BMJ. 2021 Jul 21;374:n1647. doi: 10.1136/bmj.n1647.

ABSTRACT

OBJECTIVE: To evaluate effects of remote monitoring of adjuvant chemotherapy related side effects via the Advanced Symptom Management System (ASyMS) on symptom burden, quality of life, supportive care needs, anxiety, self-efficacy, and work limitations.

DESIGN: Multicentre, repeated measures, parallel group, evaluator masked, stratified randomised controlled trial.

SETTING: Twelve cancer centres in Austria, Greece, Norway, Republic of Ireland, and UK.

PARTICIPANTS: 829 patients with non-metastatic breast cancer, colorectal cancer, Hodgkin's disease, or non-Hodgkin's lymphoma receiving first line adjuvant chemotherapy or chemotherapy for the first time in five years.

INTERVENTION: Patients were randomised to ASyMS (intervention; n=415) or standard care (control; n=414) over six cycles of chemotherapy.

MAIN OUTCOME MEASURES: The primary outcome was symptom burden (Memorial Symptom Assessment Scale; MSAS). Secondary outcomes were health related quality of life (Functional Assessment of Cancer Therapy-General; FACT-G), Supportive Care Needs Survey Short-Form (SCNS-SF34), State-Trait Anxiety Inventory-Revised (STAI-R), Communication and Attitudinal Self-Efficacy scale for cancer (CASE-Cancer), and work limitations questionnaire (WLQ).

RESULTS: For the intervention group, symptom burden remained at pre-chemotherapy treatment levels, whereas controls reported an increase from cycle 1 onwards (least squares absolute mean difference -0.15, 95% confidence interval -0.19 to -0.12; P<0.001; Cohen's D effect size=0.5). Analysis of MSAS sub-domains indicated significant reductions in favour of ASyMS for global distress index (-0.21, -0.27 to -0.16; P<0.001), psychological symptoms (-0.16, -0.23 to -0.10; P<0.001), and physical symptoms (-0.21, -0.26 to -0.17; P<0.001). FACT-G scores were higher in the intervention group across all cycles (mean difference 4.06, 95% confidence interval 2.65 to 5.46; P<0.001), whereas mean scores for STAI-R trait (-1.15, -1.90 to -0.41; P=0.003) and STAI-R state anxiety (-1.13, -2.06 to -0.20; P=0.02) were lower. CASE-Cancer scores were higher in the intervention group (mean difference 0.81, 0.19 to 1.43; P=0.01), and most SCNS-SF34 domains were lower, including sexuality needs (-1.56, -3.11 to -0.01; P<0.05), patient care and support needs (-1.74, -3.31 to -0.16; P=0.03), and physical and daily living needs (-2.8, -5.0 to -0.6; P=0.01). Other SCNS-SF34 domains and WLQ were not significantly different. Safety of ASyMS was satisfactory. Neutropenic events were higher in the intervention group.

CONCLUSIONS: Significant reduction in symptom burden supports the use of ASyMS for remote symptom monitoring in cancer care. A "medium" Cohen's effect size of 0.5 showed a sizable, positive clinical effect of ASyMS on patients' symptom experiences. Remote monitoring systems will be vital for future services, particularly with blended models of care delivery arising from the covid-19 pandemic.

TRIAL REGISTRATION: Clinicaltrials.gov NCT02356081.

PMID:34289996 | DOI:10.1136/bmj.n1647

Cureus. 2021 Jun 16;13(6):e15703. doi: 10.7759/cureus.15703. eCollection 2021 Jun.

ABSTRACT

Immune-mediated adverse events are commonly seen with immune checkpoint inhibitors like nivolumab. Oncology specialists usually have to screen patients for risk factors for autoimmune diseases, since immune checkpoint inhibitors can potentially exacerbate these events. Some of the immune-mediated side effects include polyneuropathies, colitis, and cutaneous adverse effects. Non-specific maculopapular rash, pruritus, lichenoid reactions, eczema, and vitiligo are the most common dermatologic side effects. It is thought that these adverse events are due to the blocking of the programmed cell death protein-1 (PD-1) pathway and are mediated by the cytotoxic T cells. Psoriasis has been previously reported as a side effect in a few case reports and most commonly presented as an exacerbation of preexisting psoriasis. However, de novo psoriasis occurrence as a result of nivolumab is a rare entity, especially in a non-melanoma patient. Here, we present a case of renal cell carcinoma treated with immunotherapy with nivolumab, who developed de novo psoriasis with palmoplantar involvement.

PMID:34290912 | PMC:PMC8288591 | DOI:10.7759/cureus.15703

Front Pharmacol. 2021 Jul 5;12:671835. doi: 10.3389/fphar.2021.671835. eCollection 2021.

ABSTRACT

Objective: To assess the association between PTGS1 and NOS3 variant alleles and the risk to develop upper gastrointestinal bleeding (UGIB) secondary to complicated peptic disease. Methods: A case-control study was conducted in a Brazilian complex hospital from July 2016 to March 2020. Case: Patients with UGIB diagnosis. Control: Patients admitted for surgery not related to gastrointestinal disorders. Variables: UGIB (outcome), genetic variants in PTGS1 and NOS3 genes (independent), and sex, age, schooling, ethnicity, previous history of gastrointestinal disorders, Helicobacter pylori serology, comorbidity, drug therapy, and lifestyle (confounding). The single-nucleotide polymorphisms (SNPs) of the PTSG1 gene (rs1330344, rs3842787, rs10306114, and rs5788) and NOS3 gene (rs2070744 and rs1799983) were determined using the real-time polymerase chain reaction. Helicobacter pylori serology was determined through the chemiluminescence technique. Logistic regression models were built and deviations of allelic frequencies from Hardy-Weinberg equilibrium were verified. Results: 200 cases and 706 controls were recruited. Carriers of the AG genotype of rs10306114 (OR: 2.55, CI 95%: 1.13-5.76) and CA + AA genotypes of rs5788 (OR: 2.53, CI 95%: 1.14-5.59) were associated with an increased risk for the UGIB development. In nonsteroidal anti-inflammatory drugs (NSAIDs) users, the six variants evaluated modified the magnitude of the risk of UGIB, whereas in low-dose aspirin (LDA) users, an increased risk of UGIB was observed for four of them (rs1330344, rs10306114, rs2070744, and rs1799983). Personal ulcer history (p-value: < 0.001); Helicobacter pylori infection (p-value: < 0.011); NSAIDs, LDA, and oral anticoagulant use (p-value: < 0.001); and alcohol intake (p-value: < 0.001) were also identified as independent risk factors for UGIB. Conclusion: This study presents two unprecedented analyses within the scope of the UGIB (rs10306114 and rs2070744), and our findings showing an increased risk of UGIB in the presence of the genetic variants rs10306114 and rs5788, regardless of the drug exposure. Besides, the presence of the evaluated variants might modify the magnitude of the risk of UGIB in LDA/NSAIDs users. Therefore, our data suggest the need for a personalized therapy and drug use monitoring in order to promote patient safety.

PMID:34290607 | PMC:PMC8287722 | DOI:10.3389/fphar.2021.671835

Clin Pharmacol Drug Dev. 2021 Jul 19. doi: 10.1002/cpdd.998. Online ahead of print.

ABSTRACT

This bioequivalence study was conducted to determine the pharmacokinetics and safety profiles of an originator and a generic avanafil formulation in Chinese male subjects under fed and fasting conditions. Each eligible subject was initially randomly given avanafil (200 mg) in a test-reference or reference-test order, before being switched to another study drug sequence after 7 drug-free days. The bioequivalence of test and reference avanafil were determined if the 90%CIs of the geometric mean ratio (GMR) for the area under plasma concentration-time curve (AUC) from time 0 to infinity (AUC0-∞ ), AUC from time 0 to the last detectable concentration (AUC0-t ), and the maximum plasma concentration (Cmax ) fell within the range 80%-125%. Under fasting/fed conditions, the 90%CIs of GMR for AUC0-∞ , AUC0-t , and Cmax were 98.9% to 109.5%/96.0% to 101.2%, 99.6% to 110.3%/96.6% to 102.4%, and 99.3% to 116.8%/94.3% to 106.7%, respectively, which were all within the 80%-125% range. Adverse events (AEs) occurred in 20.8% of subjects under fasting conditions and 20.7% of subjects under fed conditions, with a severity of grade 1. No significant difference was found in the rate of occurrence of AEs and drug-related AEs in the test and reference-avanafil groups (all P > .05). We concluded that the test and reference avanafil were bioequivalent in healthy Chinese male subjects under fasting and fed conditions.

PMID:34288578 | DOI:10.1002/cpdd.998

Neuropsychiatr Dis Treat. 2021 Jul 12;17:2229-2242. doi: 10.2147/NDT.S256699. eCollection 2021.

ABSTRACT

Drug resistant epilepsy (DRE) is defined as the persistence of seizures despite at least two syndrome-adapted antiseizure drugs (ASD) used at efficacious daily dose. Despite the increasing number of available ASD, about a third of patients with epilepsy still suffer from drug resistance. Several factors are associated with the risk of evolution to DRE in patients with newly diagnosed epilepsy, including epilepsy onset in the infancy, intellectual disability, symptomatic epilepsy and abnormal neurological exam. Pharmacological management often consists in ASD polytherapy. However, because quality of life is driven by several factors in patients with DRE, including the tolerability of the treatment, ASD management should try to optimize efficacy while anticipating the risks of drug-related adverse events. All patients with DRE should be evaluated at least once in a tertiary epilepsy center, especially to discuss eligibility for non-pharmacological therapies. This is of paramount importance in patients with drug resistant focal epilepsy in whom epilepsy surgery can result in long-term seizure freedom. Vagus nerve stimulation, deep brain stimulation or cortical stimulation can also improve seizure control. Lastly, considering the effect of DRE on psychologic status and social integration, comprehensive care adaptations are always needed in order to improve patients' quality of life.

PMID:34285484 | PMC:PMC8286073 | DOI:10.2147/NDT.S256699

Drug Ther Bull. 2021 Jul 20:dtb-2021-000043. doi: 10.1136/dtb.2021.000043. Online ahead of print.

NO ABSTRACT

PMID:34285129 | DOI:10.1136/dtb.2021.000043

Drug Ther Bull. 2021 Jul 20:dtb-2021-000042. doi: 10.1136/dtb.2021.000042. Online ahead of print.

ABSTRACT

Overview of: Manyonda I, Belli AM, Lumsden MA, et al Uterine-artery embolization or myomectomy for uterine fibroids. N Engl J Med 2020;383(5):440-451.

PMID:34285128 | DOI:10.1136/dtb.2021.000042

Eur J Hosp Pharm. 2021 Jul 20:ejhpharm-2021-002868. doi: 10.1136/ejhpharm-2021-002868. Online ahead of print.

ABSTRACT

OBJECTIVES: Early detection of aminoglycoside-induced acute kidney injury (AKI) is crucial in intensive care unit (ICU) patients, but it is not adequately reflected by serum creatinine (SrCr) levels. This study proposed investigating the relationship between amikacin trough levels and the development of nephrotoxicity using both conventional markers and a new biomarker of renal function in critically ill elderly patients.

METHODS: Thirty-three critically ill patients aged ≥65 years with normal SrCr who received once-daily amikacin were evaluated. Trough levels of amikacin, creatinine clearance (CrCL) and urinary neutrophil gelatinase-associated lipocalin (uNGAL) were measured during the 10-day study period. The patients were divided into three groups and were compared based on the trough levels on both day 3 and day 7: <3 µg/mL (low trough (LT)), 3-6 µg/mL (moderate trough (MT)) and >6 µg/mL (high trough (HT)).

RESULTS: In the LT group, neither CrCL nor uNGAL levels significantly changed from baseline (p=0.364 and p=0.562, respectively). In the MT group, the CrCL level altered significantly over time from baseline (p=0.007), but the uNGAL level did not change significantly over the study period (p=0.916). In the HT group, both CrCL and uNGAL levels significantly changed from baseline during the study period (p=0.002 and p=0.046, respectively).

CONCLUSIONS: In critically ill elderly patients with MT, the mean uNGAL level changed at least 4 days earlier than the SrCr level. Instead, the trough level of amikacin demonstrated a potential value for predicting subclinical AKI for implementing necessary interventions. Amikacin trough levels <3 µg/mL in the once-daily dosing regimen appeared safe, even in geriatric patients. Further studies are needed to confirm this finding.

PMID:34285109 | DOI:10.1136/ejhpharm-2021-002868

Eur J Hosp Pharm. 2021 Jul 20:ejhpharm-2021-002827. doi: 10.1136/ejhpharm-2021-002827. Online ahead of print.

ABSTRACT

OBJECTIVE: The primary endpoint of the present study was to assess the potential therapeutic effects of three different mouthwashes for alleviation and treatment of oral complications (OCs). The secondary endpoint was to assess patients' perceptions and daily functional activities after therapy of OCs in patients with colon cancer receiving 5-fluorouracil (5-FU)-based chemotherapy regimens.

METHODS: A prospective, randomised controlled study carried out on 90 patients with colon cancer eligible for 5-FU-based chemotherapy regimens at the oncology centre, Istanbul, Turkey. Patients were randomly randomised into three groups (30 patients in each group) and received a single mouthwash. The first group (group A) received benzydamine at a dose of 15 mL; the second group (group B) received sodium bicarbonate at a dose of 1.2-2.4 g in 240 mL of water; and the third group (group C) received glutamine suspension 10 g. Patients were assessed for the occurrence of oral complications based on the WHO scale for oral mucosa evaluation and National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Oral pain was assessed using a visual analogue scale alongside assessment of patients' perceptions and daily functional activities based on the Rotterdam Symptom Checklist.

RESULTS: A total of 119 oral complications were reported, including mouth dryness (n=56, 47.1%), oral mucositis (n=31, 26.1%) and oral pain (n=32, 26.8%). At the end of the study, patients of group A and group B significantly suffered from mouth dryness (p=0.0001), oral mucositis (p=0.029) and oral pain (p=0.039) compared with patients in group C. Although there was no significant change, group C patients showed a slight improvement in psychological discomfort, activity levels and quality of life at the end of the study.

CONCLUSION: The present study showed that benzydamine and sodium bicarbonate mouthwashes were significantly less effective for the alleviation and treatment of oral complications compared with glutamine among patients with colon cancer receiving 5-FU-based chemotherapy regimens.

PMID:34285108 | DOI:10.1136/ejhpharm-2021-002827

J Immunother Cancer. 2021 Jul;9(7):e002890. doi: 10.1136/jitc-2021-002890.

ABSTRACT

Expanding the US Food and Drug Administration-approved indications for immune checkpoint inhibitors in patients with cancer has resulted in therapeutic success and immune-related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1%-12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings.

PMID:34281989 | DOI:10.1136/jitc-2021-002890

Drug Ther Bull. 2021 Jul 19:dtb-2021-000045. doi: 10.1136/dtb.2021.000045. Online ahead of print.

ABSTRACT

Overview of: Medicines and Healthcare products Regulatory Agency. Chloramphenicol eye drops containing borax or boric acid buffers: use in children younger than 2 years. Drug Safety Update 2021;14:1.

PMID:34281963 | DOI:10.1136/dtb.2021.000045

J Gastroenterol Hepatol. 2021 Jul 19. doi: 10.1111/jgh.15629. Online ahead of print.

ABSTRACT

BACKGROUND & AIM: Persistent hepatocellular secretory failure (PHSF) is a rare condition of severe cholestasis caused by drugs, toxins, infection, or temporary biliary obstruction. Real-world data on rifampicin in cholestasis, particularly among patients with deep jaundice, are scarce. We aimed to expand the knowledge on the efficacy and safety of rifampicin treatment in PHSF patients.

METHODS: Sixteen patients with PHSF who had received rifampicin treatment (150-300 mg/d) at our institution from September 2016 to July 2020 were included. Treatment efficacy was assessed by 20% improvement in serum total bilirubin (TBIL) concentration at 4 weeks. Follow-up was continued until the concentration of TBIL returned to normal.

RESULTS: Among the 16 enrolled patients, 12 had predisposing factors (drugs, infection or transient biliary obstruction). ATP8B1 or ABCB11 mutations were detected in the other 4 patients without trigger events. UGT1A1 mutations were found in 7/10 patients. Before rifampicin treatment, the median TBIL level was 352 μmol/L (range 171-591 μmol/L). TBIL > 20% improvement was observed in 14 patients at 4 weeks. TBIL levels of 14 patients eventually returned to normal after 6-12 weeks of rifampicin treatment. The remaining 2 patients who did not respond to rifampicin finally recovered after nasobiliary drainage. Except for one patient with transient drug-induced hepatitis, no other serious adverse events were observed.

CONCLUSIONS: Rifampicin could be a promising option for most PHSF patients. Most PHSF patients have UGT1A1 deficiency, which may be the target of rifampicin.

PMID:34278601 | DOI:10.1111/jgh.15629

JAAD Case Rep. 2021 Jun 2;14:68-71. doi: 10.1016/j.jdcr.2021.05.015. eCollection 2021 Aug.

NO ABSTRACT

PMID:34277913 | PMC:PMC8263525 | DOI:10.1016/j.jdcr.2021.05.015

Dig Dis Sci. 2021 Jul 17. doi: 10.1007/s10620-021-07163-3. Online ahead of print.

ABSTRACT

BACKGROUND: People with inflammatory bowel disease (IBD) including ulcerative colitis are at risk for colorectal cancer. Despite available effective drugs used to treat IBD, many patients fail or lose response over time with some displaying drug-induced adverse events. Saffron (Crocus sativus) has been reported to have anti-inflammatory properties. Its protective role in IBD has not been explored extensively.

AIM: To establish whether saffron treatment alleviates inflammation in experimental colitis.

METHODS: Colitis was induced in C57BL/6 mice with 3% DSS and treated with either saffron doses (7.5, 15, 20, 25 mg/kg body weight) or vehicle through daily gavage. On day 11, mice were euthanized and analyzed for gross and microscopic inflammation. Distal colon segments were collected for mRNA and protein expression of HO-1 protein and GPX2, (the downstream targets of NRF-2). Nrf-2 translocation from cytosol to nucleus was confirmed by immunofluorescence, and further Nrf-2 protein expression in nuclear and cytosolic fraction of colon was analyzed by immunoblot. Immune cells were isolated from the lamina propria of mouse colon for flow cytometry-based immunophenotyping. Colitis was also induced in C57BL/6 Ahr knockout and wild type mice to explore the involvement of Ahr-dependent pathways in saffron's protective effect(s). The therapeutic effect of saffron was further validated in another TNBS model of colitis.

RESULTS: Saffron 20 mg/kg body weight showed improved colon gross and histology features and led to better body weight, colon length, histology score, and reduced disease activity index (DAI). Saffron significantly decreased pro-inflammatory macrophages (M1), while increasing anti-inflammatory macrophages (M2) and IL10 + dendritic cells. Saffron treatment also enhanced CD3 + T and CD3 + CD8 + T cells followed by increase in different CD3 + CD4 + T cells subsets like CD25 + T cells, FoxP3 + CD25 + regulatory T cells, and CD4 + FOXP3 + CD25-regulatory T cells. Immunoblot analysis showed a significant increase in HO-1/GPX2 protein expression. With saffron treatment, Nrf-2 translocation into nucleus from cytosol also supports the involvement of Nrf-2 and its downstream targets in the protective effect of saffron. Further, we demonstrated that saffron in part exert anti-inflammatory effect through activation of aryl hydrocarbon receptor (AhR)-nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent pathways.

CONCLUSION: These data demonstrate saffron's therapeutic potential and its protective role in part via Ahr/Nrf-2 pathways and regulatory innate and adaptive immune cells.

PMID:34275090 | DOI:10.1007/s10620-021-07163-3

J Thromb Haemost. 2021 Jul 17. doi: 10.1111/jth.15467. Online ahead of print.

NO ABSTRACT

PMID:34273222 | DOI:10.1111/jth.15467

Transpl Int. 2021 Jul 17. doi: 10.1111/tri.13976. Online ahead of print.

ABSTRACT

The aim of this retrospective single-center study was to investigate short- and long-term impact of neutropenia occurring within the first year after kidney transplantation, with a special emphasis on different neutropenia grades. In this unselected cohort, 225/721 patients (31%) developed 357 neutropenic episodes within the first year post-transplant. Based on the nadir neutrophil count, patients were grouped as neutropenia grade 2 (<1.5-1.0*109 /L; n=105), grade 3 (<1.0-0.5*109 /L; n=65), and grade 4 (<0.5*109 /L; n=55). Most neutropenia episodes were presumably drug-related (71%) and managed by reduction/discontinuation of potentially responsible drugs (mycophenolic acid [MPA] 51%, valganciclovir 25%, trimethoprim/sulfamethoxazole 19%). Steroids were added/increased as replacement for reduced/discontinued MPA. Granulocyte colony-stimulating factor was only used in 2/357 neutropenia episodes (0.6%). One-year incidence of (sub)clinical rejection, one-year mortality as well as long-term patient and graft survival were not different among patient without neutropenia and neutropenia grade 2/3/4. However, the incidence of infections was about 3-times higher during neutropenia grade 3 and 4, but not increased during grade 2. In conclusion, neutropenia within the first year after kidney transplantation represents no increased risk for rejection and has no negative impact on long-term patient and graft survival. Adding/increasing steroids as replacement for reduced/discontinued MPA might supplement management of neutropenia.

PMID:34272771 | DOI:10.1111/tri.13976

J Nucl Med. 2021 Jul 16:jnumed.121.262543. doi: 10.2967/jnumed.121.262543. Online ahead of print.

ABSTRACT

Purpose of the study: To report the safety evaluation of 177Lu-PSMA-617 derived from the cohort of 64 patients exposed to 177Lu-PSMA-617 in the RESIST-PC trial NCT03042312 Methods: RESIST-PC was a prospective multicenter phase 2 trial. Patients with progressive mCRPC after ≥1 novel androgen-axis drug, either chemotherapy naïve or post-chemotherapy, with sufficient bone marrow reserve, normal kidney function, sufficient PSMA expression by PSMA PET and no visceral PSMA-negative lesions were eligible. Patients were randomized (1:1) into two activity groups (6.0 or 7.4 GBq per cycle) and received up to 4 cycles every 8 weeks. The primary safety endpoint was assessed by collecting and grading Adverse Events (AE) using the CTCAE. Patients were followed until disease progression, death, serious or intolerable AE, study termination by sponsor, patient withdrawal, lost to follow-up or 24 months after the first cycle. Results: The study was closed at enrollment of 71/200 planned patients because of sponsorship transfer. A total of 64 (90.1%) patients received at least one cycle of 177Lu-PSMA-617: 28 (36%) in Arm 1 (6.0 GBq) and 41 (64%) in Arm 2 (7.4GBq). There were 10 (43.5%), 19 (46.5%) and 29 (45.3%) patients who completed 4 cycles of 177Lu-PSMA-617 in the 6.0 GBq arm, 7.4 GBq arm, and overall, respectively. The most common treatment-emergent adverse events (TEAEs) of any grade in the 6.0 GBq arm, the 7.4 GBq arm and overall, were dry mouth (47.8%; 63.4%; 57.8%, respectively), fatigue (56.5%; 51.2%; 53.1%), nausea (52.2%; 43.9%; 46.9%), and diarrhea (13.0%; 31.7%; 25.0%). Frequencies of all other TEAEs were comparable among the 2 groups (within 10% difference). Serious possibly drug-related TEAEs were reported for 5 (7.8%) patients overall (none were considered as probably or definitely related to treatment): one subdural hematoma Grade 4, one anemia grade 3, one thrombocytopenia grade 4, one gastrointestinal hemorrhage grade 3, and one acute kidney injury grade 3. There were no clinically significant changes in vital signs in ECGs in the 2 treatment groups. No trend to creatinine increase, or increasing frequency of shifts from normal to abnormal over time for any hematologic parameter was noted. Conclusion: 177Lu-PSMA-617 was safe and well-tolerated at 6.0 and 7.4 GBq per cycle given at 8-week intervals with side effects easily managed with standard medical support. With established safety, further clinical trials applying individualized dosimetry and testing different 177Lu-PSMA-617 administration schemes (activity levels, time intervals) are needed to optimize tumor dose delivery and treatment efficacy.

PMID:34272322 | DOI:10.2967/jnumed.121.262543

BMC Bioinformatics. 2021 Jul 15;22(Suppl 10):369. doi: 10.1186/s12859-021-04285-3.

ABSTRACT

BACKGROUND: Mitochondria play essential roles in regulating cellular functions. Some drug treatments and molecular interventions have been reported to have off-target effects damaging mitochondria and causing severe side effects. The development of a database for the management of mitochondrial toxicity-related molecules and their targets is important for further analyses.

RESULTS: To correlate chemical, biological and mechanistic information on clinically relevant mitochondria-related toxicity, a comprehensive mitochondrial toxicity database (MitoTox) was developed. MitoTox is an electronic repository that integrates comprehensive information about mitochondria-related toxins and their targets. Information and data related to mitochondrial toxicity originate from various sources, including scientific journals and other electronic databases. These resources were manually verified and extracted into MitoTox. The database currently contains over 1400 small-molecule compounds, 870 mitochondrial targets, and more than 4100 mitochondrial toxin-target associations. Each MitoTox data record contains over 30 fields, including biochemical properties, therapeutic classification, target proteins, toxicological data, mechanistic information, clinical side effects, and references.

CONCLUSIONS: MitoTox provides a fully searchable database with links to references and other databases. Potential applications of MitoTox include toxicity classification, prediction, reference and education. MitoTox is available online at http://www.mitotox.org .

PMID:34266386 | DOI:10.1186/s12859-021-04285-3

Clin Microbiol Infect. 2021 Jul 13:S1198-743X(21)00385-2. doi: 10.1016/j.cmi.2021.07.011. Online ahead of print.

ABSTRACT

OBJECTIVES: In Japan, most tuberculosis (TB) cases occur among individuals aged 65 years or older. However, data on in-hospital adverse events (AEs) associated with TB management, especially in high-income nations with an ageing population, are scarce. The present study aimed to scrutinize the current TB unit practices, incidence of in-hospital AEs, and predictors of in-hospital mortality.

METHODS: This retrospective cohort study was conducted at a tertiary care centre in Tokyo, Japan from 2012 to 2017. Inpatients with the diagnosis of TB and aged > 18 years were included. Quality of in-hospital care and factors associated with in-hospital mortality were investigated using multivariate logistic regression analysis.

RESULTS: In total, 448 patients were enrolled. The in-hospital mortality rate was 16.7% (75/448). Miliary/disseminated TB was common (59/448, 13.2%), especially in those who died (17/75, 22.7%). Factors independently associated with in-hospital mortality were a low Karnofsky performance status score on admission (score: 40-10, adjusted odds ratio [aOR]: 25.65, 95% confidence interval [CI]: 5.63-116.92 and score: 70-50, aOR: 9.47, 95% CI: 2.07-43.3), age over 89 years (aOR: 3.68, 95% CI: 1.08-12.46), Charlson Comorbidity Index > 5 (aOR: 3.56, 95% CI: 1.37-9.21), development of any healthcare-associated infection (HAI) (aOR: 2.95, 95% CI: 1.35-6.41), and development of any drug-related AE leading to discontinuation of antituberculosis agents (seven patients were unable to resume treatment with antituberculosis agents prior to death) (aOR: 2.29, 95% CI: 1.02-5.11).

CONCLUSIONS: In-hospital AEs (i.e., HAIs and drug-related AEs), as well as patient-related variables, were associated with in-hospital mortality among TB patients.

PMID:34271181 | DOI:10.1016/j.cmi.2021.07.011

Ecancermedicalscience. 2021 Jun 7;15:1245. doi: 10.3332/ecancer.2021.1245. eCollection 2021.

ABSTRACT

Palbociclib is a cyclin dependent kinase (CDK) 4/6 inhibitor that is indicated in combination with an aromatase inhibitor for first-line treatment of hormone receptor-positive, human epidermal growth factor receptor 2 -negative advanced or metastatic breast cancer. The commonly described side effects of palbociclib are neutropenia, anaemia, thrombocytopenia, fatigue, nausea, stomatitis, alopecia, diarrhoea, decreased appetite, vomiting, asthenia, peripheral neuropathy and epistaxis. However, post approval, increasing use of this drug has revealed another potentially fatal complication, in the form of pneumonitis, especially in the Asian population. The PALOMA 3 trial showed that rates of grade 3 and grade 4 adverse events were modestly higher in Asians than non-Asians, though palbociclib exposure was similar in both races. From this, we could infer that adverse effects of this drug must be monitored more specifically in individual racial populations. We report a patient who developed pneumonitis while on palbociclib and discuss the possible mechanisms and management of CDK 4/6 inhibitor-related lung injury.

PMID:34267801 | PMC:PMC8241445 | DOI:10.3332/ecancer.2021.1245