Tag: pubmed

J Neurooncol. 2022 Aug 6. doi: 10.1007/s11060-022-04092-7. Online ahead of print.

ABSTRACT

PURPOSE: Limited progress has been made in treating glioblastoma, and we hypothesise that poor concordance between preclinical and clinical efficacy in this disease is a major barrier to drug development. We undertook a systematic review to quantify this issue.

METHODS: We identified phase I trials (P1Ts) of tumor targeted drugs, subsequent trial results and preceding relevant preclinical data published in adult glioblastoma patients between 2006-2019 via structured searches of EMBASE/MEDLINE/PUBMED. Detailed clinical/preclinical information was extracted. Associations between preclinical and clinical efficacy metrics were determined using appropriate non-parametric statistical tests.

RESULTS: A total of 28 eligible P1Ts were identified, with median ORR of 2.9% (range 0.0-33.3%). Twenty-three (82%) had published relevant preclinical data available. Five (18%) had relevant later phase clinical trial data available. There was overall poor correlation between preclinical and clinical efficacy metrics on univariate testing. However, drugs that had undergone in vivo testing had significantly longer median overall survival (7.9 vs 5.6mo, p = 0.02). Additionally, drugs tested in ≥ 2 biologically-distinct in vivo models (‘multiple models’) had a significantly better median response rate than those tested using only one (‘single model’) or those lacking in vivo data (6.8% vs 1.2% vs. 0.0% respectively, p = 0.027).

CONCLUSION: Currently used preclinical models poorly predict subsequent activity in P1Ts, and generally over-estimate the anti-tumor activity of these drugs. This underscores the need for better preclinical models to aid the development of novel anti-glioblastoma drugs. Until these become widely available and used, the use of multiple biologically-distinct in vivo models should be strongly encouraged.

PMID:35933567 | DOI:10.1007/s11060-022-04092-7

NPJ Parkinsons Dis. 2022 Aug 6;8(1):99. doi: 10.1038/s41531-022-00363-2.

ABSTRACT

A number of genetic risk factors have been identified over the past decade for Parkinson’s Disease (PD), with variants in GBA prominent among them. GBA encodes the lysosomal enzyme that degrades the glycosphingolipid, glucosylceramide (GlcCer), with the activity of this enzyme defective in Gaucher disease. Based on the ill-defined relationship between glycosphingolipid metabolism and PD, we now analyze levels of various lipids by liquid chromatography/electrospray ionization-tandem mass spectrometry in four brain regions from age- and sex-matched patient samples, including idiopathic PD, PD patients with a GBA mutation and compare both to control brains (n = 21 for each group) obtained from individuals who died from a cause unrelated to PD. Of all the glycerolipids, sterols, and (glyco)sphingolipids (251 lipids in total), the only lipid class which showed significant differences were the gangliosides (sialic acid-containing complex glycosphingolipids), which were elevated in 3 of the 4 PD-GBA brain regions. There was no clear correlation between levels of individual gangliosides and the genetic variant in Gaucher disease [9 samples of severe (neuronopathic), 4 samples of mild (non-neuronopathic) GBA variants, and 8 samples with low pathogenicity variants which have a higher risk for development of PD]. Most brain regions, i.e. occipital cortex, cingulate gyrus, and striatum, did not show a statistically significant elevation of GlcCer in PD-GBA. Only one region, the middle temporal gyrus, showed a small, but significant elevation in GlcCer concentration in PD-GBA. We conclude that changes in ganglioside, but not in GlcCer levels, may contribute to the association between PD and GBA mutations.

PMID:35933559 | DOI:10.1038/s41531-022-00363-2

Sci Rep. 2022 Aug 6;12(1):13517. doi: 10.1038/s41598-022-17512-5.

ABSTRACT

Simulation in surgical training is a growing field and this study aims to understand the force and torque experienced during lumbar spine surgery to design simulator haptic feedback. It was hypothesized that force and torque would differ among lumbar spine levels and the amount of tissue removed by ≥ 7%, which would be detectable to a user. Force and torque profiles were measured during vacuum curette insertion and torsion, respectively, in multiple spinal levels on two cadavers. Multiple tests per level were performed. Linear and torsional resistances of 2.1 ± 1.6 N/mm and 5.6 ± 4.3 N mm/°, respectively, were quantified. Statistically significant differences were found in linear and torsional resistances between all passes through disc tissue (both p = 0.001). Tool depth (p < 0.001) and lumbar level (p < 0.001) impacted torsional resistance while tool speed affected linear resistance (p = 0.022). Average differences in these statistically significant comparisons were ≥ 7% and therefore detectable to a surgeon. The aforementioned factors should be considered when developing haptic force and torque feedback, as they will add to the simulated lumbar discectomy realism. These data can additionally be used inform next generation tool design. Advances in training and tools may help improve future surgeon training.

PMID:35933556 | DOI:10.1038/s41598-022-17512-5

Ann Surg Oncol. 2022 Aug 6. doi: 10.1245/s10434-022-12369-4. Online ahead of print.

ABSTRACT

BACKGROUND: The present study was conducted to evaluate the clinical, pathological response, and prognosis characteristics of human epidermal growth factor receptor 2 (HER2)-low breast cancer in the neoadjuvant chemotherapy setting.

METHODS: Patients with HER2-negative breast cancer who received neoadjuvant chemotherapy from January 2017 to December 2019 were retrospectively analyzed. HER2-negative breast cancer was divided into two groups: HER2-zero (defined as immunohistochemistry [IHC] 0) and HER2-low (defined as IHC 1+, or IHC 2+ and fluorescence in-situ hybridization-negative.

RESULTS: Overall, 314 patients with HER2-negative breast cancer were analyzed. The proportion of HER2-low patients with hormone receptor (HR)-positive disease was higher than in triple-negative breast cancer (TNBC; 75.3% vs. 63.2%, p = 0.032). In HR-positive breast cancer, HER2-low tumors presented less nodal involvement (p = 0.023) and earlier clinical stage (p = 0.015) compared with HER2-zero tumors; however, in TNBC, HER2-low patients had a later clinical stage (p = 0.028). With the pathological complete response (pCR) defined as ypTis/0ypN0, there was no difference in pCR rates among the entire cohort, HR-positive disease, and TNBC. However, with the pCR defined as ypT0ypN0, the pCR rate in HER2-low breast cancer was significantly lower than HER2-zero breast cancer in the entire cohort (24.3% vs. 36.4%, p = 0.032) and the HR-positive subgroup (18.7% vs. 32.1%, p = 0.035), but not for TNBC. Multivariate analysis demonstrated that HER2 status (low vs. zero) was an independent predictive factor for pCR (p = 0.013) in HR-positive breast cancer. There were no statistically significant differences in 3-year disease-free survival and overall survival between HER2-low and HER2-zero breast cancer among the entire cohort, HR-positive disease, and TNBC.

CONCLUSIONS: HER2-low breast cancer exhibits specific clinical features and different response to treatment associated with HR status in the neoadjuvant chemotherapy setting.

PMID:35933542 | DOI:10.1245/s10434-022-12369-4

Sci Rep. 2022 Aug 6;12(1):13513. doi: 10.1038/s41598-022-17794-9.

ABSTRACT

The rate of cholangiocarcinoma (CCA) is increasing every year, especially in northeastern Thailand. Screening for CCA using ultrasonography (US) is the fastest technique to identify patients in early stage of CCA development. Currently, few studies have examined patterns of hepatobiliary abnormalities identified using US, which can be indicative of CCA. We aim to evaluate the rate of CCA and its relations to history of US findings. Our study included participants who underwent US and pathological diagnosis of CCA from the Cholangiocarcinoma Screening and Care Program, Northeast Thailand between 2013 and 2020. Data on histological findings were based on the standard protocol of the tertiary hospital at Khon Kaen University. CCA data is categorized into two groups (yes/no) to find the relationship with history of US findings. The adjusted odds ratio (AOR) and their 95% confidence intervals (CI) were used to evaluate the relationship obtained by multiple logistic regression. Of 1880 subjects who underwent US and a pathological diagnosis of CCA, the overall rate of CCA was 35.74%. CCA rate among those with liver mass (LM) was 54.85% and with dilated bile duct (DBD) was 62.01%. The relationship between DBD and CCA was highly significant (AOR = 3.46; 95% CI 2.74-4.36) followed by LM (AOR = 2.28; 95% CI 1.81-2.86) P value < 0.001. Our study reveals that US findings history have a strong association with CCA, especially in people diagnosed with DBD and LM. Therefore, these abnormalities can be indicators for suspected CCA diagnosis through US.

PMID:35933509 | DOI:10.1038/s41598-022-17794-9

World J Surg. 2022 Aug 6. doi: 10.1007/s00268-022-06685-9. Online ahead of print.

ABSTRACT

OBJECTIVE: The effectiveness of intraperitoneal local anesthesia (IPLA) has been confirmed in other fields, but its use in bariatric surgery remains debatable. This study aimed to evaluate the analgesic effect of IPLA in bariatric surgery.

METHODS: PubMed, Web of Science, Embase, and the Cochrane Library were searched from inception to February 2022. All randomized controlled trials (RCTs) assessing IPLA’s analgesic effect in bariatric surgery were included in this study. Pain-related indicators were the outcome.

RESULTS: Ten RCTs with 979 patients were included. Postoperative pain scores were significantly lower in IPLA group. Subgroup analysis demonstrated that IPLA was associated with lower pain scores in 6 h and at 24 h compared to the control group, without significant differences at 8, 12, and 48 h. Meanwhile, IPLA reduced the dose of opioids taken postoperatively. Additionally, there were no differences in adverse events between the two groups. As far as the number of postoperative analgesics used and hospital stays were concerned, our results did not show statistical differences between the two groups.

CONCLUSION: IPLA can reduce postoperative pain safely and effectively, particularly during the early postoperative stage.

PMID:35933496 | DOI:10.1007/s00268-022-06685-9

J Neurol. 2022 Aug 6. doi: 10.1007/s00415-022-11294-6. Online ahead of print.

ABSTRACT

BACKGROUND: Freezing of gait (FOG) is a common, disabling symptom of Parkinson’s disease (PD), and its exact pathophysiological mechanism is still poorly understood. The control of gait is a complex process that may be influenced by emotions modulated by serotonergic networks. Therefore, this study aimed to determine factors associated with FOG in PD patients and to evaluate the importance of the dorsal raphe nucleus (DRN; central node in the serotoninergic system) in FOG pathophysiology.

METHODS: We combined cross-sectional survey data from 453 PD patients. According to the Freezing of Gait Questionnaire (FOGQ), patients were divided into two groups: the “PD with frozen gait (PD-FOG)” and “PD without frozen gait (PD-nFOG)” groups. Demographic characteristics, clinical features, and motor and nonmotor symptoms (NMS) assessments of PD patients were recorded. Univariate statistical analysis was performed between the two groups, and then regression analysis was performed on related factors. We also acquired resting-state functional MRI (rs-fMRI) data from 20 PD-FOG, 21 PD-nFOG, and 22 healthy controls (HCs) who were randomly chosen. We defined seeds in the DRN to evaluate functional connectivity (FC) patterns.

RESULTS: The overall frequency of FOG was 11.9% patients in the PD-FOG group were older, had a longer disease duration, had a higher levodopa equivalent daily dose, had more severe motor symptoms and worse quality of life, had a higher proportion of dyskinesia, wearing-off and postural instability/gait difficulty (PIGD) clinical phenotype, and experienced more depression and impaired sleep function than those in the PD-nFOG group. Logistic regression analysis showed that H&Ystage ≥ 3, UPDRS-III scores, PIGD clinical phenotype and excessive daytime sleepiness were associated with FOG. In addition, there was significantly lower FC between the DRN and some cortical structures, including the supplementary motor area (SMA), left superior frontal gyrus (SFG), and left median cingulated cortex (MCC) in PD-FOG patients than HCs and PD-nFOG patients.

CONCLUSIONS: These results demonstrate that the severity of PD and PIGD clinical phenotype are associated factors for freezing and that DRN dysfunction may play a key role in PD-related NMS and FOG. An abnormal cortical and brainstem networks may contribute to the mechanisms underlying FOG.

PMID:35933494 | DOI:10.1007/s00415-022-11294-6

Breast Cancer Res Treat. 2022 Aug 6. doi: 10.1007/s10549-022-06691-4. Online ahead of print.

ABSTRACT

PURPOSE: To investigate if molecular subtype is associated with outcome in stage 1 breast cancer (BC).

METHODS: Tissue samples from 445 women with node-negative BC ≤ 15 mm, treated in 1986-2004, were classified into surrogate molecular subtypes [Luminal A-like, Luminal B-like (HER2-), HER2-positive, and triple negative breast cancer (TNBC)]. Information on treatment, recurrences, and survival were gathered from medical records.

RESULTS: Tumour subtype was not associated with overall survival (OS). Luminal B-like (HER2-) and TNBC were associated with higher incidence of distant metastasis at 20 years (Hazard ratio (HR) 2.26; 95% CI 1.08-4.75 and HR 3.24; 95% CI 1.17-9.00, respectively). Luminal B-like (HER2-) and TNBC patients also had worse breast cancer-specific survival (BCSS), although not statistically significant (HR 1.53; 95% CI 0.70-3.33 and HR 1.89; 95% CI 0.60-5.93, respectively). HER2-positive BC was not associated with poor outcome despite no patient receiving HER2-targeted therapy, with most of these tumours being ER+.

CONCLUSIONS: Stage 1 TNBC or Luminal B-like (HER2-) tumours behave more aggressively. Women with HER2+/ER+ tumours do not have an increased risk of distant metastasis or death, absent targeted treatment.

PMID:35933487 | DOI:10.1007/s10549-022-06691-4

Osteoporos Int. 2022 Aug 6. doi: 10.1007/s00198-022-06430-x. Online ahead of print.

ABSTRACT

Osteosarcopenia is a common condition among elderly and postmenopausal female patients. Site-specific bone mineral density is more predictive of bone-related complications. Few studies have investigated muscle-bone associations. Our results demonstrated that in women, significant positive associations between paraspinal muscles FCSA and vBMD exist at different lumbosacral levels. These regional differences should be considered when interpreting bone-muscle associations in the lumbar spine.

INTRODUCTION: There is increasing evidence between bone and muscle volume associations. Previous studies have demonstrated comorbidity between osteoporosis and sarcopenia. Recent studies showed that sarcopenic subjects had a fourfold higher risk of concomitant osteoporosis compared to non-sarcopenic individuals. Although site-specific bone mineral density (BMD) assessments were reported to be more predictive of bone-related complications after spinal fusions than BMD assessments in general, there are few studies that have investigated level-specific bone-muscle interactions. The aim of this study is to investigate the associations between muscle functional cross-sectional area (FCSA) on magnetic resonance imaging (MRI) and site-specific quantitative computed tomography (QCT) volumetric bone mineral density (vBMD) in the lumbosacral region among spine surgery patients.

METHODS: We retrospectively reviewed a prospective institutional database of posterior lumbar fusion patients. Patients with available MRI undergoing posterior lumbar fusion were included. Muscle measurements and FCSA were conducted and calculated utilizing a manual segmentation and custom-written program at the superior endplate of the L3-L5 vertebrae level. vBMD measurements were performed and calculated utilizing a QCT pro software at L1-L2 levels and bilateral sacral ala. We stratified by sex for all analyses.

RESULTS: A total of 105 patients (mean age 61.5 years and 52.4% females) were included. We found that female patients had statistically significant lower muscle FCSA than male patients. After adjusting for age and body mass index (BMI), there were statistically significant positive associations between L1-L2 and S1 vBMD with L3 psoas FCSA as well as sacral ala vBMD with L3 posterior paraspinal and L5 psoas FCSA. These associations were not found in males.

CONCLUSIONS: Our results demonstrated that in women, significant positive associations between the psoas and posterior paraspinal muscle FCSA and vBMD exist in different lumbosacral levels, which are independent of age and BMI. These regional differences should be considered when interpreting bone and muscle associations in the lumbar spine.

PMID:35933479 | DOI:10.1007/s00198-022-06430-x

Pediatr Cardiol. 2022 Aug 7. doi: 10.1007/s00246-022-02980-3. Online ahead of print.

ABSTRACT

Opioids or benzodiazepines use is known to increase the risk of delirium. The prevalence of delirium is high in pediatric cardiac intensive care units (CICUs) with associated morbidity and mortality. We investigate the short-term effects of quetiapine, an atypical antipsychotic medication, on opioid and benzodiazepine requirements, and any associated adverse events as we utilize quetiapine to treat delirium symptoms in this single-center, retrospective study. Twenty-eight patients who received quetiapine between January 2018 and June 2019 in the CICU met inclusion criteria for the analysis. The quetiapine initiation dose was 0.5 mg/kg/dose every 8 h and we allowed 48 h for quetiapine to reach a steady state. Overall opioid and benzodiazepine requirements were compared 72 h before and 72 h after the quetiapine steady state. There was a statistically significant reduction in the total daily opioid (p = 0.001) and benzodiazepine (p = 0.01) amounts following quetiapine initiation. There was also a statistically significant decrease in the total number of daily PRNs requirement for both opioids (p < 0.001) and benzodiazepines (p = 0.03). Nine out of 13 patients were completely weaned off continuous opioid drips following quetiapine initiation (p = 0.01). The presence of steady-state habituation medications, including methadone or lorazepam, did not have any statistically significant effect on weaning continuous opioid (p = 0.18) or benzodiazepine (p = 0.62) drips. There was no statistically significant effect of quetiapine on the QTc interval after quetiapine initiation (p = 0.58) with no clinically significant arrhythmias observed during the study period. Our study demonstrates a statistically significant reduction in opioid and benzodiazepine requirements following quetiapine initiation to treat delirium symptoms without significant adverse effects in patients with congenital heart disease in the short term.

PMID:35933475 | DOI:10.1007/s00246-022-02980-3