Improving Pharmacist-Led Pediatric Patient Education on Oral Chemotherapy at Home.

Oral chemotherapy (OC) has been increasingly used in pediatric patients diagnosed with cancer, which is primarily managed in the outpatient setting. Different from adults, pediatric patients face unique challenges in administering these hazardous medications at home. Because of the complexity of pediatric pharmaceutical care and the hazardous nature of chemotherapy agents, comprehensive patient education is imperative to mitigate the potential safety risks associated with OC administration at home. Pharmacists play a vital role in patient education and medication consultations. However, the lack of practice guidelines and limited resources supporting OC counseling are noted. Additional barriers include insufficient knowledge and training on OC, which can be improved by continuing education. In a regional children's hospital, a comprehensive OC education checklist was developed for pediatric patients and their caregivers to standardize consultations led by pharmacists. An infographic OC handout was also formulated to improve patient knowledge and awareness. Moreover, innovative approaches such as using telepharmacy, smartphone applications, and artificial intelligence have been increasingly integrated into patient care, which can help optimize OC consultations for children and adolescents. Further studies are warranted to enhance oral chemotherapy education specifically tailored for pediatric patients in outpatient settings.

Sulfenylation links oxidative stress to protein disulfide isomerase oxidase activity and thrombus formation.

BACKGROUND: Oxidative stress contributes to thrombosis in atherosclerosis, inflammation, infection, aging, and malignancy. Oxidant-induced cysteine modifications, including sulfenylation, can act as a redox-sensitive switch that controls protein function. Protein disulfide isomerase (PDI) is a prothrombotic enzyme with exquisitely redox-sensitive active-site cysteines. OBJECTIVES: We hypothesized that PDI is sulfenylated during oxidative stress, contributing to the prothrombotic potential of PDI. METHODS: Biochemical and enzymatic assays using purified proteins, platelet and endothelial cell assays, and in vivo murine thrombosis studies were used to evaluate the role of oxidative stress in PDI sulfenylation and prothrombotic activity. RESULTS: PDI exposure to oxidants resulted in the loss of PDI reductase activity and simultaneously promoted sulfenylated PDI generation. Following exposure to oxidants, sulfenylated PDI spontaneously converted to disulfided PDI. PDI oxidized in this manner was able to transfer disulfides to protein substrates. Inhibition of sulfenylation impaired disulfide formation by oxidants, indicating that sulfenylation is an intermediate during PDI oxidation. Agonist-induced activation of platelets and endothelium resulted in the release of sulfenylated PDI. PDI was also sulfenylated by oxidized low-density lipoprotein (oxLDL). In an in vivo model of thrombus formation, oxLDL markedly promoted platelet accumulation following an arteriolar injury. PDI oxidoreductase inhibition blocked oxLDL-mediated augmentation of thrombosis. CONCLUSION: PDI sulfenylation is a critical posttranslational modification that is an intermediate during disulfide PDI formation in the setting of oxidative stress. Oxidants generated by vascular cells during activation promote PDI sulfenylation, and interference with PDI during oxidative stress impairs thrombus formation.

Engineered PROTAC-CID Systems for Mammalian Inducible Gene Regulation.

Gene regulation via chemically induced dimerization (CID) is useful for biomedical research. However, the number, type, versatility, and in vivo applications of CID tools remain limited. Here, we demonstrate the development of proteolysis-targeting chimera-based scalable CID (PROTAC-CID) platforms by systematically engineering the available PROTAC systems for inducible gene regulation and gene editing. Further, we show orthogonal PROTAC-CIDs that can fine-tune gene expression at gradient levels or multiplex biological signals with different logic gating operations. Coupling the PROTAC-CID platform with genetic circuits, we achieve digitally inducible expression of DNA recombinases, base- and prime-editors for transient genome manipulation. Finally, we package a compact PROTAC-CID system into adeno-associated viral vectors for inducible and reversible gene activation in vivo. This work provides a versatile molecular toolbox that expands the scope of chemically inducible gene regulation in human cells and mice.

Inhibition of interferon-gamma-stimulated melanoma progression by targeting neuronal nitric oxide synthase (nNOS).

Interferon-gamma (IFN-γ) is shown to stimulate melanoma development and progression. However, the underlying mechanism has not been completely defined. Our study aimed to determine the role of neuronal nitric oxide synthase (nNOS)-mediated signaling in IFN-γ-stimulated melanoma progression and the anti-melanoma effects of novel nNOS inhibitors. Our study shows that IFN-γ markedly induced the expression levels of nNOS in melanoma cells associated with increased intracellular nitric oxide (NO) levels. Co-treatment with novel nNOS inhibitors effectively alleviated IFN-γ-activated STAT1/3. Further, reverse phase protein array (RPPA) analysis demonstrated that IFN-γ induced the expression of HIF1α, c-Myc, and programmed death-ligand 1 (PD-L1), in contrast to IFN-α. Blocking the nNOS-mediated signaling pathway using nNOS-selective inhibitors was shown to effectively diminish IFN-γ-induced PD-L1 expression in melanoma cells. Using a human melanoma xenograft mouse model, the in vivo studies revealed that IFN-γ increased tumor growth compared to control, which was inhibited by the co-administration of nNOS inhibitor MAC-3-190. Another nNOS inhibitor, HH044, was shown to effectively inhibit in vivo tumor growth and was associated with reduced PD-L1 expression levels in melanoma xenografts. Our study demonstrates the important role of nNOS-mediated NO signaling in IFN-γ-stimulated melanoma progression. Targeting nNOS using highly selective small molecular inhibitors is a unique and effective strategy to improve melanoma treatment.

Changing trends in the microvascular reconstruction and oral rehabilitation following maxillary cancer.

PURPOSE: The maxillectomy defect is complex and the best means to achieve optimal reconstruction, and dental rehabilitation is a source of debate. The refinements in zygomatic implant techniques have altered the means and speed by which rehabilitation can be achieved and has also influenced the choice regarding ideal flap reconstruction. The aim of this study is to report on how the method of reconstruction and oral rehabilitation of the maxilla has changed since 1994 in our Institution, and to reflect on case mix and survival. METHODS: Consecutive head and neck oncology cases involving maxillary resections over a 27-year period between January 1994 and November 2020 were identified from hospital records and previous studies. Case note review focussed on clinical characteristics, reconstruction, prosthetic rehabilitation, and survival. RESULTS: There were 186 patients and the tumour sites were: alveolus for 56% (104), hard palate for 19% (35), maxillary sinus for 18% (34) and nasal for 7% (13). 52% (97) were Brown class 2 defects. Forty-five patients were managed by obturation and 78% (142/183) had free tissue transfer. The main flaps used were radial (52), anterolateral thigh (27), DCIA (22), scapula (13) and fibula (11). There were significant changes over time regarding reconstruction type, use of primary implants, type of dental restoration, and length of hospital stay. Overall survival after 24 months was 64% (SE 4%) and after 60 months was 42% (SE 4%). CONCLUSION: These data reflect a shift in the reconstruction of the maxillary defect afforded by the utilisation of zygomatic implants.

The impact of blood pressure on the risk of major bleeding complication after renal transplant biopsy.

PURPOSE: To assess the impact of elevated blood pressure on the rate of major hemorrhagic complication after renal transplant biopsy. METHODS: Pre-procedural systolic (SBP), diastolic (SBP), and mean arterial (MAP) blood pressure for consecutive patients undergoing US-guided renal transplant biopsies from 08/01/2015 to 7/31/2017 were retrospectively recorded. Patients who had a major bleeding complication were identified. The risk of complication as a function of SBP, DBP, and MAP was statistically analyzed, with significance set at p < 0.05. RESULTS: Of 1689 biopsies, there were 10 bleeding complications (10/1689, 0.59%). There was no statistically significant difference between biopsies with complication compared to those without complication based on SBP (p = 0.351), DBP (p = 0.088), or MAP (p = 0.132). Using risk dichotomization criteria, the odds ratio for hemorrhagic complication when the patient had SBP ≥ 180 mmHg and DBP ≥ 95 mmHg was 75.63 (95% CI 6.87-516.8, p = 0.002). CONCLUSION: The rate of hemorrhagic complication from renal transplant biopsy is low, and there is no statistically significant threshold for increased biopsy risk based on SBP, DBP, or MAP alone. The risk of complication was significantly higher only when both the SBP is ≥ 180 mmHg and DBP is ≥ 95 mmHg.

Autologous Fat Transfer Harvest-site Complications: Incidence, Risk Factors, and Management.

PURPOSE: Autologous fat transfer is an effective tool for volume restoration to the aging face. Although numerous reports exist regarding injection site complications, there is limited data on donor-site morbidity in the cosmetic surgery literature. METHODS: This study is a large-scale retrospective review to determine incidence of fat harvest-site complications, identify risk factors, and describe management strategies. Records of all patients who underwent autologous fat harvesting and facial grafting at a single oculofacial plastic surgery practice from 2010 to 2019 were reviewed. Patient demographics and clinical data were collected and assessed. A statistical analysis was performed using a two-tailed T-test with p values of <0.05 considered significant. RESULTS: Four-hundred sixteen patients were followed for an average of 6.2 months postoperatively. There was an overall 5.5% harvest-site complication rate. There was no correlation of harvest-site complications with gender (p = 0.249) or age (p = 0.881). Harvest location did not significantly correlate with complication rate. The most common complications were contour irregularities, prolonged induration, and prolonged erythema. Low body mass index was associated with higher complication rate (p = 0.003), even when excluding those patients with contour irregularities (p = 0.001). Various treatment modalities were used to manage donor-site morbidity with consistent improvement. CONCLUSIONS: Autologous fat transfer used for facial volume augmentation has low donor-site morbidity. Minor harvest-site complications occur more commonly in patients with low body mass index, irrespective of age, gender, or fat source.

The Flipped Ovary Sign in Ovarian Torsion.

The diagnosis of ovarian torsion is challenging and relies mostly on morphologic findings. Occasionally, women or children with acute pelvic pain who have undergone an initial ultrasound (US) evaluation with results interpreted as negative for ovarian torsion will return with recurrent or increasing pain, prompting an US reevaluation. The flipped ovary sign refers to a demonstrable change in the orientation of the ovary on follow-up US examinations, recognized by changing positions of ovarian landmarks established by follicles, cysts, or masses. This sign is valuable for identifying ovarian torsion in these patients, even in the absence of classic morphologic or Doppler features of ovarian torsion.

Detection of Bleeding Complications After Renal Transplant Biopsy.

OBJECTIVE. The purpose of this study was to analyze the timing of major bleeding complications after renal transplant biopsy in the context of a standardized 1-hour postprocedure observation protocol. MATERIALS AND METHODS. We retrospectively reviewed the electronic medical records for consecutive patients who underwent ultrasound-guided renal transplant biopsies between January 1, 2012, and December 31, 2017, and were observed according to a newly implemented 1-hour postprocedure observation protocol. The development of a major bleeding complication (Common Terminology Criteria for Adverse Events class 3 or higher) was recorded along with all available details regarding the time course of patient symptoms and presentation. Complications were grouped into one of four categories according to onset time after biopsy: 2 hours or less (timing category 1), more than 2 hours but 4 hours or less (timing category 2), more than 4 hours but 8 hours or less (timing category 3), and more than 8 hours (timing category 4). RESULTS. In 1824 patients (769 women, 1055 men) who underwent 4519 consecutive ultrasound-guided renal transplant biopsies during the study period, 11 class 3 complications were found (11/4519 [0.2%]). Four of the 11 patients (36.4%) had symptoms during the 1-hour observation period. Of these four patients, three (3/11 [27.3%]) had substantial symptoms related to major bleeding and were classified as timing category 1, and one (1/11 [9.1%]) had initially minor symptoms that increased in severity more than 2 hours but within 4 hours and was classified as timing category 2. Seven of the 11 patients (63.6%) did not have any symptoms at 1 hour of observation and were discharged; three (27.3%) were classified as timing category 3, and four (36.4%) were classified as category 4. CONCLUSION. Major bleeding complications following ultrasound-guided renal transplant biopsy are rare (0.2% of patients in this study). In our study, more than half were not clinically apparent within 4 hours of biopsy. A 1-hour postprocedure recovery period can be safely used after renal transplant biopsy.

Growth Rate of Ovarian Serous Cystadenomas and Cystadenofibromas.

OBJECTIVES: We analyzed growth rates of benign ovarian serous cystadenomas and cystadenofibromas to understand what percentage would show a volume doubling time (DT) of less than 3 years, between 3 and 5 years, or greater than 5 years. METHODS: We retrospectively reviewed pathology records (January 1, 2014, to June 30, 2019) to find all surgically excised ovarian serous cystadenomas and cystadenofibromas. Imaging records were then reviewed to identify those that had been confidently identified with ultrasound imaging, magnetic resonance imaging, or computed tomography at least twice before surgical removal, with at least a 60-day interval between studies. Three orthogonal measurements were recorded on the first and last imaging studies on which the mass was detected, with volume calculations by the prolate formula (product of 3 measurements multiplied by 0.52). The volume DT was calculated and grouped into 1 of 5 categories: (1) DT of less than 1 year; (2) DT of 1 to 3 years; (3) DT of 3 to 5 years; (4) DT of 5 to 10 years; and (5) no growth (any mass with a DT >10 years or showing a decrease in volume). RESULTS: A total of 102 of 536 cystadenomas and 44 of 227 cystadenofibromas met inclusion criteria. Of the 146 tumors, 40 (27.4%) had a DT of less than 1 year; 38 (26.0%) had a DT of 1 to 3 years; 22 (15.1%) had a DT of 3 to 5 years; 10 (6.8%) had a DT of 5 to 10 years; and 36 (24.7%) showed no growth. CONCLUSIONS: A total of 53.4% of ovarian serous cystadenomas/cystadenofibromas have a DT of less than 3 years; 15.1% have a DT between 3 and 5 years; and 31.5% have a DT of greater than 5 years or show no growth.

Comparison of Phasix, polypropylene, and primary closure of the abdominal donor site after bilateral free flap breast reconstruction: Long-term evaluation of abdominal hernia and bulge formation.

BACKGROUND: Abdominal free flap harvest for breast reconstruction may result in significant morbidity in terms of hernias and bulges. Reinforcement of the donor site with mesh has been recommended to minimize the risk of hernias and bulges, but no studies exist evaluating the optimal type of mesh. Polypropylene has traditionally been used but the development of Phasix restorable mesh may be a reasonable alternative. Here, we compared the use of Phasix to polypropylene and primary closure and hypothesize that the former has lower rates of abdominal morbidity in the long term. PATIENTS AND METHODS: A retrospective review of all patients undergoing bilateral free flap breast reconstruction from the abdomen was performed while patients with pedicle flaps or alternative donor sites were excluded. Patient demographics, medical/surgical history, cancer treatments, and flap type were analyzed. All patients were monitored for a minimum of 2 years for early donor site complications as well as hernia/bulges. RESULTS: Sixty-six consecutive patients were included (40 patients with Phasix, 20 patients with polypropylene, and 6 patients with primary closure). Use of Phasix mesh resulted in higher initial operative costs ($2,750 vs. $72 vs. $0). Two patients with polypropylene mesh and one patient undergoing primary closure developed an abdominal bulge in an average follow-up of 25.2 months (11.5% vs. 0%, p = .04). CONCLUSIONS: Mesh placement for abdominal wall reinforcement after bilateral free flap breast reconstruction minimizes the risk of hernias and bulges. Although Phasix results in increased initial costs, abdominal morbidity is significantly decreased after follow-up beyond 2 years.

The appropriateness of oral surgery referrals and treatment in contracted intermediate minor oral surgery practices in East Kent.

Objectives To assess the appropriateness of oral surgery referrals, after triage, to intermediate minor oral surgery (IMOS) practices in East Kent and whether or not referrals vary according to the referring general dental practitioner's (GDP's) place of qualification and experience.Design A retrospective study of the records of 441 triaged referrals sent to three IMOS practices in East Kent, over a ten-week period. An assessment tool was developed in line with local and national referral guidelines. Information on all referrals was obtained from the IMOS provider and referral records. Descriptive analysis of the data was performed.Results The most common reason for referral was for extraction of teeth requiring bone removal (n = 155; 35%). However, the majority of teeth removed were recorded as a non-surgical extraction (n = 363; 82%). Medical histories were included appropriately in the referral communications, with only 0.2% of all referrals being inappropriate. The proportion of appropriate and inappropriate referrals was very similar and it was found that referral rate was lower from dentists who had been qualified for more than ten years. GDPs working in the same location as the IMOS provider made a greater total number of referrals as well as more inappropriate referrals.Conclusions In the group of GDPs and IMOS providers studied, a wide variation was observed between the GDP's reason for referral and the treatment provided. It may be concluded that the vast majority of extractions were safely completed in an IMOS dental practice in a primary care setting.

Dynamics of postoperative serum cortisol after transsphenoidal surgery for Cushing's disease: implications for immediate reoperation and remission.

OBJECTIVESuccessful transsphenoidal surgery for adrenocorticotropin hormone (ACTH)-producing pituitary tumors is associated with subnormal postoperative serum cortisol levels, which may guide decisions regarding immediate reoperation. However, little is known about the detailed temporal course of changes in serum cortisol in the immediate postoperative period, and the relationship of postoperative cortisol dynamics to remission and late recurrence.METHODSA single-center retrospective cohort analysis was performed for all patients undergoing pituitary surgery from 2007 through 2015. Standardized diagnostic and treatment algorithms were applied to all patients with potential Cushing's disease (CD), including microsurgical transsphenoidal adenomectomy (TSA) by a single surgeon. All patients had serum cortisol levels drawn at 6-hour intervals for 72 hours after surgery, and were offered reoperation within 3 days for normal or supranormal postoperative cortisol levels. Primary outcomes were 6-month remission and late recurrence; secondary outcomes were persistent postoperative hypocortisolism and surgical morbidity. Discriminatory levels of postoperative serum cortisol for predicting remission were calculated at various intervals after surgery using receiver operating characteristic (ROC) curves.RESULTSAmong 89 patients diagnosed with CD, 81 underwent initial TSA for a potentially curable lesion; 23 patients (25.8%) underwent an immediate second TSA. For the entire cohort, 6-month remission was achieved in 77.8% and late recurrences occurred in 9.5%, at a mean of 43.5 months. Compared with patients with a single surgery, those with an immediate second TSA had similar rates of remission (78.3% vs 77.6%) and late recurrence (5.6% vs 11.1%). The rate of hypocortisolism for patients with 2 surgeries (12/23, 52.2%) was significantly greater than that for patients with single surgeries (13/58, 22.4%; p < 0.001). There was no difference in the incidence of CSF leaks between the first and second operations. Remission was achieved in 58 (92.1%) of 64 patients who completed the 2-surgery protocol. The temporal course of postoperative serum cortisol levels among patients varied considerably, with subnormal nadir levels < 2 µg/dl occurring between 12 hours and 66 hours. Patients achieving remission had significantly lower mean serum cortisol levels at every time point after surgery (p < 0.01). By ROC curve analysis, nadir cortisol levels < 2.1 µg/dl were predictive of 6-month remission for the entire cohort over 3 days (positive predictive value [PPV] = 94%); discriminating cortisol levels for predicting remission on postoperative day (POD) 2 were < 5.4 µg/dl (PPV = 97%), although patients with remission after postoperative cortisol levels of 2-5 µg/dl had a significantly higher rate of late recurrence.CONCLUSIONSThere is substantial variation in the temporal course of serum cortisol levels over the first 72 hours after TSA for CD, with nadir levels predictive for remission occurring as late as POD 3. Although a cortisol level of 2.1 µg/dl at any point was an accurate predictor of 6-month remission, levels less than 5.4 µg/dl on POD 2 were reasonably accurate. These data may enable decisions regarding the efficacy of an immediate second surgical procedure performed during the same hospitalization; immediate reoperation is associated with excellent remission rates and low recurrence rates in patients otherwise unlikely to achieve remission, but carries a higher risk of permanent hypocortisolism.

Glucocorticoids induce production of reactive oxygen species/reactive nitrogen species and DNA damage through an iNOS mediated pathway in breast cancer.

BACKGROUND: Psychological stress increases the circulating levels of the stress hormones cortisol and norepinephrine (NE). Chronic exposure to elevated stress hormones has been linked to a reduced response to chemotherapy through induction of DNA damage. We hypothesize that stress hormone signalling may induce DNA damage through the production of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and interference in DNA repair processes, promoting tumourigenesis. METHODS: Breast cancer cell lines were incubated with physiological levels of cortisol and NE in the presence and absence of receptor antagonists and inducible nitric oxide synthase (iNOS) inhibitors and DNA damage measured using phosphorylated γ-H2AX. The rate of DNA repair was measured using comet assays and electrochemical sensors were used to detect ROS/RNS in the cell lysates from cells exposed to stress hormones. A syngeneic mouse model was used to assess the presence of iNOS in mammary tumours in stressed versus control animals and expression of iNOS was examined using western blotting and qRT-PCR. RESULTS: Acute exposure to cortisol and NE significantly increased levels of ROS/RNS and DNA damage and this effect was diminished in the presence of receptor antagonists. Cortisol induced DNA damage and the production of RNS was further attenuated in the presence of an iNOS inhibitor. An increase in the expression of iNOS in response to psychological stress was observed in vivo and in cortisol-treated cells. Inhibition of glucocorticoid receptor-associated Src kinase also produced a decrease in cortisol-induced RNS. CONCLUSION: These results demonstrate that glucocorticoids may interact with iNOS in a non-genomic manner to produce damaging levels of RNS, thus allowing an insight into the potential mechanisms by which psychological stress may impact breast cancer.