Modification Of Regimen Research Articles

Sphingosine Kinase Inhibition Enhances Dimerization of Calreticulin at the Cell Surface in Mitoxantrone-Induced Immunogenic Cell Death.

Agents that induce immunogenic cell death (ICD) alter the cellular localization of calreticulin (CRT), causing it to become cell surface-exposed within the plasma membrane lipid raft microdomain [cell surface-exposed CRT (ectoCRT)] where it serves as a damage associated-molecular pattern that elicits an antitumor immune response. We have identified the sphingolipid metabolic pathway as an integral component of the process of ectoCRT exposure. Inhibition of the sphingosine kinases (SphKs) enhances mitoxantrone-induced production of hallmarks of ICD, including ectoCRT production, with an absolute mean difference of 40 MFI (95% CI: 19-62; P = 0.0014) and 1.3-fold increase of ATP secretion with an absolute mean difference of 87 RLU (95% CI: 55-120; P < 0.0001). Mechanistically, sphingosine kinase inhibition increases mitoxantrone-induced accumulation of ceramide species, including C16:0 ceramide 2.8-fold with an absolute mean difference of 1.390 pmol/nmol Pi (95% CI: 0.798-1.983; P = 0.0023). We further examined the localization of ectoCRT to the lipid raft microdomain and demonstrate that ectoCRT forms disulfide-bridged dimers. Together, our findings suggest that ceramide accumulation impinges on the homeostatic function of the endoplasmic reticulum to induce ectoCRT exposure and that structural alterations of ectoCRT may underlie its immunogenicity. Our findings further suggest that inhibition of the SphKs may represent a means to enhance the therapeutic immunogenic efficacy of ICD-inducing agents while reducing overt toxicity/immunosuppressive effects by allowing for the modification of dosing regimens or directly lowering the dosages of ICD-inducing agents employed in therapeutic regimens. SIGNIFICANCE STATEMENT: This study demonstrates that inhibition of sphingosine kinase enhances the mitoxantrone-induced cell surface exposure of a dimeric form of the normally endoplasmic reticulum resident chaperone calreticulin as part of the process of a unique form of regulated cell death termed immunogenic cell death. Importantly, inhibition of sphingosine kinase may represent a means to enhance the therapeutic efficacy of immunogenic cell death-inducing agents, such as mitoxantrone, while reducing their overt toxicity and immunosuppressive effects, leading to better therapeutic outcomes for patients.

Skin Cancers and Lung Transplant.

It is well known that solid-organ transplant recipients (SOTRs) have a 65- to 100-fold increase in the risk of developing skin cancer, namely, nonmelanoma skin cancers (NMSCs) such as cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC). In addition, these patients are also at increased risk for development of melanoma as well as other less common cutaneous malignancies (Merkel's cell carcinoma, Kaposi's sarcoma). SOTRs with NMSC (namely cSCC) are also at significantly increased risk of poor clinical outcomes including local recurrence, nodal and distant metastasis, and disease-specific death relative to patients who are not immunosuppressed. Increased surveillance and monitoring in patients at risk of aggressive disease and poor outcomes who are on immunosuppression is essential in patients with lung transplants given the high degree of immunosuppression. Increased awareness of risks, treatments, and management allows for improved outcomes in these patients. This article will provide an overview of the risk factors for the development of cutaneous malignancies in organ transplant recipients as well as a detailed discussion of various immunosuppressant and prophylactic medications used in this patient population that contribute to the risk of developing cutaneous malignancies, with an emphasis on NMSC (cSCC and BCC) in lung transplant recipients. Finally, this article includes a discussion on the clinical and dermatologic management of this high-risk immunosuppressed population including a review of topical and systemic agents for field therapy of actinic damage and chemoprevention of keratinocyte carcinomas. In addition, indications for additional treatment and preventive measures such as adjuvant radiation treatment after surgical management of cutaneous malignancies and potential modification of immunosuppressive medication regimens are discussed.

Isolation and Enumeration of Circulating Tumor Cells (CTC) as Prognostic and Predictive Biomarkers in Post-Operative m-CRC

Circulating Tumor Cells (CTCs) presents non-invasive, repeatable investigation of patient‘s disease. In metastatic Colorectal Cancer (m-CRC) patients, CTC enumerations have been comprehensively studied in evaluating metastatic disease. CTC analysis has been shifting from enumeration to more sophisticated molecular depiction of tumor cells, which is used for liquid biopsy of the tumor, reflecting cytological and molecular changes in metastatic patients over time. In this study, CTC enumeration in advanced and localized metastatic colorectal cancer, highlights the vital gains as well as the challenges posed by various approaches, and their implications for advancing disease management. Detection of circulating tumor cells (CTC‘s) or circulating free tumor DNA (ctDNA) to conduct chemotherapy and reporting prognosis is extremely important, In view of the detail CTC has the potential to offer multiple samples by way of sequential minimally-invasive liquid biopsies. In fastidious, there is escalating evidence for the efficacy of CTC‘s in the clinical management of metastatic colorectal cancer (CRC). With most studies confirming the association of elevated CTC counts with worse prognosis. CTC‘s were first identified by Ashworth in 1869. CTC research has been vulnerable by the failure to constantly detect these typical cells. While the normal range of WBCs in human blood is 4.5-119/L, there may only be a few CTC‘s. The most widely used CTC enumeration platform, Cell-Search (Veridex LLC, NJ, USA) was approved for clinical use. As treatment options expand for metastatic colorectal cancer (mCRC), a blood marker with a prognostic and predictive role could guide treatment. Investigations were carried out that Circulating Tumor Cells (CTCs) could predict clinical prognosis in patients with mCRC. This pilot study, demonstrates that CTCs can serve as both prognostic and predictive factor for patients with mCRC. The presence of at least three CTCs at baseline and follow-up is a strong independent prognostic factor for inferior PFS and OS. When utilized in combination with imaging studies, CTCs provide additional prognostic information. There are several studies for which CTCs could have efficacy inmetastatic colorectal cancer. The statistics suggests that CTCs may be used as a stratification feature in metastatic disease treatment trials. The current list of validated prognostic factors is short, with only routine status being universally recognized. Further study should prospectively deal with modification of regimens based on unfavorable CTCs early in the course of treatment will result in enhancement in PFS or OS. As treatment has become more effective for metastatic disease, decision making has become more complicated. Five classes of drugs are on hand for treatment. The most common initial chemotherapy is a fluoropyrimidine with oxaliplatin or irinotecan. CTC levels drawn at 3 to 5 weeks and 6 to 12 weeks, before PET imaging, may lead to prospective regimen choices and standby patients from unnecessary drug toxicity by suggesting that an early change in treatment is defensible.

Optimizing outcomes for haploidentical hematopoietic stem cell transplantation in severe aplastic anemia with intensive GVHD prophylaxis: a review of current findings

ABSTRACT Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has resulted in increased levels of disease-free survival in severe aplastic anemia (SAA). Haploidentical transplantation (haplo-SCT) was previously not recommended due to unacceptable incidences of graft-versus-host disease (GvHD) and graft failures. With the advent of intensive GvHD prophylaxis strategies, the outcomes obtained with haplo-SCT for SAA have gradually improved. Areas covered: A comprehensive search considered PubMed reported articles before 1 February 2021, presented abstracts, and clinical trials pertaining to haplo-HSCT for SAA. This manuscript covers modern approaches with intensive GvHD prophylaxis in haplo-SCT for SAA. The representative methods consist of granulocyte colony stimulating factor (G-CSF) plus ATG-based and posttransplantation cyclophosphamide (PT-Cy)-based protocols. Expert opinion: Currently, haplo-SCT has become a feasible option for treating SAA. The G-CSF/ATG-based protocol included the largest sample size and reported comparable survival rates with identical siblings. The PT-Cy protocol resulted in a relatively lower incidence of GvHD and seemingly poorer but continuously improved engraftment with augmented conditioning. The optimized outcomes are constantly updated with the modification of the conditioning regimen, donor selection, graft source and GvHD prophylaxis. In the future, we should pay more attention to quality of life in addition to survival, and personalized haplo-SCT may improve outcomes.

Tongue and Hypoglossal Motoneuron Gene Therapy in a Rat Model of Pompe Disease

Pompe disease is a progressive lysosomal storage disorder resulting from deficiency in the lysosomal enzyme acid α-glucosidase (GAA). The only approved treatment is human recombinant GAA (enzyme replacement therapy) which does not cross the blood brain barrier and thus does not mitigate central nervous system pathology. Lingual dysfunction is prominent, leading to common impairments such as dysphagia, dysarthria, and/or disordered breathing. Towards the goal of new treatments that address the underlying neural pathology of lingual impairment, we tested the hypothesis that a single intramuscular delivery of adeno-associated virus (AAV) encoding GAA delivered to the tongue can drive GAA expression throughout lingual myofibers and associated hypoglossal motoneurons in a rat model of Pompe disease. In addition, we evaluated immune response to the transgene product and sought to determine if an FDA-approved immunosuppressive drug which inhibits T-cell activation (Abatacept®) can enhance the efficacy of gene transfer. Experiments were completed using a Gaa-/- rat model of Pompe disease that recapitulates many aspects of the clinical condition. An immunosuppression group (n=3) received three loading doses of Abatacept (10mg/kg) via tail vein 30 days, 14 days, and 1 day prior to intralingual injection of rAAV9-des-hGAA (100µl, 1.55x1013 vg/ml) followed by a maintenance dose 30 days later. Blood and serum samples were taken at 3, 7, 14, 30, and 60 days after AAV9 injection and tongue and brainstem tissues were harvested after 60 days. Immunohistochemistry and blood assay results were compared to Pompe rats receiving gene therapy without immunosuppression (n=3), sham injection (n=3) and “wild type” control rats (n=3). Immunohistochemistry with anti-GAA antibodies unequivocally confirmed that lingual rAAV9-des-hGAA delivery drove GAA expression in tongue and hypoglossal motoneurons. In addition, Periodic Acid Shiff (PAS) staining revealed decreased glycogen accumulation in tissues in which GAA immunostaining was prominent. Initial qualitative assessment suggests that Abatacept treatment increases gene therapy efficacy. Anti-GAA IgG assay results indicate that Abatacept significantly blunted the immune response to the GAA transgene product at 14 days (f(4)= 6.021, p=0.002) but not 30 days post injection (f(4)=6.021, p=0.0736). Lingual injection with rAAV9-des-hGAA results in GAA protein expression and glycogen clearance in the tongue as well as the hypoglossal nucleus in animals with Pompe disease. The immunosuppression regimen tested here blunted the initial immune response to the transgene product, and this may have therapeutic benefit. However, modification of this immunosuppression regimen by providing additional maintenance doses may be required for maximal benefit. These data represent a significant step toward a new clinically viable treatment for lingual dysfunction. The results show conclusively that lingual gene therapy can drive expression of a therapeutic protein to correct brainstem and tongue muscle histopathology in a rat model of Pompe disease, and indicate possible additional benefit of immunosuppression.

Hepatitis C Virus Core Antigen for On-treatment Prediction of Sustained Virological Response to Direct Acting Antivirals in Chronic Hepatitis C

Background and Aim: Cirrhotic patients have lower response rates to DAAs with increased frequency of adverse events. This study aims to evaluate the value of HCVcAg as an early predictor of SVR to DAAs in cirrhotic patients to justify the treatment and avoid side effects.&#x0D; Patients and Methods: This prospective cohort study was conducted on 85 treatment-naive HCV cirrhotic patients who had fulfilled the inclusion and exclusion criteria of the National Treatment Protocol of chronic HCV infection. HCVcAg detection was done on 10th day of treatment. Predictivity of HCVcAg for SVR was assessed in terms of specificity, sensitivity, positive predictive value (PPV), negative predictive value (NPV) and accuracy rates. ROC curve was conducted to assess predictivity of HCVcAg as well.&#x0D; Results: SVR12 was (91.76%). HCVcAg was negative in 79 patients; 78 of them achieved SVR, while it was positive in 6 patients; all of whom did not achieve SVR. HCVcAg had sensitivity, specificity, PPV, NPV and accuracy rates of 100%, 98.73%, 85.71%, 100% and 98.82% respectively in prediction of SVR. With AUC of 0.929. There was a positive strong significant correlation between HCVcAg and SVR12 (r = 0.898, P = 0.015).&#x0D; Conclusion: HCVcAg is a sensitive, specific, accurate, easily available, and affordable on- treatment predictor of SVR in cirrhotic patients with chronic HCV with possible future treatment regimen modification to improve efficacy and tolerability in difficult to treat cirrhotic patients.

Contrast enhanced ultrasound quantitative parameters for assessing neoadjuvant chemotherapy response in patients with locally advanced breast cancer.

To evaluate the role of contrast-enhanced ultrasound (CEUS) quantitative parameters in predicting neoadjuvant chemotherapy (NACT) response in patients with locally advanced breast cancer (LABC). 30 patients with histologically proven LABC scheduled for NACT were recruited. CEUS was performed using a contrast bolus of 4.8 ml and time intensity curves (TICs) were obtained by contrast dynamics software. CEUS quantitative parameters assessed were peak enhancement (PE), time-to-peak (TTP), area under the curve (AUC) and mean transit time (MTT). The parameters were documented on four consecutive instances: before NACT and 3 weeks after each of the three cycles. The gold-standard was pathological response using Miller Payne Score obtained pre NACT and post-surgery. A decrease in mean values of PE and an increase in mean values of TTP and MTT was observed with each cycle of NACT among responders. Post each cycle of NACT (compared with baseline pre-NACT), there was a statistically significant difference in % change of mean values of PE, TTP and MTT between good responders and poor responders (p-value < 0.05). The diagnostic accuracy of TTP post-third cycle was 87.2% (p = 0.03), and MTT post--second and third cycle was 76.7% (p = 0.004) and 86.7% (p = 0.006) respectively. In responders, a decrease in the tumor vascularity was reflected in the CEUS quantitative parameters as a reduction in PE, and a prolongation in TTP, MTT. Prediction of NACT response by CEUS has the potential to serve as a diagnostic modality for modification of chemotherapy regimens during ongoing NACT among patients with LABC, thus affecting patient prognosis.

A Retrospective Analysis of Perioperative Chemotherapy and Coronavirus Disease in Patients With Breast Cancer.

Since January 2020, coronavirus disease (COVID-19) cases have been confirmed in Japan, and the number of patients with COVID-19 has been increasing. Two emergency declarations have been made previously and one is currently in effect. Based on our experience of a situation that could affect cancer treatment, this study retrospectively examined the correlation between perioperative anticancer therapy and COVID-19 incidence in patients with breast cancer. Patients who underwent perioperative anticancer therapy for breast cancer at our hospital from February 2020 to February 2021 were included in this study. The presence or absence of COVID-19, timing of anticancer drug initiation, and clinical data were collected. No cases of COVID-19 were diagnosed in patients receiving perioperative anticancer therapy at our hospital. Regimen modification, active use of supportive care, and patient lifestyle were factors reducing the incidence of COVID-19.

Is alteration in single drug anticoagulant/antiplatelet regimen necessary in patients who need minor oral surgery? A systematic review with meta-analysis.

This study aimed to systematically review literature about the effect of alteration of the pharmacological regimen in adult patients using anticoagulants or antiplatelets who need minor oral surgery. A search strategy was performed in three databases-PubMed-Medline, Scopus, and Embase-and included randomized clinical trials (either parallel or crossover), involving individuals under anticoagulant or antiplatelet therapy who underwent oral surgeries. Studies comprised two groups: those who stopped their medication prior to the dental procedure (control) or those who did not (test). Meta-analyses were conducted for the pooled risk ratio (RR) between the groups. Subgroup analyses were performed for anticoagulant and antiplatelet therapies. Thirteen studies were included. It was found that patients who did not stop therapy had 157% higher intraoperative bleeding occurrences (95%CI: 1.40-4.71). In the subgroup analysis, warfarinazed patients showed significantly higher occurrences of intraoperative bleeding when compared with the control (RR: 1.79; 95%CI: 1.00-3.21). Conversely, there was no statistically significant difference in postoperative bleeding between the groups (RR: 0.81; 95%CI: 0.54-1.22; p = 0.42). Minor oral surgeries can be safely performed in patients under antiplatelets or anticoagulants without drug regimen modification. Because these patients tend to bleed more during procedures, use of local hemostatic measures is strongly advised. Management of patients under antiplatelet or anticoagulant drugs is still challenging in clinical practice. However, clinicians may perform minor oral surgeries safely without changing the pharmacological regimen. Use of local hemostatic measures is strongly advised during these procedures.

Effect of the COVID-19 outbreak on paediatric cancer care in low-income and middle-income countries

Effect of the COVID-19 outbreak on paediatric cancer care in low-income and middle-income countries

Medication incident recovery and prevention utilising an Australian community pharmacy incident reporting system: the QUMwatch study.

To identify factors in community pharmacy that facilitate error recovery from medication incidents (MIs) and explore medication safety prevention strategies from the pharmacist perspective. Thirty community pharmacies in Sydney, Australia, participated in a 30-month prospective incident reporting program of MIs classified in the Advanced Incident Management System (AIMS) and the analysis triangulated with case studies. The main outcome measures were the relative frequencies and patterns in MI detection, minimisation, restorative actions and prevention recommendations of community pharmacists. Participants reported 1013 incidents with 831 recovered near misses and 165 purported patient harm. MIs were mainly initiated at the prescribing (68.2%) and dispensing (22.6%) stages, and most were resolved at the pharmacy (76.9%). Detection was efficient within the first 24 h in 54.6% of MIs, but 26.1% required one month or longer; 37.2% occurred after the patient consumed the medicine. The combination of specific actions/attributes (85.5%), appropriate interventions (81.6%) and effective communication (77.7%) minimised MIs. An array of remedial actions were conducted by participants including notification, referral, advice, modification of medication regimen, risk management and documentation corrections. Recommended prevention strategies involved espousal of medication safety culture (97.8%), better application of policies/procedures (84.6%) and improvements in healthcare providers' education (79.9%). Incident reporting provided insights on the human and organisational factors involved in the recovery of MIs in community pharmacy. Optimising existing safeguards and redesigning certain structures and processes may enhance the resilience of the medication use system in primary care.

A Physiologically Based Pharmacokinetic-Pharmacodynamic Model for Capecitabine in Colorectal Cancer Rats: Simulation of Antitumor Efficacy at Various Administration Schedules.

Capecitabine is an oral prodrug of 5-fluorouracil and is widely used for colorectal cancer (CRC) treatment. However, knowledge of its antitumor efficacy after modification of the dosing schedule is insufficient. The aim of this study was to predict the antitumor efficacy of capecitabine using a physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model based on metabolic enzyme activities. CRC model rats were administrated 180mg/kg of capecitabine for 2weeks. Blood samples were collected at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, and 8h following capecitabine administration. Plasma concentrations of capecitabine and its metabolites were measured on days 1, 7, and 14. Metabolic enzyme activities were determined in vitro using the liver and small intestine of the CRC model rats. A PBPK-PD model was developed based on metabolic enzyme activities. The antitumor efficacy of capecitabine after regimen modification was simulated using the PBPK-PD model. Capecitabine antitumor efficacy was dose-dependent. A dose of >500μmol/kg was needed to inhibit tumor growth. After capecitabine regimen modification, a 1-week postponement of capecitabine administration was more efficacious than a reduction in the dosage to 80%. The PBPK-PD model could simulate the antitumor efficacy at various capecitabine administration schedules. PBPK-PD models can contribute to the development of an appropriate CRC chemotherapy regimen with capecitabine.

The Effectiveness of Goksuradi Guggulu and Varunadi Kwath with Goksuradi Guggulu in the Management of Mutrasmari w.s.r. to Urolithiasis

Introduction: Mutrasmari is considered as Astamahagada in Ayurveda in which there is formation of stone in the Mutravaha srota. It is an ancient disease with global distribution. The symptoms of Mutrasmari are excruciating pain in urethra, ureter, urinary bladder and over umbilical region, haematuria etc and later that may lead to emergence by the obstruction in urination. Hence on the basis of pathology and its clinical presentation the disease is correlated with Renal calculus or Urolithiasis in modern Urology.&#x0D; Methodology: 38 patients diagnosed as Mutrasmari were randomly divided in two groups as per the lottery system of randomization. The patients of Group A were given 1000mg Goksuradi guggulu twice a day for 45 days. The patients of Group B were given 1000 mg of Gokshuradi guggulu along with 45 ml of Varunadi kwatha twice a day for 45 days. The patients of both the groups were advised to follow the dietary regimen and lifestyle modification. The effect of the intervention was assessed before and after treatment.&#x0D; Result: The treatment outcomes were statically analyzed and found that both treatment groups were significant in relieving the symptoms like abdominal pain, burning micturition, dysuria and expulsion of renal culculi. 100% relief noted on Surudhir mutrata (Hematuria) where only single patient complaint had been registered as Hematuria in Group B. In case of Mutradaha (Burning micturation) there was mild improvement in group A and moderate improvement in group B. Similarly there was complete remission in Mahati vedana (Dysuria and Pain in abdomen) case in both Group A and Group B after the treatment. Conclusion: Gokshuradi guggulu along with Varunadi Kwatha shows more significant result than Gokshuradi guggulu.

Trends and factors associated with modification or discontinuation of the initial antiretroviral regimen during the first year of treatment in the Turkish HIV-TR Cohort, 2011\u20132017

BackgroundThere is limited evidence on the modification or stopping of antiretroviral therapy (ART) regimens, including novel antiretroviral drugs. The aim of this study was to evaluate the discontinuation of first ART before and after the availability of better tolerated and less complex regimens by comparing the frequency, reasons and associations with patient characteristics.MethodsA total of 3019 ART-naive patients registered in the HIV-TR cohort who started ART between Jan 2011 and Feb 2017 were studied. Only the first modification within the first year of treatment for each patient was included in the analyses. Reasons were classified as listed in the coded form in the web-based database. Cumulative incidences were analysed using competing risk function and factors associated with discontinuation of the ART regimen were examined using Cox proportional hazards models and Fine-Gray competing risk regression models.ResultsThe initial ART regimen was discontinued in 351 out of 3019 eligible patients (11.6%) within the first year. The main reason for discontinuation was intolerance/toxicity (45.0%), followed by treatment simplification (9.7%), patient willingness (7.4%), poor compliance (7.1%), prevention of future toxicities (6.0%), virologic failure (5.4%), and provider preference (5.4%). Non-nucleoside reverse transcriptase inhibitor (NNRTI)-based (aHR = 4.4, [95% CI 3.0–6.4]; p < 0.0001) or protease inhibitor (PI)-based regimens (aHR = 4.3, [95% CI 3.1–6.0]; p < 0.0001) relative to integrase strand transfer inhibitor (InSTI)-based regimens were significantly associated with ART discontinuation. ART initiated at a later period (2015-Feb 2017) (aHR = 0.6, [95% CI 0.4–0.9]; p < 0.0001) was less likely to be discontinued. A lower rate of treatment discontinuation for intolerance/toxicity was observed with InSTI-based regimens (2.0%) than with NNRTI- (6.6%) and PI-based regimens (7.5%) (p < 0.001). The percentage of patients who achieved HIV RNA < 200 copies/mL within 12 months of ART initiation was 91% in the ART discontinued group vs. 94% in the continued group (p > 0.05).ConclusionART discontinuation due to intolerance/toxicity and virologic failure decreased over time. InSTI-based regimens were less likely to be discontinued than PI- and NNRTI-based ART.

Adverse Drug Reactions with First-Line and Second-Line Drugs in Treatment of Tuberculosis

Drug-susceptible tuberculosis (DS-TB) requires treatment with first-line drugs (FLDs) whereas drug-resistant TB (DR-TB) are treated with combination of second-line drugs (SLDs) and fewer FLDs. Adverse drug reactions (ADRs) to these drugs are quite evident as they are being used for longer duration. The overall prevalence of ADRs with FLDs and SLDs are estimated to vary from 8.0 to 85 and 69 to 96%, respectively. Most ADRs are observed in the intensive phase as compared to continuation phase. Major concerns exist regarding treatment of DR-TB patients, especially with SLDs having lower efficacy more toxicity and high cost as compared to FLDs. A variety of ADRs may be produced by anti-TB drugs ranging from mild or minor to severe or major like gastrointestinal toxicity (nausea/vomiting, diarrhoea, and hepatotoxicity), ototoxicity, neurotoxicity (peripheral neuropathy and seizures), nephrotoxicity, cutaneous toxicity, and cardiotoxicity. Most of ADRs are minor and can be managed without discontinuation of treatment. Few ADRs' can be major causing life-threatening experience leading to either modification or discontinuation of regimen and even mortality. A careful monitoring of ADRs during the treatment with anti-TB drugs and early recognition and appropriate management of these ADRs might improve adherence leading to favorable outcome.

Association of headache, anxiety, and depression with the treatment of levetiracetam for epilepsy

The current case report bears the details of the adverse drug reactions (ADRs) associated after the administration of the levetiracetam for the management of newly diagnosed epilepsy in a female patient aged 37 years. Datum related to the patient, medications and observed ADRs were noted after getting the consent from the patient during which she has explained her experiences after the beginning of the consumption of the said drug. The Naranjo's scale and World Health Organisation, Uppsala Monitoring Centre scales analysis for the assessment of the correctness of the ADR paved for the certainty of the side effect. Drug regimen modification was initiated by the neurologist after the complaints of uneasiness from the patient after which she was identified to be complying with the other medication. Therefore, it can be said that if any patient on antiepileptic medications experiences discomfort, must bring those issues in light as there is always other options available for the management of the epilepsy without delay.

1022. Impact of Hospitalization on Antiretroviral Therapy for People Living with HIV

BackgroundPersons living with HIV (PLWH) are frequently hospitalized for reasons often unrelated to HIV. Transitioning of antiretroviral therapy (ART) while inpatient may not always be an immediate priority due to lack of knowledge, formulary restrictions, and patient status. This could lead to medication errors and gaps in therapy, which can persist at discharge, and could lead to viral rebound and disease progression. The purpose of this study was to identify effects of hospitalization on ART for PLWH.MethodsThis was an IRB approved, multi-center, retrospective cohort study of patients with HIV and/or AIDS based on ICD codes. Patients were included if they were at least 18 years old, receiving outpatient ART prior to admission, and hospitalized between March 2016 and March 2018. Patients were excluded if they were pregnant and only received intravenous zidovudine during their hospitalization. The primary objective was to determine the rate of ART restarted during hospitalization. Secondary objectives included rate at which inpatient ART was modified compared to outpatient regimen, and risk factors associated with regimen modification.ResultsOf 400 patients screened, 295 (74%) patients were on an outpatient ART regimen and were included in the study. Approximately half, 51%, were on a single tablet regimen (STR) outpatient. This population was majority male (59%) and of black race (87%). Median age was 49 years. Median CD4 count was 160 cells/mm3, while median HIV RNA for those with detectable viral load was 57,095 copies/mL.236 of 295 patients (80%) received ART during their inpatient stay. However, 70 (30%) of these patients received a regimen that differed from their outpatient ART regimen. 69% of regimens were modified for reasons other than to optimize therapy. Patient sex, place of admission, and receipt of a STR or multi-tablet regimen (MTR) as an outpatient did not significantly impact rate of regimen modification.ConclusionEnsuring appropriate transition of ART during hospitalization remains an area in need of improvement. No one specific factor was associated with whether outpatient ART was appropriately and accurately restarted during hospitalization. Thus, there are many opportunities to improve transitions of care and antiretroviral stewardship.Disclosures All Authors: No reported disclosures

MBCL-28. LONG-TERM FOLLOW-UP RESULTS OF REDUCED DOSE CRANIOSPINAL RADIOTHERAPY AND TANDEM HIGH-DOSE CHEMOTHERAPY IN PATIENTS WITH HIGH-RISK MEDULLOBLASTOMA

BACKGROUNDIn this study, we report the follow-up results of reduced-dose of craniospinal radiotherapy (CSRT) followed by tandem high-dose chemotherapy (HDCT) in patients with high-risk medulloblastoma (MB).METHODSNewly diagnosed high-risk MB patients (metastatic disease, postoperative residual tumor > 1.5 cm2 or large cell/anaplastic histology) over 3 years of age were enrolled in this study. Two cycles of pre-RT chemotherapy, RT including reduced-dose CSRT (23.4 or 30.6 Gy), 4 cycles of post-RT chemotherapy and tandem HDCT were given. NanoString and DNA sequencing were done with archival tissues.RESULTSForty patients were enrolled, and molecular subgrouping was possible in 21 patients (2 WNT, 3 SHH, 8 Group 3 and 8 group 4). All patients including two patients who experienced progression during the induction chemotherapy underwent HDCT. Relapse/progression occurred only in four patients (10-year cumulative incidence 10.4 ± 0.3%). However, six patients died from treatment-related mortality (TRM) (4 acute TRMs and 2 late TRMs) resulting in 18.5 ± 0.5% of 10-year cumulative incidence. Taken together, the 10-year event-free survival and overall survival were 71.1 ± 8.0% and 68.9 ± 8.5%, respectively. Late effects were evaluated in 25 patients and high-tone hearing loss, endocrine dysfunction, dyslipidemia, and growth retardation were common.CONCLUSIONSStrategy using tandem HDCT following reduced-dose CSRT showed promising results in terms of low relapse/progression rate, however, the high TRM rate indicates that modification of HDCT regimen and careful selection of patients who can have benefit from HDCT will be needed in the future study.

NCCN Guidelines Insights: Soft Tissue Sarcoma, Version 1.2021.

The NCCN Guidelines for Soft Tissue Sarcoma provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with soft tissue sarcomas. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including the development of a separate and distinct guideline for gastrointestinal stromal tumors (GISTs); reconception of the management of desmoid tumors; inclusion of further recommendations for the diagnosis and management of extremity/body wall, head/neck sarcomas, and retroperitoneal sarcomas; modification and addition of systemic therapy regimens for sarcoma subtypes; and revision of the principles of radiation therapy for soft tissue sarcomas.

Abstract PO-117: Population pharmacokinetics of vincristine and its metabolite in Kenyan pediatric cancer patients

Abstract Purpose: Pharmacokinetic (PK) dispositions of vincristine (VCR) and its M1 metabolite were characterized through PK co-modeling for Kenyan pediatric cancer patients with acute lymphoblastic leukemia or nephroblastoma. VCR dosing strategies are largely empirical regardless of its extensive use in pediatric oncology. Little information is known about its disposition and optimal therapeutic dosing. Renbarger and associates reported that CYP3A5 enzyme metabolizes VCR to M1 more efficiently than CYP3A4 enzyme. This may be clinically significant as CYP3A5 expression varies among Kenyans (90%), African Americans (AA, 70%) and Caucasians (10-20%). Therefore, it is essential to characterize the disposition of M1 in humans to provide an insight into the inter-ethnic variability in VCR metabolism and clearance, which will be helpful for future dosing regimen optimization. Methods: Pharmacokinetic Study: Dried blood spot (DBS) samples were collected, via finger stick at various time points depending on the feasibility, from 25 Kenyan pediatric cancer patients (13 males/12 females, 1-14 years, BSA of 0.36 - 1.3 m2) after an IV dose of VCR (1.6 – 3.1 mg/m2). Concentrations of VCR and M1 from DBS were quantified using a validated LC-MS-MS assay. Pharmacokinetic Modeling: A population PK (pop PK) co-model was developed using Phoenix® NLMETM software to simultaneously capture and predict the PK of VCR and M1 concentrations. A correlation between the observed and predicted concentrations of VCR and M1 PK was established by pop PK fitting. Model discrimination was performed on data by visual inspection, the goodness of fit plots and AIC values. Results: The best fit pop PK co-model for VCR and its M1 metabolite was established. PK parameter estimates were derived for both analytes. Volumes of distribution for VCR and M1 were 0.12 L (33.55 %CV) and 249.07 L (33.42 %CV), respectively. The elimination rate constants for VCR and M1 were 5.6 hr-1 (22.81 %CV) and 0.00015 hr-1 (66.85 %CV), respectively. The conversion rate constant of VCR to M1 was 9.66 hr-1 (32.49 %CV). Finally, clearance values were 0.67 L/hr for VCR and 0.04 L/hr for M1. In conclusion, VCR and its M1 metabolite exhibit distinct PK characteristics, in that M1 distribution is substantially larger than that of VCR (249 vs 0.12 L), and clearance is slower than that of VCR (0.04 vs 0.67 L/hr). The conversion kinetics of VCR to M1 is characterized for the first time, which may potentially offer a rationale for ethnic disparity in VCR therapy. In addition, a large inter-patient variability is documented even within the same ethnic Kenyan population. After model refinement and validation, our model could potentially serve as a tool for rational VCR dosing regimen modification for Kenyan/AA pediatric cancer patients. Citation Format: Lorita Agu, Lei Wu, Jamie Renbarger, Jodi Skiles, Andi Masters, Diana S-L. Chow. Population pharmacokinetics of vincristine and its metabolite in Kenyan pediatric cancer patients [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-117.