A prospective pilot study of pharmacogenetic-based dosing of 5-fluouracil (5-FU) and irinotecan (IRI) in patients (pts) with gastrointestinal (GI) malignancies.

e16138 Background: 5-FU and IRI are core components of chemotherapies for GI malignancies. Previous studies have shown that mutations in DPYP and TYMS predispose the pts to 5-FU toxicities. Mutations in UGT1A1 predispose pts to increased IRI toxicities. Retrospective data suggest that these mutations may have implications in selecting dosage and/or schedule of 5-FU and IRI. We present here a prospective study of upfront pharmacogenetic testing with tailored dose of respective drugs in pts with these mutations. Methods: Pts with GI malignancies were tested for DPYD, TYMS and UGT1A1 mutations before initiating 5-FU and/or IRI. Mutation analyses were performed at Quest Diagnostics Nichols Institute. Pts were dosed at 50% if DPYD was abnormal and 25% dose reduction if indicated by TYMS or UGT1A1 * 28 (homozygous) abnormality. Adverse events (AEs) were graded according to CTCAE v.5.0. We compared AEs to our previously collected data in DPYD, TYMS deficient pts who underwent genetic testing due to toxicity to 5-FU. Results: Of 226 pts screened, 5 pts had DPYP mutations with genotypes (3: c.1905+1G/A; 1: c.2846A/T; 1: c.557A/G). TYMS mutations were identified in 24 pts. For 3'-UTR, distributions were: intermediate expression genotype 4: INS/DEL, low expression genotype 5: DEL/DEL. For 5'TSER, distributions were: low expression genotypes (6:2R/2R; 3:2R/3RC; 4: 3RC/3RC) and high expression genotypes (2: 2R/3RG, 2: 3RG/3RC, 1: 3RG/3RG). UGT1A1*28 mutation was identified in 53 pts – 19 homozygous and 34 heterozygous. No grade ≥3 neutropenia was observed with reduced dose of IRI in UGT1A 1 variant pts compared to 33% reported in pts not tested. For TYMS and DPYD variants, no grade ≥3 AEs were seen. Comparison of AEs in pts with post treatment genetic testing is listed in Table. Conclusions: Pharmacogenetic based dosing of 5-FU and IRI led to less frequent, less severe toxicities and no death related to AEs was observed in our pts. This can improve pts’ quality of life and lessen economic burden of managing severe AEs. Currently, there are no formal guidelines regarding testing for DPYD, TYMS and UGT1A1. Although non-randomized, this study advocates for systemic screening of pharmacogenetic testing in pts with GI malignancies. [Table: see text]

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Enzalutamide: Do treatment modifications allow drug continuation without losing disease control?

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.326 ◽

2018 ◽

Vol 36 (6_suppl) ◽

pp. 326-326

Author(s):

Emma Samah Massalha ◽

Lenka Zvirinska

Keyword(s):

Quality Of Life ◽

Prostate Cancer ◽

Adverse Events ◽

Dose Reduction ◽

Metastatic Prostate Cancer ◽

Performance Status ◽

North Wales ◽

Grade 3 ◽

A Prospective Study

326 Background: Enzalutamide improves progression free and overall survival in men with metastatic prostate cancer (Beer T, et al. 2014; Cabot R, et al. 2012). Grade 3 adverse events occur in up to 48% (Beer T, et al. 2014; Cabot R, et al. 2012). and lead to treatment discontinuation in up to 8% (Beer T, et al. 2014; Cabot R, et al. 2012). The purpose of this retrospective analysis is to determine whether treatment modification (TM) with dose reduction (DR), treatment break (TB) or both, still allow control of prostate cancer in men who may have otherwise stopped treatment due to intolerable side effects. Methods: All patients in North Wales, UK, who commenced enzalutamide for metastatic prostate cancer in 2016 were eligible. Data was collected and recorded from electronic notes and prescriptions. Results: 66 men aged 61 to 92 (median 77) commenced treatment with enzalutamide in 2016. 17% performance status (PS) 0, 51% PS 2, 3% PS 3. Treatment has been discontinued in 80%. Adverse events (AEs) led to discontinuation in 25% cases including 2 deaths. The most common AE was fatigue in 37%. 11 patients (17%) had TM due to AEs. Mean treatment duration was 9.6 months (range 1 to 19.2 months), without TM 8.9 months, with TM, 12.8 months. Men with PS 2 were more likely to require TM or discontinuation (D) due to AEs (29% each) compared to PS 1 (24% TM, 21% D) or PS 0 (1% TM, 27% D). TBs lasted between 2 weeks and 7 months. PSA rose during that time but quality of life improved and PSA responded once treatment was recommenced. After a TB, enzalutamide was continued for 2 to 11 months (median 5.9 months). DR did not adversely affected PSA in 6 of 7 cases and improved quality of life in 2 cases. Patients continued enzalutamide 2-12 months (median 5.9 months) after dose reduction, including 4 still on treatment. Conclusions: This shows that both treatment breaks and dose reductions can improve quality of life whilst not adversely affecting outcome. However, the numbers are small and this needs to be confirmed in a prospective study. Those with lower PS are more likely to require modification.

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72: Quality of Life and Patient Satisfaction of Care Among Women with Urinary Incontinence: A Prospective Study

The Journal of Urology ◽

10.1016/s0022-5347(18)30337-9 ◽

2007 ◽

Vol 177 (4S) ◽

pp. 25-26

Author(s):

Simon Kim ◽

Rodney L. Dunn ◽

Edward J. McGuire ◽

John O.L. DeLancey ◽

John T. Wei

Keyword(s):

Quality Of Life ◽

Urinary Incontinence ◽

Patient Satisfaction ◽

Prospective Study ◽

A Prospective Study

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Superselective Radioembolization of Hepatocellular Carcinoma: 5-Year Results of a Prospective Study

Nuklearmedizin ◽

10.1055/s-0038-1629756 ◽

1994 ◽

Vol 33 (05) ◽

pp. 206-214 ◽

Cited By ~ 1

Author(s):

J. Triller ◽

H. U. Baer ◽

Livia Geiger ◽

H. F. Beer ◽

C. Becker ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Survival Rates ◽

Absorbed Dose ◽

Pulmonary Complications ◽

Pulmonary Shunt ◽

Recurrent Tumour ◽

Activity Distribution ◽

A Prospective Study ◽

Overall Survival Rates

SummaryTwenty patients with unresectable hepatocellular carcinoma (HCC) were followed up to 5 years after transarterial radiotherapy with 90Y-resin particles. Diagnostic radioembolizations of 99mTc-macroaggregates facilitated scintigraphic assessment of activity distribution, dose evaluation and final procedural verification. The overall survival rates were 56, 38 and 14% (after 1, 2 and 3 years, resp.). Patients with unifocal HCC and a single feeding artery (n = 7) even presented 83, 67 and 40% (2 alive after 2.75 and 4 years). With multiple arteries (n = 7), the longest survival was 26 months. Patients with multifocal HCC survived up to 33 months after selective radioembolization. Quality of life was improved in all. Survival was positively correlated with absorbed dose but residual/recurrent tumour occurred even after ≥300 Gy. Post-treatment symptoms were minimal (35 applications), pulmonary shunt rates were correctly predicted and pulmonary complications avoided.

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Quality of Life Before and After Endovascular and Open Repair of Asymptomatic AAAs: A Prospective Study

Journal of Endovascular Therapy ◽

10.1583/1545-1550(2000)007<0372:qolbaa>2.0.co;2 ◽

2000 ◽

Vol 7 (5) ◽

pp. 372-379 ◽

Cited By ~ 17

Author(s):

Martin Malina ◽

Marie Nilsson ◽

Jan Brunkwall ◽

Krasnodar Ivancev ◽

Timothy Resch ◽

...

Keyword(s):

Quality Of Life ◽

Prospective Study ◽

Open Repair ◽

Before And After ◽

A Prospective Study

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Prospective Randomized Trial Comparing Mitomycin, Cisplatin, and Protracted Venous-Infusion Fluorouracil (PVI 5-FU) With Epirubicin, Cisplatin, and PVI 5-FU in Advanced Esophagogastric Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2002.08.105 ◽

2002 ◽

Vol 20 (8) ◽

pp. 1996-2004 ◽

Cited By ~ 340

Author(s):

P. Ross ◽

M. Nicolson ◽

D. Cunningham ◽

J. Valle ◽

M. Seymour ◽

...

Keyword(s):

Randomized Study ◽

Squamous Carcinoma ◽

Undifferentiated Carcinoma ◽

Palmar Erythema ◽

Esophagogastric Cancer ◽

Equivalent Efficacy ◽

Venous Infusion ◽

Grade 3 ◽

To Receive

PURPOSE: We report the results of a prospectively randomized study that compared the combination of epirubicin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) (ECF) with the combination of mitomycin, cisplatin, and PVI 5-FU (MCF) in previously untreated patients with advanced esophagogastric cancer. PATIENTS AND METHODS: Five hundred eighty patients with adenocarcinoma, squamous carcinoma, or undifferentiated carcinoma were randomized to receive either ECF (epirubicin 50 mg/m2 every 3 weeks, cisplatin 60 mg/m2 every 3 weeks and PVI 5-FU 200 mg/m2/d) or MCF (mitomycin 7 mg/m2 every 6 weeks, cisplatin 60 mg/m2 every 3 weeks, and PVI 5-FU 300 mg/m2/d) and analyzed for survival, response, toxicity, and quality of life (QOL). RESULTS: The overall response rate was 42.4% (95% confidence interval [CI], 37% to 48%) with ECF and 44.1% (95% CI, 38% to 50%) with MCF (P = .692). Toxicity was tolerable, and there were only two toxic deaths. ECF resulted in more grade 3/4 neutropenia and grade 2 alopecia, but MCF caused more thrombocytopenia and plantar-palmar erythema. Median survival was 9.4 months with ECF and 8.7 months with MCF (P = .315); at 1 year, 40.2% (95% CI, 34% to 46%) of ECF and 32.7% (95% CI, 27% to 38%) of MCF patients were alive. Median failure-free survival was 7 months with both regimens. Global QOL scores were better with ECF at 3 and 6 months. CONCLUSION: This study confirms response, survival, and QOL benefits of ECF observed in a previous randomized study. The equivalent efficacy of MCF was demonstrated, but QOL was superior with ECF. ECF remains one of the reference treatments for advanced esophagogastric cancer.

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GCT-61. CORRELATION OF PATTERNS OF DISEASE RECURRENCE WITH RADIOTHERAPY TECHNIQUES AND DOSE IN INTRACRANIAL GERM CELL TUMOURS (icGCT): LESSONS FROM THE UK COHORT OF SIOP GCT96 STUDY

Neuro-Oncology ◽

10.1093/neuonc/noaa222.278 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii340-iii340

Author(s):

Thankamma Ajithkumar ◽

Henry Mandeville ◽

Fernando Carceller ◽

Milind Ronghe ◽

Tina Foord ◽

...

Keyword(s):

Clinical Trials ◽

Disease Recurrence ◽

Germ Cell Tumours ◽

Prospective Data ◽

Data Collection And Analysis ◽

Radiotherapy Techniques ◽

The Uk ◽

A Prospective Study ◽

Patterns Of Recurrence

Abstract BACKGROUND There are global variations in radiotherapy approaches for icGCT. An understanding of patterns of disease recurrence correlated with radiation techniques and doses is important in standardising and improving the quality of radiotherapy using high-precision techniques. METHODS AND RESULTS Data from 20 patients with tumour recurrence after treatment within the SIOP GCT96 study in the UK were analysed. Seven (35%) patients had germinoma and 13 (65%) had non-germinoma. Twelve patients had local recurrence, 5 had metastatic and 3 had local and metastatic disease. Radiotherapy details were retrieved in only 8 patients (40%). Six patients had received focal radiotherapy and two craniospinal radiotherapy. Of the patients who received focal radiotherapy, 4 had recurrence within the radiation portal, one had periventricular recurrence and one had marker-positive recurrence with no radiological lesions. Both patients who received CSI recurred within the CSF space. The main reasons for poor retrieval of treatment details were difficulty in retrieving archived information and that the study was conducted during a period before PACS or electronic radiotherapy records. CONCLUSION This study highlights the importance prospective data collection and analysis to understand the patterns of recurrence in icGCT. Even within a prospective study, radiotherapy techniques varied between centres. There is therefore an urgent need for centralised radiological review and prospective radiotherapy quality assurance measures in future clinical trials.

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Slowly resorbable biosynthetic mesh: 2-year results in VHWG grade 3 hernia repair

Hernia ◽

10.1007/s10029-021-02453-1 ◽

2021 ◽

Author(s):

M. M. J. Van Rooijen ◽

T. Tollens ◽

L. N. Jørgensen ◽

T. S. de Vries Reilingh ◽

G. Piessen ◽

...

Keyword(s):

Quality Of Life ◽

Hernia Repair ◽

Hernia Recurrence ◽

Recurrence Rates ◽

Elective Repair ◽

Significant Difference ◽

Grade 3

Abstract Introduction Information on the long-term performance of biosynthetic meshes is scarce. This study analyses the performance of biosynthetic mesh (Phasix™) over 24 months. Methods A prospective, international European multi-center trial is described. Adult patients with a Ventral Hernia Working Group (VHWG) grade 3 incisional hernia larger than 10 cm2, scheduled for elective repair, were included. Biosynthetic mesh was placed in sublay position. Short-term outcomes included 3-month surgical site occurrences (SSO), and long-term outcomes comprised hernia recurrence, reoperation, and quality of life assessments until 24 months. Results Eighty-four patients were treated with biosynthetic mesh. Twenty-two patients (26.2%) developed 34 SSOs, of which 32 occurred within 3 months (primary endpoint). Eight patients (11.0%) developed a hernia recurrence. In 13 patients (15.5%), 14 reoperations took place, of which 6 were performed for hernia recurrence (42.9%), 3 for mesh infection (21.4%), and in 7 of which the mesh was explanted (50%). Compared to baseline, quality of life outcomes showed no significant difference after 24 months. Despite theoretical resorption, 10.7% of patients reported presence of mesh sensation in daily life 24 months after surgery. Conclusion After 2 years of follow-up, hernia repair with biosynthetic mesh shows manageable SSO rates and favorable recurrence rates in VHWG grade 3 patients. No statistically significant improvement in quality of life or reduction of pain was observed. Few patients report lasting presence of mesh sensation. Results of biosynthetic mesh after longer periods of follow-up on recurrences and remodeling will provide further valuable information to make clear recommendations. Trial registration Registered on clinicaltrials.gov (NCT02720042), March 25, 2016.

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810 Preliminary safety, tolerability and efficacy results of KN026 in combination with KN046 in patients with HER2 aberrated solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0810 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A861-A861

Author(s):

Jifang Gong ◽

Lin Shen ◽

Zhi Dong ◽

Dan Liu ◽

June Xu ◽

...

Keyword(s):

Disease Progression ◽

Solid Tumors ◽

Dose Escalation ◽

Bispecific Antibody ◽

Her2 Overexpression ◽

Her2 Positive ◽

Her2 Mutation ◽

Grade 3 ◽

Experienced Grade ◽

Low Expression

BackgroundHER2 potently inhibits innate immunity through cGAS–STING signaling [Ref],meanwhile HER2 antibody induced ADCP will also lead to macrophage mediated immune suppression. Both preclinical and clinical studies have suggested a coordination of engagement of innate and adaptive immunity with the combination of an anti-HER2 antibody and an immune checkpoint blockade. KN026 is a novel bispecific antibody that simultaneously binds to two distinct HER2 epitopes. KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD-1/CD80 and CTLA-4 interaction with CD80/CD86. Here we reported the interim results from an ongoing phase Ib dose escalation and expansion study assessing the safety, tolerability and preliminary efficacy for KN026 in combination with KN046 in Patients with HER2 aberrated solid tumors.MethodsThis study enrolled pts with solid tumors who failed available standard of care, HER2 aberration status confirmed locally (HER2 mutation, HER2 amplification and/or HER2 overexpression). Eligible pts received combination of KN026 and KN046 at three dose levels until disease progression, unacceptable toxicity or withdrawal of informed consent (DL1: KN026 20 mg/kg Q2W + KN046 3 mg/kg Q2W; DL2: KN026 20 mg/kg Q2W with loading on Days 1, 8 of Cycle 1 + KN046 5 mg/kg Q3W; DL3: KN026 30 mg/kg Q3W with loading on Days 1, 8 of Cycle 1 + KN046 5 mg/kg Q3W). Tumor response was evaluated Q8W per RECIST 1.1. Primary endpoint was DLT and key secondary endpoints were efficacy parameters (ORR, DOR, PFS).ResultsAs of the Sep. 08, 2020, 25 pts were enrolled into DL1 (n = 20, 3 for dose escalation), DL2 (n = 3) and DL3 (n = 2) (mGC/GEJ 15 pts; mCRC 8 pts; other solid tumors 2 pts). 15 pts remained on the study treatment and 10 pts discontinued treatment due to disease progression (n=5), death (n=2) and other reasons (n=3). 18 pts had HER2-positive status (12 of 18 failed previous trastuzumab therapy), 2 pts had HER2 mutation and 5 pts had HER2 low expression (without FISH amplification). No DLTs were observed. No pts experienced LVEF decreased or other clinically meaningful cardiac AEs. Treatment-related TEAEs occurred in 23 (92%) pts, of which 6 (24%) pts experienced grade 3 or above treatment-related TEAEs. 11 (44%) pts experienced irAEs, majority were of grade 1 or 2 except that 1 patient experienced grade 3 immune-mediated endocrinopathy. The most common (frequency ≥ 15%) KN026 or KN046 related TEAEs were infusion related reaction (n=11, 44.0%), anaemia (n=9, 36.0%), white blood cell count decreased (n=6, 24.0%), diarrhea (n=5, 20.0%), AST increased (n=5, 20.0%), platelet count decreased (n=5, 20.0%), rash (n=5, 20.0%) and ALT increased (n=4, 16.0%). The objective response rate in pts with HER2-positive tumors (n = 14 efficacy evaluable pts) was 9/14 (64.3%, 95% CI 35.1~87.2%) and disease control rate 13/14 (92.9%, 95% CI 66.1~99.8%). 4 out of 5 pts with HER2 mutation or low expression achieved SD including one patient with SD for more than 24 weeks. 2 death cases due to disease progression were reported, both only received one cycle of KN026 plus KN046 due to COVID-19 restriction.ConclusionsKN026 combined with KN046 is well tolerated and has demonstrated preliminary albeit profound anti-tumor activity in HER2-positive solid tumors.Trial RegistrationClinical trial information: NCT04040699ReferenceShiying Wu, Qian Zhang, Fei Zhang, et al. HER2 recruits AKT1 to disrupt STING signalling and suppress antiviral defence and antitumour immunity. Nature Cell Biology 2019;21:1027–1040.

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A Longitudinal Assessment of the Quality of Insulin Prescribing with Different Prescribing Systems

Pharmacy ◽

10.3390/pharmacy9010053 ◽

2021 ◽

Vol 9 (1) ◽

pp. 53

Author(s):

Amandeep Setra ◽

Yogini Jani

Keyword(s):

Care Setting ◽

Electronic Prescribing ◽

Longitudinal Assessment ◽

Prescribing Practices ◽

Record System ◽

Audit Data ◽

Core Components ◽

Secondary Care Setting ◽

The Impact

Accurate and complete prescriptions of insulin are crucial to prevent medication errors from occurring. Two core components for safe insulin prescriptions are the word ‘units’ being written in full for the dose, and clear documentation of the insulin device alongside the name. A retrospective review of annual audit data was conducted for insulin prescriptions to assess the impact of changes to the prescribing system within a secondary care setting, at five time points over a period of 7 years (2014 to 2020). The review points were based on when changes were made, from standardized paper charts with a dedicated section for insulin prescribing, to a standalone hospital wide electronic prescribing and medicines administration (ePMA) system, and finally an integrated electronic health record system (EHRS). The measured outcomes were compliance with recommended standards for documentation of ‘units’ in full, and inclusion of the insulin device as part of the prescription. Overall, an improvement was seen in both outcomes of interest. Device documentation improved incrementally with each system change—34% for paper charts, 23%–56% for standalone ePMA, and 100% for ePMA integrated within EHRS. Findings highlight that differences in ePMA systems may have varying impact on safe prescribing practices.

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