Publications by authors named "Richard Fisher"

230 Publications

COVID-19-related acute kidney injury; incidence, risk factors and outcomes in a large UK cohort.

BMC Nephrol 2021 11 1;22(1):359. Epub 2021 Nov 1.

Renal Unit, King's College Hospital NHS Foundation Trust, Denmark Hill, London, SE5 9RS, UK.

Background: Acute kidney injury (AKI) is common among patients hospitalised with COVID-19 and associated with worse prognosis. The aim of this study was to investigate the epidemiology, risk factors and outcomes of AKI in patients with COVID-19 in a large UK tertiary centre.

Methods: We analysed data of consecutive adults admitted with a laboratory-confirmed diagnosis of COVID-19 across two sites of a hospital in London, UK, from 1st January to 13th May 2020.

Results: Of the 1248 inpatients included, 487 (39%) experienced AKI (51% stage 1, 13% stage 2, and 36% stage 3). The weekly AKI incidence rate gradually increased to peak at week 5 (3.12 cases/100 patient-days), before reducing to its nadir (0.83 cases/100 patient-days) at the end the study period (week 10). Among AKI survivors, 84.0% had recovered renal function to pre-admission levels before discharge and none required on-going renal replacement therapy (RRT). Pre-existing renal impairment [odds ratio (OR) 3.05, 95%CI 2.24-4,18; p <  0.0001], and inpatient diuretic use (OR 1.79, 95%CI 1.27-2.53; p <  0.005) were independently associated with a higher risk for AKI. AKI was a strong predictor of 30-day mortality with an increasing risk across AKI stages [adjusted hazard ratio (HR) 1.59 (95%CI 1.19-2.13) for stage 1; p < 0.005, 2.71(95%CI 1.82-4.05); p < 0.001for stage 2 and 2.99 (95%CI 2.17-4.11); p < 0.001for stage 3]. One third of AKI3 survivors (30.7%), had newly established renal impairment at 3 to 6 months.

Conclusions: This large UK cohort demonstrated a high AKI incidence and was associated with increased mortality even at stage 1. Inpatient diuretic use was linked to a higher AKI risk. One third of survivors with AKI3 exhibited newly established renal impairment already at 3-6 months.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12882-021-02557-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557997PMC
November 2021

Criteria, Processes, and Determination of Competence in Basic Critical Care Echocardiography Training: A Delphi Process Consensus Statement by the Learning Ultrasound in Critical Care (LUCC) Initiative.

Chest 2021 Sep 8. Epub 2021 Sep 8.

University of Sydney Nepean Clinical School, Intensive Care Medicine, Kingswood, NSW, Australia.

With the paucity of high-quality studies on longitudinal basic critical care echocardiography (BCCE) training, expert opinion guidelines have guided BCCE competence educational standards and processes. However, existing guidelines lack precise detail due to methodological flaws during guideline development. To formulate methodologically robust guidelines on BCCE training using evidence and expert opinion, detailing specific criteria for every step, we conducted a modified Delphi process using the principles of the validated AGREE-II tool. Based on systematic reviews, the following domains were chosen: components of a longitudinal BCCE curriculum; pass-grade criteria for image-acquisition and image-interpretation; and formative/summative assessment and final competence processes. Between April 2020 and May 2021, a total of 21 BCCE experts participated in four rounds. Rounds 1 and 2 used five web-based questionnaires, including branching-logic software for directed questions to individual panelists. In round 3 (videoconference), the panel finalized the recommendations by vote. During the journal peer-review process, Round 4 was conducted as Web-based questionnaires. Following each round, the agreement threshold for each item was determined as ≥ 80% for item inclusion and ≤ 30% for item exclusion. Following rounds 1 and 2, agreement was reached on 62 of 114 items. To the 49 unresolved items, 12 additional items were added in round 3, with 56 reaching agreement and five items remaining unresolved. There was agreement that longitudinal BCCE training must include introductory training, mentored formative training, summative assessment for competence, and final cognitive assessment. Items requiring multiple rounds included two-dimensional views, Doppler, cardiac output, M-mode measurement, minimum scan numbers, and pass-grade criteria. Regarding objective criteria for image-acquisition and image-interpretation quality, the panel agreed on maintaining the same criteria for formative and summative assessment, to categorize BCCE findings as major vs minor and a standardized approach to errors, criteria for readiness for summative assessment, and supervisory options. In conclusion, this expert consensus statement presents comprehensive evidence-based recommendations on longitudinal BCCE training. However, these recommendations require prospective validation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chest.2021.08.077DOI Listing
September 2021

Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3.

Am J Med Genet A 2021 11 26;185(11):3446-3458. Epub 2021 Aug 26.

Neurology Clinic, Department of Medicine, Santa Maria della Misericordia Hospital, University of Perugia, Perugia, Italy.

The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.62465DOI Listing
November 2021

Clinical validation of AggreGuide A-100 ADP, a novel assay for assessing the antiplatelet effect of oral P2Y antagonists.

J Thromb Thrombolysis 2021 Jul 18;52(1):272-280. Epub 2021 Jun 18.

PCS Houston LLC, Houston, TX, USA.

In this prospective, 3-arm, repeated-measure multicenter investigation in 280 patients with cardiovascular risk factors, platelet aggregation was measured with the novel AggreGuide A-100 ADP (A-100 ADP) and VerifyNow (VN)-PRU assays at baseline, and after United States Food and Drug Administration approved loading and 7 days maintenance doses of clopidogrel (n = 94), prasugrel (n = 43) or ticagrelor, (n = 143). Based on the predetermined cutoff values of < 4.7 platelet activity index with A-100 ADP assay to indicate antiplatelet response, more than 91% of patients met the criteria following loading and maintenance doses of prasugrel and more than 84% patients met the criteria following loading and maintenance doses of ticagrelor whereas only 32% and 51% of patients met the criteria following loading and maintenance doses of clopidogrel, respectively. The total percent agreement between the A-100 ADP and VN-PRU assays was 89%. The A-100 ADP assay, which includes whole blood in motion, performs comparably to the VN-PRU assay in a study of patients with cardiovascular risk factors treated with P2Y inhibitors possessing known differences in antiplatelet potencies. Trial registration ClinicalTrials.gov Identifier: NCT3111420.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11239-021-02498-0DOI Listing
July 2021

Randomized Trial of Radiation Therapy With Weekly Cisplatin or Cetuximab in Low-Risk HPV-Associated Oropharyngeal Cancer (TROG 12.01) - A Trans-Tasman Radiation Oncology Group Study.

Int J Radiat Oncol Biol Phys 2021 11 4;111(4):876-886. Epub 2021 Jun 4.

Genesiscare St Vincent's Hospital, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia.

Purpose: The excellent prognosis of patients with low-risk human papillomavirus (HPV)- associated oropharyngeal squamous cell carcinoma has led to concerns about overtreatment and excessive toxicity with radiation therapy and cisplatin, leading to interest in de-intensification trials. We investigated whether cetuximab, an epidermal growth factor receptor targeting antibody, when combined with radiation therapy would result in a decrease in symptom burden and toxicity with similar efficacy compared with weekly cisplatin.

Methods And Materials: TROG12.01, a randomized, multicenter trial involving 15 sites in Australia and New Zealand enrolled patients with HPV-associated oropharyngeal squamous cell carcinoma, American Joint Committee on Cancer 7th edition stage III (excluding T1-2N1) or stage IV (excluding T4 and/or N3 and/or N2b-c if smoking history >10 pack years and/or distant metastases). Patients were randomized (1:1) to receive radiation therapy (70 Gy in 35 fractions) with either weekly cisplatin, 7 doses of 40 mg/m, or cetuximab, loading dose of 400 mg/m followed by 7 weekly doses of 250 mg/m. The primary outcome was symptom severity assessed by the MD Anderson Symptom Inventory Head and Neck Symptom Severity Scale from baseline to 13 weeks postcompletion of radiation therapy using the area under the curve. Trial was registered on ClinicalTrials.gov: NCT01855451.

Results: Between June 17, 2013, and June 7, 2018, 189 patients were enrolled, with 92 in cisplatin arm and 90 in cetuximab included in the main analysis. There was no difference in the primary endpoint of symptom severity; difference in area under the curve cetuximab-cisplatin was 0.05 (95% confidence interval [CI], -0.19, 0.30), P = .66. The T-score (mean number of ≥grade 3 acute adverse events) was 4.35 (standard deviation 2.48) in the cisplatin arm and 3.82 (standard deviation 1.8) in the cetuximab arm, P = .108. The 3-year failure-free survival rates were 93% (95% CI, 86%-97%) in the cisplatin arm and 80% (95% CI, 70%-87%) in the cetuximab arm (hazard ratio = 3.0 [95% CI, 1.2-7.7]); P = .015.

Conclusions: For patients with low-risk HPV-associated oropharyngeal cancer, radiation therapy and cetuximab had inferior failure-free survival without improvement in symptom burden or toxicity compared with radiation therapy and weekly cisplatin. Radiation therapy and cisplatin remain the standard of care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2021.04.015DOI Listing
November 2021

Managing Harlequin Syndrome in VA-ECMO - do not forget the right ventricle.

Perfusion 2021 May 31:2676591211020895. Epub 2021 May 31.

Department of Adult Intensive Care, Royal Brompton and Harefield NHS Foundation Trust, London, UK.

Harlequin Syndrome (also known as North-South Syndrome) is a complication of veno-arterial extracorporeal membrane oxygenation (V-A ECMO) that can occur when left ventricular function starts to recover. While most commonly due to continued impaired gas exchange in the lungs, we present a case caused by right ventricular dysfunction, successfully managed by conversion of the ECMO circuit to a veno-veno-arterial (VV-A) configuration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/02676591211020895DOI Listing
May 2021

Advances in the Formulation and Assembly of Non-Cationic Lipid Nanoparticles for the Medical Application of Gene Therapeutics.

Nanomaterials (Basel) 2021 Mar 23;11(3). Epub 2021 Mar 23.

Department of Surgery, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway Box U-11, Knoxville, TN 37920, USA.

Lipid nanoparticles have become increasingly popular delivery platforms in the field of gene therapy, but bench-to-bedside success has been limited. Many liposomal gene vectors are comprised of synthetic cationic lipids, which are associated with lipid-induced cytotoxicity and immunogenicity. Natural, non-cationic PEGylated liposomes (PLPs) demonstrate favorable biocompatibility profiles but are not considered viable gene delivery vehicles due to inefficient nucleic acid loading and reduced cellular uptake. PLPs can be modified with cell-penetrating peptides (CPPs) to enhance the intracellular delivery of liposomal cargo but encapsulate leakage upon CPP-PLP assembly is problematic. Here, we aimed to identify parameters that overcome these performance barriers by incorporating nucleic acid condensers during CPP-PLP assembly and screening variable ethanol injection parameters for optimization. CPP-PLPs were formed with R8-amphiphiles via pre-insertion, post-insertion and post-conjugation techniques and liposomes were characterized for size, surface charge, homogeneity, siRNA encapsulation efficiency and retention and cell associative properties. Herein we demonstrate that pre-insertion of stearylated R8 into PLPs is an efficient method to produce non-cationic CPP-PLPs and we provide additional assembly parameter specifications for a modified ethanol injection technique that is optimized for siRNA encapsulation/retention and enhanced cell association. This assembly technique could provide improved clinical translation of liposomal based gene therapy applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nano11030825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004789PMC
March 2021

Provision of acute renal replacement therapy, using three separate modalities, in critically ill patients during the COVID-19 pandemic. An after action review from a UK tertiary critical care centre.

J Crit Care 2021 04 28;62:190-196. Epub 2020 Dec 28.

Department of Critical Care, King's College Hospital NHS Foundation Trust, London, United Kingdom. Electronic address:

Purpose: The aim of this study is to describe the incidence of Acute Kidney Injury (AKI) amongst patients admitted to the Intensive Care Unit (ICU) with COVID-19. In addition we aim to detail the range of Renal Replacement Therapy (RRT) modalities offered to these patients (including peritoneal dialysis - PD - and intermittent haemodialysis - IHD) in order to meet demand during pandemic conditions.

Materials And Methods: Single-centre retrospective case note review of adult patients with confirmed COVID-19 admitted to ICU.

Results: Amongst 136 patients without a prior history of End Stage Kidney Disease (ESKD), 108 (79%) developed AKI and 63% of admitted patients received RRT. Due to resource limitations the range of RRT options were expanded from solely Continuous Veno-Venous HaemoDiaFiltration (CVVHDF - our usual standard of care) to include PD (in 35 patients) and IHD (in 15 patients). During the study period the proportion of RRT provided within ICU as CVVHDF fell from 100% to a nadir of 39%. There were no significant complications of either PD or IHD.

Conclusions: During periods of resource limitations PD and IHD can safely be used to reduce dependence on CVVHDF in select patients with AKI secondary to COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcrc.2020.12.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837302PMC
April 2021

Posterior Surgical Approach for Ventral Cervical Spinal Cord Herniation: 2-Dimensional Operative Video.

Oper Neurosurg (Hagerstown) 2021 02;20(3):E215-E216

Spinal cord herniation (SCH) is a rare condition that is typically of idiopathic origin. Although SCH is mostly found in the thoracic region because of a dural defect, there are some reports of cervical SCH following surgery or trauma.1-3 Spinal cord tethering can be a result of SCH or as a standalone issue.4,5 These conditions can lead to progressive neurological deficits, including numbness, gait disturbances, and decreased muscle strength, requiring surgical correction. There are limited reports of surgical procedures for ventral SCHs. Several reports exist using a ventral approach for intradural tumors, but it is not commonly employed because of the inability to obtain adequate dural closure.6 Much of the literature on SCH comes from idiopathic and congenital cases in the thoracic spine.7,8 Posterior and posterolateral approaches for a ventral thoracic SCH have been described, as well as an anterior approach for a ventral cervical SCH.9-12 In this video, we describe a posterior approach for a ventral cervical SCH. A 38-yr-old male presented with progressive cervical myelopathy 9 yr after a C2-C3 schwannoma resection requiring an anterior approach and corpectomy of C3 with partial corpectomies of C2 and C4. A preoperative magnetic resonance imaging showed a ventrally herniated spinal cord at the top of the C3 vertebral body and below the C4 vertebral body. Informed consent was obtained. The posterior surgical approach involved a C1-C5 laminectomy, sectioning the dentate ligament, ventral cord untethering, removal of residual tumor, and placement of a ventral sling. A significant improvement in sensory and motor function was observed postoperatively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ons/opaa340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133320PMC
February 2021

Adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (TROG 08.03/ANZUP RAVES): a randomised, controlled, phase 3, non-inferiority trial.

Lancet Oncol 2020 10;21(10):1331-1340

Auckland Hospital, Auckland, New Zealand.

Background: Adjuvant radiotherapy has been shown to halve the risk of biochemical progression for patients with high-risk disease after radical prostatectomy. Early salvage radiotherapy could result in similar biochemical control with lower treatment toxicity. We aimed to compare biochemical progression between patients given adjuvant radiotherapy and those given salvage radiotherapy.

Methods: We did a phase 3, randomised, controlled, non-inferiority trial across 32 oncology centres in Australia and New Zealand. Eligible patients were aged at least 18 years and had undergone a radical prostatectomy for adenocarcinoma of the prostate with pathological staging showing high-risk features defined as positive surgical margins, extraprostatic extension, or seminal vesicle invasion; had an Eastern Cooperative Oncology Group performance status of 0-1, and had a postoperative prostate-specific antigen (PSA) concentration of 0·10 ng/mL or less. Patients were randomly assigned (1:1) using a minimisation technique via an internet-based, independently generated allocation to either adjuvant radiotherapy within 6 months of radical prostatectomy or early salvage radiotherapy triggered by a PSA of 0·20 ng/mL or more. Allocation sequence was concealed from investigators and patients, but treatment assignment for individual randomisations was not masked. Patients were stratified by radiotherapy centre, preoperative PSA, Gleason score, surgical margin status, and seminal vesicle invasion status. Radiotherapy in both groups was 64 Gy in 32 fractions to the prostate bed without androgen deprivation therapy with real-time review of plan quality on all cases before treatment. The primary endpoint was freedom from biochemical progression. Salvage radiotherapy would be deemed non-inferior to adjuvant radiotherapy if freedom from biochemical progression at 5 years was within 10% of that for adjuvant radiotherapy with a hazard ratio (HR) for salvage radiotherapy versus adjuvant radiotherapy of 1·48. The primary analysis was done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT00860652.

Findings: Between March 27, 2009, and Dec 31, 2015, 333 patients were randomly assigned (166 to adjuvant radiotherapy; 167 to salvage radiotherapy). Median follow-up was 6·1 years (IQR 4·3-7·5). An independent data monitoring committee recommended premature closure of enrolment because of unexpectedly low event rates. 84 (50%) patients in the salvage radiotherapy group had radiotherapy triggered by a PSA of 0·20 ng/mL or more. 5-year freedom from biochemical progression was 86% (95% CI 81-92) in the adjuvant radiotherapy group versus 87% (82-93) in the salvage radiotherapy group (stratified HR 1·12, 95% CI 0·65-1·90; p=0·15). The grade 2 or worse genitourinary toxicity rate was lower in the salvage radiotherapy group (90 [54%] of 167) than in the adjuvant radiotherapy group (116 [70%] of 166). The grade 2 or worse gastrointestinal toxicity rate was similar between the salvage radiotherapy group (16 [10%]) and the adjuvant radiotherapy group (24 [14%]).

Interpretation: Salvage radiotherapy did not meet trial specified criteria for non-inferiority. However, these data support the use of salvage radiotherapy as it results in similar biochemical control to adjuvant radiotherapy, spares around half of men from pelvic radiation, and is associated with significantly lower genitourinary toxicity.

Funding: New Zealand Health Research Council, Australian National Health Medical Research Council, Cancer Council Victoria, Cancer Council NSW, Auckland Hospital Charitable Trust, Trans-Tasman Radiation Oncology Group Seed Funding, Cancer Research Trust New Zealand, Royal Australian and New Zealand College of Radiologists, Cancer Institute NSW, Prostate Cancer Foundation Australia, and Cancer Australia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(20)30456-3DOI Listing
October 2020

Positron Emission Tomography-Directed Therapy for Patients With Limited-Stage Diffuse Large B-Cell Lymphoma: Results of Intergroup National Clinical Trials Network Study S1001.

J Clin Oncol 2020 09 13;38(26):3003-3011. Epub 2020 Jul 13.

Division of Hematology/Oncology, Wilmot Cancer Institute, University of Rochester, Rochester, NY.

Purpose: Diffuse large B-cell lymphoma (DLBCL) presents as a limited-stage disease in 25% to 30% of patients, with better overall survival (OS) than that for advanced-stage disease but with continuous relapse regardless of treatment approach. The preferred treatment is abbreviated rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and radiation therapy. On the basis of promising results of positron emission tomography (PET)-directed treatment approaches, we designed a National Clinical Trials Network (NCTN) study to improve outcomes and decrease toxicity.

Methods: Patients with nonbulky (< 10 cm) stage I/II untreated DLBCL received 3 cycles of standard R-CHOP therapy and underwent a centrally reviewed interim PET/computed tomography scan (iPET). Those with a negative iPET proceeded with 1 additional cycle of R-CHOP, whereas those with a positive iPET received involved field radiation therapy followed by ibritumomab tiuxetan radioimmunotherapy.

Results: Of 158 patients enrolled, 132 were eligible and 128 underwent iPET, which was positive in 14 (11%) of the patients. With a median follow-up of 4.92 years (range, 1.1-7.7 years), only 6 patients progressed and 3 died as a result of lymphoma. Eleven patients died as a result of nonlymphoma causes at a median age of 80 years. The 5-year progression-free survival estimate was 87% (95% CI, 79% to 92%) and the OS estimate was 89% (95% CI, 82% to 94%), with iPET-positive and iPET-negative patients having similar outcomes.

Conclusion: To our knowledge, S1001 is the largest prospective study in the United States of limited-stage DLBCL in the rituximab era, with the best NCTN results in this disease subset. With PET-directed therapy, 89% of the patients with a negative iPET received R-CHOP × 4, and only 11% had a positive iPET and required radiation, with both groups having excellent outcomes. The trial establishes R-CHOP × 4 alone as the new standard approach to limited-stage disease for the absolute majority of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.00999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479758PMC
September 2020

Acute kidney injury in critically ill cancer patients is associated with mortality: A retrospective analysis.

PLoS One 2020 21;15(5):e0232370. Epub 2020 May 21.

Department of Critical Care, King's College London, Guy's & St Thomas' Hospital Foundation Trust, London, United Kingdom.

Background: In critically ill patients, acute kidney injury (AKI) is common and associated with short- and long-term complications. Our objectives were to describe the epidemiology and impact of AKI in cancer patients admitted to the Intensive Care Unit (ICU).

Methods: We identified all patients with a haematological malignancy (HM) or solid tumour (ST) who had an emergency admission to the ICU in a tertiary care centre between January 2004 and July 2012. AKI was defined according to the KDIGO criteria.

Results: 429 patients were included of whom 259 (60%) had AKI. Among HM patients, 73 (78%) had AKI (70% AKI on admission to ICU; 7% during ICU stay); among ST patients, 186 (56%) had AKI (45% on admission to ICU, 11% during ICU stay). ICU and 28-day mortality rates were 33% and 48%, respectively in HM patients, and 22% and 31%, respectively in ST patients. Multivariable analysis showed that AKI was an independent risk factor for both ICU and 28-day mortality. New AKI after 24 hours in ICU was associated with higher mortality than AKI on admission.

Conclusions: AKI is common in critically ill cancer patients and independently associated with ICU and 28-day mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232370PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241809PMC
July 2020

Does institutional patient accrual volume impact overall survival in patients with inoperable non-small-cell lung cancer receiving radical (chemo)radiation? A secondary analysis of TROG 99.05.

J Med Imaging Radiat Oncol 2020 Aug 11;64(4):556-562. Epub 2020 May 11.

Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Introduction: Increased hospital patient volume, reflecting greater experience, has been shown to be associated with improved survival for some cancers. However, there is no evidence to support the volume-outcome hypothesis for inoperable non-small-cell lung cancer (NSCLC) patients within the Australasian setting. We examined the relationship between overall survival (OS) and institutional patient accrual volume (IPAV) in a large prospective Australasian NSCLC database (TROG 99.05).

Methods: TROG 99.05 was an observational study which accrued patients from 1999 to 2007 to examine the relationship between primary lung cancer volume and survival. To be eligible for inclusion, patients had to have inoperable, biopsy-proven NSCLC planned for radiotherapy to a minimum dose of 50Gy in 20 fractions, with or without chemotherapy. Participating institutions were de-identified and grouped according to whether accrual was low, medium or high. OS was compared between groups and adjusted for prognostic factors using Cox regression.

Results: About 509 patients were accrued from 16 centres. Median potential follow-up time was 60 months. Median survival for all groups was 20 months (95% CI 18.3-21.8 months). There were no statistically significant differences in OS with increasing patient accrual across the three groups after adjustment for prognostic factors (P = 0.84, 2 df). The hazard ratios (HR) for group accrual volumes, relative to that for high-accrual volume, were as follows: low, 1.18; medium, 1.14. Test for trend: HR = 0.91 per group (95% CI 0.76-1.09, P = 0.31).

Conclusion: In the setting of a clinical trial with rigorous quality assurance, we found no evidence for an association between institutional accrual and survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1754-9485.13042DOI Listing
August 2020

A War on Two Fronts: Cancer Care in the Time of COVID-19.

Ann Intern Med 2020 06 27;172(11):756-758. Epub 2020 Mar 27.

Fox Chase Cancer Center, Philadelphia, Pennsylvania (A.K., D.S.W., M.J.E., E.M.H., R.G.U., R.I.F.).

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7326/M20-1133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7133056PMC
June 2020

Optimizing First-Line Therapy for Follicular Lymphoma: Is It Time for Chemotherapy-Free Approaches?

Authors:
Richard I Fisher

J Natl Compr Canc Netw 2019 11;17(11.5):1414-1416

Over the past several decades, tremendous progress has been made in the treatment of follicular lymphoma. The addition of rituximab to chemotherapy led to significant improvements in survival in the 1990s. Current standard of care in advanced-stage, previously untreated follicular lymphoma is rituximab plus chemotherapy, sometimes followed by rituximab maintenance. Now, as more research is conducted in the field of chemotherapy-free treatment, Dr. Richard I. Fisher discussed the importance of carefully constructed phase II or III trials at the NCCN 2019 Annual Congress: Hematologic Malignancies. He maintained that a nonchemotherapy treatment regimen comprising rituximab + lenalidomide can be considered in carefully selected patients, and that it is currently the only chemotherapy-free treatment that should be recommended.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.6004/jnccn.2019.5038DOI Listing
November 2019

Recurrent heterozygous PAX6 missense variants cause severe bilateral microphthalmia via predictable effects on DNA-protein interaction.

Genet Med 2020 03 8;22(3):598-609. Epub 2019 Nov 8.

MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

Purpose: Most classical aniridia is caused by PAX6 haploinsufficiency. PAX6 missense variants can be hypomorphic or mimic haploinsufficiency. We hypothesized that missense variants also cause previously undescribed disease by altering the affinity and/or specificity of PAX6 genomic interactions.

Methods: We screened PAX6 in 372 individuals with bilateral microphthalmia, anophthalmia, or coloboma (MAC) from the Medical Research Council Human Genetics Unit eye malformation cohort (HGU) and reviewed data from the Deciphering Developmental Disorders study. We performed cluster analysis on PAX6-associated ocular phenotypes by variant type and molecular modeling of the structural impact of 86 different PAX6 causative missense variants.

Results: Eight different PAX6 missense variants were identified in 17 individuals (15 families) with MAC, accounting for 4% (15/372) of our cohort. Seven altered the paired domain (p.[Arg26Gln]x1, p.[Gly36Val]x1, p.[Arg38Trp]x2, p.[Arg38Gln]x1, p.[Gly51Arg]x2, p.[Ser54Arg]x2, p.[Asn124Lys]x5) and one the homeodomain (p.[Asn260Tyr]x1). p.Ser54Arg and p.Asn124Lys were exclusively associated with severe bilateral microphthalmia. MAC-associated variants were predicted to alter but not ablate DNA interaction, consistent with the electrophoretic mobility shifts observed using mutant paired domains with well-characterized PAX6-binding sites. We found no strong evidence for novel PAX6-associated extraocular disease.

Conclusion: Altering the affinity and specificity of PAX6-binding genome-wide provides a plausible mechanism for the worse-than-null effects of MAC-associated missense variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-019-0685-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056646PMC
March 2020

Phase II Study of the PD-1 Inhibitor Pembrolizumab for the Treatment of Relapsed or Refractory Mature T-cell Lymphoma.

Clin Lymphoma Myeloma Leuk 2019 06 3;19(6):356-364.e3. Epub 2019 Apr 3.

Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, TX.

Background: Programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) are frequently expressed in T-cell lymphomas. This provides a rationale for exploration of immune checkpoint inhibitors in the management of T-cell lymphomas.

Patients And Methods: In this phase II single-arm multicenter trial, patients with relapsed or refractory systemic T-cell lymphoma were treated with 200 mg pembrolizumab intravenously every 21 days. The primary endpoint was progression-free survival (PFS). The secondary endpoints were response rate, overall survival, response duration, and safety. We assessed PD-L1, p-AKT expression, and peripheral blood immune cells as potential predictive biomarkers.

Results: Of 18 enrolled patients, 13 were evaluable for the primary endpoint. The trial was halted early after a preplanned interim futility analysis. The overall response rate was 33% (95% confidence interval [CI], 9%-55%); 4 patients achieved a complete response (27%; 95% CI, 5%-49%). The median PFS was 3.2 months (95% CI, 1.2-3.7 months), and the median overall survival was 10.6 months (95% CI, 3.2-100 months). The median duration of response was 2.9 months (95% CI, 0-10.1 months). Two of the 4 complete responders remain in remission > 15 months. Rash was the most common adverse event (17%; n = 3). The most common ≥ grade 3 treatment-emergent adverse events were rash and pneumonitis (11%; n = 2 each). Neither PD-L1 nor p-AKT expression were associated with outcomes. However, a higher relative frequency of CD4 T lymphocytes pre-treatment was associated with improved PFS (hazard ratio, 0.15; 95% CI, 0.03-0.74).

Conclusion: Pembrolizumab demonstrated modest single-agent activity in relapsed or refractory T-cell lymphoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2019.03.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433797PMC
June 2019

Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303.

J Clin Oncol 2019 07 2;37(21):1790-1799. Epub 2019 Apr 2.

14 Cornell University Medical College, New York, NY.

Purpose: Alliance/CALGB 50303 (NCT00118209), an intergroup, phase III study, compared dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as frontline therapy for diffuse large B-cell lymphoma.

Patients And Methods: Patients received six cycles of DA-EPOCH-R or R-CHOP. The primary objective was progression-free survival (PFS); secondary clinical objectives included response rate, overall survival (OS), and safety.

Results: Between 2005 and 2013, 524 patients were registered; 491 eligible patients were included in the final analysis. Most patients (74%) had stage III or IV disease; International Prognostic Index (IPI) risk groups included 26% IPI 0 to 1, 37% IPI 2, 25% IPI 3, and 12% IPI 4 to 5. At a median follow-up of 5 years, PFS was not statistically different between the arms (hazard ratio, 0.93; 95% CI, 0.68 to 1.27; = .65), with a 2-year PFS rate of 78.9% (95% CI, 73.8% to 84.2%) for DA-EPOCH-R and 75.5% (95% CI, 70.2% to 81.1%) for R-CHOP. OS was not different (hazard ratio, 1.09; 95% CI, 0.75 to 1.59; = .64), with a 2-year OS rate of 86.5% (95% CI, 82.3% to 91%) for DA-EPOCH-R and 85.7% (95% CI, 81.4% to 90.2%) for R-CHOP. Grade 3 and 4 adverse events were more common ( < .001) in the DA-EPOCH-R arm than the R-CHOP arm, including infection (16.9% 10.7%, respectively), febrile neutropenia (35.0% 17.7%, respectively), mucositis (8.4% 2.1%, respectively), and neuropathy (18.6% 3.3%, respectively). Five treatment-related deaths (2.1%) occurred in each arm.

Conclusion: In the 50303 study population, the more intensive, infusional DA-EPOCH-R was more toxic and did not improve PFS or OS compared with R-CHOP. The more favorable results with R-CHOP compared with historical controls suggest a potential patient selection bias and may preclude generalizability of results to specific risk subgroups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.18.01994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774813PMC
July 2019

A challenging ECG in a heterotopic heart transplant: double the trouble.

Acta Cardiol 2020 Apr 10;75(2):156-157. Epub 2019 Jan 10.

Division of Adult Intensive Care and Cardiology, Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/00015385.2018.1557795DOI Listing
April 2020

Autologous transplantation as consolidation for high risk aggressive T-cell non-Hodgkin lymphoma: a SWOG 9704 intergroup trial subgroup analysis.

Leuk Lymphoma 2019 08 10;60(8):1934-1941. Epub 2019 Jan 10.

a Cardinal Bernardin Cancer Center, Loyola University Medical Center , Maywood , IL , USA.

Phase II data suggest a benefit to autotransplantation for aggressive T-cell non-Hodgkin lymphoma (T-NHL) in first remission; randomized trials have yet to validate this. We performed a retrospective analysis of aggressive T-NHL patients in the intergroup randomized consolidative autotransplant trial (SWOG 9704). Of the 370 enrolled, 40 had T-NHL: 12 were not randomized due to ineligibility ( = 1), choice ( = 2), or progression ( = 9), leaving 13 randomized to control and 15 to autologous stem cell transplantation (ASCT). Two ASCT patients refused transplant and one failed mobilization. The 5-year landmark PFS/OS estimates for ASCT vs. control groups were 40% vs. 38% ( = .56), and 40% vs. 45% ( = .98), respectively. No difference was seen based on IPI, or histologic subtype. Only 1/7 receiving BCNU-based therapy survived vs. 4/5 receiving TBI. Aggressive T-NHL autotransplanted in first remission did not appear to benefit from consolidative ASCT. This and the 30% who dropped out pre-randomization mostly to progression, suggests that improved induction regimens be developed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2018.1563691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620162PMC
August 2019

Survival Outcomes of Younger Patients With Mantle Cell Lymphoma Treated in the Rituximab Era.

J Clin Oncol 2019 02 7;37(6):471-480. Epub 2019 Jan 7.

13 Johns Hopkins University, Baltimore, MD.

Purpose: Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by cyclin D1 expression. Autologous hematopoietic cell transplantation (AHCT) consolidation after induction chemotherapy is often used for eligible patients; however, the benefit remains uncertain in the rituximab era. Herein we retrospectively assessed the impact of AHCT consolidation on survival in a large cohort of transplantation-eligible patients age 65 years or younger.

Patients And Methods: We retrospectively studied transplantation-eligible adults age 65 years or younger with newly diagnosed MCL treated between 2000 and 2015. The primary objective was to assess for improved progression-free survival (PFS) with AHCT consolidation and secondarily to assess for improved overall survival (OS). Cox multivariable regression analysis and propensity score-weighted (PSW) analysis were performed.

Results: Data were collected from 25 medical centers for 1,254 patients; 1,029 met inclusion criteria. Median follow-up for the cohort was 76 months. Median PFS and OS were 62 and 139 months, respectively. On unadjusted analysis, AHCT was associated with improved PFS (75 v 44 months with v without AHCT, respectively; P < .01) and OS (147 v 115 months with v without AHCT, respectively; P < .05). On multivariable regression analysis, AHCT was associated with improved PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66; P < .01) and a trend toward improved OS (HR, 0.77; 95% CI, 0.59 to 1.01; P = .06). After PSW analysis, AHCT remained associated with improved PFS (HR, 0.70; 95% CI, 0.59 to 0.84; P < .05) but not improved OS (HR, 0.87; 95% CI, 0.69 to 1.1; P = .2).

Conclusion: In this large cohort of younger, transplantation-eligible patients with MCL, AHCT consolidation after induction was associated with significantly improved PFS but not OS after PSW analysis. Within the limitations of a retrospective analysis, our findings suggest that in younger, fit patients, AHCT consolidation may improve PFS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.18.00690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554677PMC
February 2019

Optimal Management of Adverse Events From Copanlisib in the Treatment of Patients With Non-Hodgkin Lymphomas.

Clin Lymphoma Myeloma Leuk 2019 03 29;19(3):135-141. Epub 2018 Nov 29.

Department of Internal Medicine, University of Munich, Munich, Germany.

Introduction: Copanlisib is a phosphoinositol 3-kinase (PI3K) inhibitor approved for the third-line treatment of follicular non-Hodgkin lymphoma. Although the drug is generally well-tolerated, it can be associated with several unique and potentially serious adverse effects (AEs). Two of the most common toxicities not seen with other PI3K inhibitors include hyperglycemia and hypertension, which primarily occur during infusion and resolve shortly thereafter, and likely relate to targeting the PI3K alpha isoform. Other toxicities less commonly observed with copanlisib than with other approved drugs in this class include non-infectious pneumonitis, infections, diarrhea and colitis, and hepatobiliary toxicity.

Materials And Methods: A panel composed of experts in lymphoma, diabetes, and hypertension convened to develop guidance pertaining to the administration of copanlisib and the management of the AEs associated with copanlisib treatment.

Results: Recommendations were formulated pertaining to the management of AEs associated with copanlisib treatment, particularly infusion-related hyperglycemia and hypertension, noninfectious pneumonitis, infections, diarrhea, and colitis. The recommendations herein reflect the consensus of the members of this panel, all of whom contributed to these suggested approaches to patient supportive care.

Conclusion: There are a number of challenges associated with the use of copanlisib. Infusion-related hypertension and hyperglycemia occur frequently, although they are transient, reversible, and rarely of clinical significance; this report provides guidance as to their management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2018.11.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642803PMC
March 2019

Cell mimetic liposomal nanocarriers for tailored delivery of vascular therapeutics.

Chem Phys Lipids 2019 01 21;218:149-157. Epub 2018 Dec 21.

Department of Surgery, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, 37920, TN, United States. Electronic address:

Liposomal delivery systems (LDSs) have been at the forefront of medicinal nanotechnology for over three decades. Increasing LDS association to target cells and cargo delivery is crucial to bolstering overall nanodrug efficacy. Our laboratory aims to develop LDSs for molecular therapeutics aimed at vascular pathology. We have previously established a liposome platform that is an effective delivery system for RNA interference in vascular cell types by using polyethylene glycol (PEG) decorated liposomes bearing an octa-arginine (R8) cell penetrating peptide (CPP). Further tailoring liposome membranes to mimic vascular cell membrane lipid constituents may be a promising strategy for increasing cargo delivery. Here we aimed to develop liposomal formulations that could make use of diacylglycerol (DAG) and phosphatidylserine (PS), naturally occurring lipid species that are known to influence vascular cell function, as a facile and efficient means to increase nanodrug efficacy without compromising clinical viability. We investigated the ability of DAG and PS to amplify the cellular uptake of our previously established LDS platform loaded with small interfering ribonucleic acid (siRNA) cargo. Cellular fluorescence microscopy experiments were performed in conjunction with quantitative cell association assays and cytotoxicity assays to analyze the effect of DAG/PS on the differential delivery of fluorescently-tagged liposomes to vascular smooth muscle cells (VSMCs) and vascular endothelial cells (VECs) and on liposomal-mediated toxicity. In these studies, significant, dose-dependent increases in association to target cells were observed, as well as cell-type specific effects on cell viability. The stability and encapsulation-efficiency of the DAG/PS-modified LDSs were analyzed by standard nanoparticle characterization methods, and siRNA transfection efficacy was quantified to gauge delivery potential as a function of DAG/PS modification. Our results suggest that the signaling lipids tested here imbue our LDS architectures with increased therapeutic potential, without compromising stability, encapsulation efficiency, or biocompatibility, thus presenting a natural strategy to increase nanodrug efficacy and specificity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chemphyslip.2018.12.009DOI Listing
January 2019

Reply to M. Sorigue et al.

J Clin Oncol 2019 01 26;37(3):257-258. Epub 2018 Nov 26.

Michael MacManus, MD, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Victoria, Australia; Richard Fisher, MD, PhD, and Bev McClure, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; and John F. Seymour, PhD, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, and Royal Melbourne Hospital, Parkville, Victoria, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2018.18.01309DOI Listing
January 2019
-->