100, 100 mg/ml in 35 horses) or preservative-free gentamicin (0.05 ml, 80 mg/ml in 52 horses) under sedation and local anesthesia. All 86 horses were observed for immediate peri-injection and post-injection complications. Response to therapy was evaluated in 59 of the 86 horses (follow-up: 30 to 780 days). RESULTS: Peri-injection complications consisted of subconjunctival (26/86; 30.2%) or intracameral hemorrhage (4/86; 4.7%); both of which completely resolved within 5 days. Post-injection complications consisted of cataract formation/maturation (5/59 horses, 8.5%) and diffuse retinal degeneration (3/59 eyes 5.1%). The majority of horses 52/59 (88.1%) with a minimum follow-up period of 30 days were controlled (absence of recurrent or persistent inflammation) at their last recheck examination. Recurrent inflammation was documented in 5/59 (8.5%) horses and persistent inflammation was diagnosed in 2/59 (3.4%) horses. CONCLUSIONS: Intravitreal injection of low-dose gentamicin shows promise at controlling different types and stages of uveitis. The ability of intravitreal injections of low-dose gentamicin (4 mg) to control persistent and recurrent inflammation warrants further investigation.

Medical and Surgical Management of Equine Recurrent Uveitis.

Equine recurrent uveitis (ERU) is characterized by recurrent bouts of inflammation interrupted by periods of quiescence that vary in duration. There is little consensus on the clinical manifestations, the underlying causes, or the management. The 3 commonly recognized syndromes of ERU (classic, insidious, and posterior) do not accurately separate the clinical manifestations of disease into distinct categories. An accurate diagnosis and early intervention are essential to minimizing the effects of disease and preserving vision. There are multiple medical and surgical options for controlling ERU as long as the disease is recognized early and targeted treatment is initiated immediately.

EGFR-targeting peptide-coupled platinum(IV) complexes.

The high mortality rate of lung cancer patients and the frequent occurrence of side effects during cancer therapy demonstrate the need for more selective and targeted drugs. An important and well-established target for lung cancer treatment is the occasionally mutated epidermal growth factor receptor (EGFR). As platinum(II) drugs are still the most important therapeutics against lung cancer, we synthesized in this study the first platinum(IV) complexes coupled to the EGFR-targeting peptide LARLLT (and the shuffled RTALLL as reference). Notably, HPLC-MS measurements revealed two different peaks with the same molecular mass, which turned out to be a transcyclization reaction in the linker between maleimide and the coupled cysteine moiety. With regard to the EGFR specificity, subsequent biological investigations (3-day viability, 14-day clonogenic assays and platinum uptake) on four different cell lines with different verified EGFR expression levels were performed. Unexpectedly, the results showed neither an enhanced activity nor an EGFR expression-dependent uptake of our new compounds. Consequently, fluorophore-coupled peptides were synthesized to re-evaluate the targeting ability of LARLLT itself. However, also with these molecules, flow cytometry measurements showed no correlation of drug uptake with the EGFR expression levels. Taken together, we successfully synthesized the first platinum(IV) complexes coupled to an EGFR-targeting peptide; however, the biological investigations revealed that LARLLT is not an appropriate peptide for enhancing the specific uptake of small-molecule drugs into EGFR-overexpressing cancer cells.

Inverse relationship between body mass index and mitochondrial oxidative phosphorylation capacity in human subcutaneous adipocytes.

Obesity is characterized by a substantial increase in adipose tissue that may contribute to energy balance. Recently, obesity was suggested to be associated with impaired mitochondrial function in adipocytes. In this study, we investigated the following: 1) the respiratory capacities of mitochondria isolated from mature adipocytes of female subjects whose body mass index (BMI) values were distributed over a wide range and 2) the amounts of electron transport chain complexes in these mitochondria. Fat cells were isolated from adipose tissue specimens by collagenase digestion. Mitochondria were isolated from these fat cells, and their respiratory capacity was determined using a Clark-type electrode. Fat cells were also sorted on the basis of their size into large and small fractions to assess their respiration. Western blot analyses were performed to quantify respiratory chain complex components. We also examined mitochondrial activity development during differentiation using human Simpson-Golabi-Behmel syndrome cells. Our results showed that mitochondrial respiratory capacities in adipocytes were inversely associated with BMI values but were independent of cell size. Western blot analyses revealed significantly fewer complex I and IV components in adipose tissues from obese compared with nonobese women. These results suggest that differences at the level of respiratory chain complexes might be responsible for the deterioration of respiratory capacity in obese individuals. In particular, electron transport at the level of complexes I and IV seems to be most affected.

Poly(lactic acid) nanoparticles of the lead anticancer ruthenium compound KP1019 and its surfactant-mediated activation.

Nanoparticle formulations offer besides the advantage of passive drug targeting also the opportunity to increase the stability of drugs. KP1019 is a lead ruthenium(III) compound which has been successfully tested in a clinical phase I trial. However, it is characterized by low stability in aqueous solution especially at physiological pH. To overcome this limitation, poly(lactic acid) (PLA) nanoparticles of KP1019 with two different surfactants (Pluronic F68 and Tween 80) were prepared by a single oil-in-water (o/w) emulsion. Cytotoxicity measurements comparing different aged Tween 80 nanoparticles revealed that the color change from brown to green was associated with an up to 20 fold increased activity compared to "free" KP1019. Further investigations suggested that this is based on the formation of enhanced intracellular reactive oxygen species levels. Additional studies revealed that the origin of the green color is a reaction between KP1019 and Tween 80. Kinetic studies of this reaction mixture using UV-Vis, ESI-MS and ESR spectroscopy indicated on the one hand a coordination of Tween 80 to KP1019, and on the other hand, the color change was found to correlate with a reduction of the Ru(III) center by the surfactant. Together, the results provide a first experimental approach to stabilize a biologically active Ru(II) species of KP1019 in aqueous solution, which probably can be also used to selectively generate this activated species in the tumor tissue via delivery of KP1019 using Tween 80 nanoparticles.

Reduced capacity of heart rate regulation in response to mild hypoglycemia induced by glibenclamide and physical exercise in type 2 diabetes.

OBJECTIVE: Decreased heart rate variability (HRV) is associated with enhanced mortality due to abnormal cardiac rhythm. While hypoglycemic events are increasingly common in the treatment of type 2 diabetes, HRV is part of the counter-regulation against low blood glucose levels. We hypothesized that HRV was impaired in mild hypoglycemia in diabetic individuals. MATERIALS/METHODS: Hyperinsulinemic-hypoglycemic clamps were performed in twelve type 2 diabetic patients without cardiovascular disease and in non-diabetic subjects matched for age, sex, and weight. In an additional study, hypoglycemic events, induced by either a single morning dose of glibenclamide or physical exercise, were recorded for the subsequent 24h. Blood glucose concentrations and electrocardiograms were continuously monitored. Serum hormone levels, hypoglycemic symptoms, and forearm blood flow were measured at defined time points. RESULTS: Occurrence of a symptomatic hypoglycemic episode (mean blood glucose 3.1±0.4 mmol/l) attenuated most of the time and frequency domain measurements in both healthy and diabetic individuals. The magnitude of reduction of HRV parameters was significantly lower in diabetic compared to healthy subjects. Glibenclamide taken in the morning enhanced the daily number of mild hypoglycemic events compared with placebo or moderate exercise. Concordantly, 24-h mean HRV measurements were decreased. CONCLUSION: HRV response to hypoglycemia is impaired in type 2 diabetic subjects resulting in a higher than expected risk for sudden arrhythmia following mild hypoglycemic episodes.

Immunomodulation with heat shock protein DiaPep277 to preserve beta cell function in type 1 diabetes - an update.

IMPORTANCE OF THE FIELD: Type 1 diabetes is a chronic autoimmune disease in which pancreatic beta cells are selectively destroyed. Ultimately hyperglycemia develops and insulin substitution becomes necessary. Immunomodulation aims at arresting this autoimmune attack. DiaPep277, the major T-cell epitope of heat shock protein 60 (hsp60), has been shown to be effective as a modulator of the immune system in type 1 diabetes and is the focus of this review. AREAS COVERED IN THIS REVIEW: A literature search of Pubmed listed publications covering 1990 - 2009 and a website search of the licensing company were performed. WHAT THE READER WILL GAIN: DiaPep277 has been successfully employed in animal models and has been investigated in Phase I - III studies in humans. A combined analysis of the Phase II trials showed a significant preservation of beta cell function in adults without adverse effects, but HbA1c was not changed. A Phase III clinical trial is ongoing, and a second Phase III trial will start in early 2010. Addressing the underlying autoimmune process is the call of the future in type 1 diabetes. TAKE HOME MESSAGE: Use of Diapep277 is a promising therapeutic strategy currently being tested in Phase III trials.

Nocturnal glucose metabolism after bedtime injection of insulin glargine or neutral protamine hagedorn insulin in patients with type 2 diabetes.

AIMS/HYPOTHESIS: Insulin glargine is a long-acting human insulin analog often administered at bedtime to patients with type 2 diabetes. It reduces fasting blood glucose levels more efficiently and with less nocturnal hypoglycemic events compared with human neutral protamine Hagedorn (NPH) insulin. Therefore, bedtime injections of insulin glargine and NPH insulin were compared overnight and in the morning. METHODS: In 10 type 2 diabetic patients, euglycemic clamps were performed, including [6,6'](2)H(2) glucose, to study the rate of disappearance (Rd) and endogenous production (EGP) of glucose during the night. On separate days at bedtime (2200 h), patients received a sc injection of insulin glargine, NPH insulin, or saline in a randomized, double-blind fashion. RESULTS: Similar doses of both insulins had different metabolic profiles. NPH insulin had a greater effect on both Rd and EGP in the night compared with insulin glargine. By contrast, in the morning, insulin glargine was more effective, increasing Rd by 5.8 micromol/kg(-1).min(-1) (95% confidence interval 4.7-6.9) and reducing EGP -5.7 (-5.0 to -6.4) compared with NPH insulin. Nearly 80% of the glucose lowering effect in the morning was due to insulin glargine's reduction of EGP. Its injection was associated with one-third lower morning glucagon levels compared with NPH insulin (P = 0.021). CONCLUSION/INTERPRETATION: Nocturnal variations of EGP and Rd explain the reduced incidence of hypoglycemia and lower fasting glucose levels reported for insulin glargine compared with human NPH insulin.