Therapeutic applications of germline testing for cancer predisposition genes in Asia in the real world.

BACKGROUND: Germline genetic testing is traditionally carried out in patients suspected with hereditary cancer syndrome for enhanced cancer surveillance and/or preventive strategies, but is increasingly carried out for therapeutic indications. MATERIALS AND METHODS: We conducted a retrospective review of patients who underwent germline genetic testing at our centre to determine the prevalence of actionable pathogenic germline variants (PGV) and their clinical utility. RESULTS: From 2000 to 2022, 1154 cancer patients underwent germline testing, with the majority (945/1154) tested with multi-gene panels. Four hundred and eleven (35.6%) patients harboured a PGV and 334 (81%) were clinically actionable. BRCA1/2 accounted for 62.3% of actionable mutations, followed by mismatch repair (18%), and other homologous recombination repair (HRR) genes (19.7%). One hundred and fifty-two germline-positive patients have advanced cancers, and 79 received germline-directed therapies (poly ADP ribose polymerase inhibitors = 75; immunotherapy = 4). Median duration of immunotherapy and poly ADP ribose polymerase were 20.5 months (range 5-40 months) and 8 months (range 1-76 months), respectively. Among BRCA/HRR mutation carriers who received platinum-based chemotherapy, pathological complete response rate in the neoadjuvant setting was 53% (n = 17 breast cancers) and objective response rate was >80% in the advanced setting (n = 71). CONCLUSIONS: One-third of cancer patients tested carried a PGV and ∼80% were clinically actionable. Three-quarters of germline-positive advanced cancer patients received germline-directed therapies in the real world, underscoring the practical utility of germline testing to guide cancer therapeutics.

Efficacy and safety of shunt surgery in patients with idiopathic normal-pressure hydrocephalus: can we predict shunt response by preoperative magnetic resonance imaging (MRI)?

AIM: The aim of this study was to identify preoperative magnetic resonance imaging (MRI) findings that can predict the shunt responsiveness in idiopathic normal-pressure hydrocephalus (iNPH) patients and to investigate postoperative outcome and complications. MATERIALS AND METHODS: A total of 192 patients with iNPH who underwent shunt at our hospital between 2000 and 2021 were included to investigate complications. Of these, after exclusion, 127 (1-month postoperative follow-up) and 77 (1-year postoperative follow-up) patients were evaluated. The preoperative MRI features (the presence of tightness of the high-convexity subarachnoid space, Sylvian fissure enlargement, Evans' index, and callosal angle) of the shunt-response and nonresponse groups were compared, and a systematic review was conducted to evaluate whether preoperative MRI findings could predict shunt response. RESULTS: Postoperative complications within one month after surgery were observed in 6.8% (13/192), and the most common complication was hemorrhage. Changes in corpus callosum were observed in 4.2% (8/192). The shunt-response rates were 83.5% (106/127) in the 1-month follow-up group and 70.1% (54/77) in 1-year follow-up group. In the logistic regression analysis, only Evans' index measuring >0.4 had a significant negative relationship with shunt response at 1-month follow-up; however, no significant relationship was observed at 1-year follow-up. According to our systematic review, it is still controversial whether preoperative MRI findings could predict shunt response. CONCLUSION: Evans' index measure of >0.4 had a significant relationship with the shunt response in the 1-month follow-up group. In systematic reviews, there is ongoing debate about whether preoperative MRI findings can accurately predict responses to shunt surgery. Postoperative corpus callosal change was observed in 4.2% of iNPH patients.

Efficacy of Oral SERDs in the treatment of ER+, HER2 - metastatic breast cancer, a stratified analysis of the ESR1 wild type and mutant subgroups.

BACKGROUND: Oral SERDs are a novel drug class that have been developed to counteract resistance due to ESR1 mutations. Several SERDs have emerged from phase 2 and 3 trials, with the FDA limiting approval for Elacestrant to patients with ESR1mt tumours despite PFS benefit in the overall population. However, questions remain on whether patients with ESR1wt tumours stand to benefit from oral SERDs. PATIENTS AND METHODS: Manuscripts and conference presentations of Randomised Controlled Trials were extracted after a systematic search of Embase, PubMed and Cochrane from inception until January 21,2023. RCTs investigating the efficacy of oral SERDs versus endocrine therapy for ER positive, HER2 negative advanced breast cancer, and which reported the Kaplan Meier (KM) curves of PFS in the overall and ESR1 mutant (ESR1mt) population were selected. A graphical reconstructive algorithm was applied to estimate time-to-event outcomes from reported KM curves in all overall and ESR1mt cohorts. A bipartite matching algorithm, KMSubtraction, was used to derive survival data for unreported (ESR1wt) subgroups. An individual patient data (IPD) meta-analysis was then pursued, pooling data by ESR1 mutation status in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane Guidelines for IPD. RESULTS: The randomized clinical trials ACELERA, AMEERA-3, EMERALD and SERENA-2 were included, totalling 1290 patients. In the pooled analysis of the overall cohort, PFS benefit was observed with oral SERDs when compared with treatment of physicians choice (TPC) (HR 0.783, 95%CI 0.681-0.900, p<0.001). In the ESR1mt subgroup, oral SERDs demonstrated improved PFS (HR 0.557, 95%CI 0.440-0.705, p<0.001) compared to TPC. In the ESR1wt subgroup, oral SERDs demonstrated no significant PFS benefit (HR 0.944, 95%CI 0.783-1.138, p=0.543) when compared to TPC. CONCLUSIONS: The results of this IPD meta-analysis suggests that PFS benefit in the overall population is mainly driven by the ESR1mt subgroup.

Maintaining breast cancer care in the face of COVID-19.

The battle of COVID-19 is currently at different levels of intensity in each country and even each city. The authors have prepared succinct recommendations regarding the care of patients with breast cancer, divided into phases that can easily be adapted to each units' needs and resources, and stepped up or stepped down according to escalating and de-escalating circumstances. The structure can also be transposed easily to different cancer types, enabling continued provision of best standards of care despite unprecedented stressors. Surgery must go on.

Effect of cholinergic pathway disruption on cortical and subcortical volumes in subcortical vascular cognitive impairment.

BACKGROUND AND PURPOSE: The brain's cholinergic network has various interconnections with the cortical and subcortical structures. Disruption of cholinergic pathways by white matter hyperintensities (WMH) may cause pathologic changes within brain regions. Thus, WMH may represent an important pathological contributor to subcortical vascular cognitive impairment (scVCI). We aimed to investigate associations between the magnitude of WMH and volumetric changes in cortical and subcortical regions innervated by cholinergic neurons in patients with scVCI. METHODS: We enrolled patients with scVCI, defined as moderate to severe WMH or multiple (>2) lacunar infarcts outside the brainstem. Cholinergic Pathway HyperIntensities Scale (CHIPS) scores were used to quantify the magnitude of cholinergic pathway disruptions by WMH. We measured cortical thickness and subcortical volumes of 11 brain regions innervated by cholinergic neurons. Partial correlation of brain region volumes with total CHIPS scores was obtained using multiple linear regression. RESULTS: In total, 80 patients were enrolled. The mean age was 78.4 ± 6.5 years, median Mini-Mental State Examination score was 17 (interquartile range, 13-20) and median CHIPS score was 11 (interquartile range, 7-17). CHIPS scores were positively correlated with subcortical volumes of the putamen (r' = 0.46, P = 0.002) and pallidum (r' = 0.45, P = 0.002), and were negatively associated with inferior temporal (r' = -0.35, P = 0.002) and medial orbitofrontal (r' = -0.32, P = 0.002) cortical thickness. CONCLUSION: Our study suggested that WMH in cholinergic pathways may contribute to volumetric structural changes in cortical and subcortical structures innervated by cholinergic neurons.

Sex-dependent effects of uric acid on cerebral microbleed: a cross-sectional study in the general population.

BACKGROUND AND PURPOSE: Elevated serum uric acid (UA) is known to be associated with stroke. However, there is little information on the association between serum UA levels and cerebral microbleed (CMB), a precursor of stroke. Therefore, we investigated the association between UA and CMB in a general population taking into consideration sex-related differences. METHODS: The subjects in this cross-sectional study consisted of 2686 individuals of 40-79 years of age (1403 men and 1283 women) who underwent regular health screenings, including brain magnetic resonance imaging, at Seoul National University Hospital Health Promotion Center. Subjects were categorized into three groups according to tertiles of UA levels by sex. The presence and location of CMB were assessed by gradient-recalled echo magnetic resonance imaging. RESULTS: The prevalence of CMB was 3.8%. In multivariate logistic regression analysis by sex, the highest tertile of UA in male subjects was independently associated with the presence of CMB compared with the lowest tertile of UA (adjusted odds ratio, 2.46; P = 0.013). Meanwhile, the highest tertile of UA in female subjects was inversely associated with CMB compared with the lowest tertile of UA (adjusted odds ratio, 0.39; P = 0.040). CONCLUSIONS: High serum UA value was associated with higher prevalence of CMB in male, but lower prevalence of CMB in female subjects.

Clinical relevance of abnormal neuroimaging findings and long-term risk of stroke recurrence.

BACKGROUND AND PURPOSE: Previous studies have revealed that the predictors of short- and long-term stroke recurrence are different. We designed a comprehensive stroke recurrence (CSR) model, composed of demographic, clinical and radiological findings, to predict long-term ischaemic stroke recurrences. METHODS: We retrospectively collected the derivation cohort from consecutive patients with first-ever ischaemic stroke within 7 days of symptom onset. Univariate and multivariable Cox regression analysis were used to evaluate the association between 2-year recurrence and demographic, clinical and neuroradiological factors. The CSR score was calculated by adding the integer value of independent predictors that was derived from the ß-coefficient in the multivariable analysis. To qualify the model, we analyzed the receiver operating characteristics curve. We assessed internal validation with bootstrap methods and assessed external validation with another independent cohort. RESULTS: A total of 958 patients were enrolled, and 63 patients had recurrent strokes during the follow-up periods. The rate of stroke recurrence was 7.0% at 2 years. In the multivariable analysis, multiple stage lesions, isolated cortical lesions on diffusion-weighted imaging, severe white matter hyperintensities, multiple lacunar infarctions and relevant arterial stenosis were independently associated with stroke recurrence. The CSR model showed good discrimination [area under the curve (AUC), 0.81 (0.74-0.88)], which was consistent with internal [AUC, 0.75 (0.66-0.85)] and external [AUC, 0.80 (0.69-0.90)] validation. CONCLUSIONS: Abnormal neuroimaging findings, rather than cardiovascular risk factors, are predictive of long-term ischaemic stroke recurrence. Causative mechanism of stroke and underlying hostile brain milieu seem to be associated with long-term stroke recurrence.

Integration of radiotherapy and chemotherapy for abdominal lymph node recurrence in gastric cancer.

PURPOSE: Abdominal lymph node (ALN) recurrence in gastric cancer (GC) is rare and usually unresectable. We investigated the effects of integration of radiotherapy (RT) and chemotherapy against ALN recurrence in GC. METHODS: We retrospectively categorized GC patients with ALN recurrence treated between 2005 and 2013 into two groups: those treated with integration of RT and chemotherapy (RCT) and those who received systemic chemotherapy only (CT). The median follow-up period after ALN recurrence for all patients was 20 months. RESULTS: Of 53 patients, 31 and 22 were in the RCT and CT groups, respectively. Isolated distant failure (DF; 35.5%) without local progression (LP) was the dominant pattern of failure (POF) in the RCT group (median DF-free period, 26 months). LP followed by DF (31.8%) was the dominant POF in the CT group; LP (median LP-free period, 8 months) occurred 10 months earlier than DF (median DF-free period, 18 months). RCT patients had significantly longer median progression-free survival (PFS) compared to CT patients (25 vs. 8 months; P = 0.021). On multivariate analysis, treatment (CT vs. RCT) was an independent prognostic factor for PFS (hazard ratio 2.085; 95% confidence interval 1.073-4.050; P = 0.013). CONCLUSIONS: Integration of RT and chemotherapy achieved long-term local control and prolonged PFS in GC patients with ALN recurrence. Local RT is feasible for treating isolated ALN recurrences.

Locoregional relapse after gastrectomy with D2 lymphadenectomy for gastric cancer.

BACKGROUND: Risk for and site of locoregional relapse have not been well studied in patients undergoing gastrectomy with D2 lymphadenectomy for gastric cancer. METHODS: Patients who had undergone gastrectomy with D2 lymphadenectomy for gastric cancer between 2004 and 2007 were identified from an institutional database. The locoregional relapse rate was estimated by competing risk analysis, and risk groups were derived according to locoregional relapse risk using recursive partitioning analysis (RPA). The locations of nodal relapses were evaluated according to Japanese Classification of Gastric Carcinoma criteria. RESULTS: Some 2618 patients were included. With a median follow-up of 78·0 (range 28·5-122·6) months, relapse was diagnosed in 471 of 2618 patients (18·0 per cent). The cumulative incidence of locoregional relapse at 5 years was 8·5 (95 per cent c.i. 7·4 to 9·6) per cent. The 5-year locoregional recurrence rates for high-risk (N3), intermediate-risk (N1-2) and low-risk (N0) groups were 32·4, 12·3 and 1·7 per cent respectively (P < 0·001). Among patients with regional relapse, 90·4 per cent had involvement outside the D2 dissected area, and the most commonly involved site was station 16b1. This pattern was maintained in the RPA risk groups (P = 0·329). CONCLUSION: Locoregional relapse at 5 years after gastrectomy with D2 lymphadenectomy was 8·5 per cent, and was most often seen outside the D2 dissected area.

Distal hyperintense vessel sign is associated with neurological deterioration in acute ischaemic stroke.

BACKGROUND AND PURPOSE: The aim was to evaluate the relationship between distal hyperintense vessel sign (HVS) and early neurological deterioration (END) in acute ischaemic stroke with large vessel steno-occlusion. METHODS: Acute ischaemic stroke patients with symptomatic severe steno-occlusion in the middle cerebral artery or internal carotid artery were recruited within 24 h from symptom onset. Stroke outcomes were evaluated using the National Institutes of Health Stroke Scale (NIHSS) score at the time of admission and at 72 h and 7 days. END was defined as an increment of ≥1 in the motor NIHSS score or ≥2 in the total NIHSS score. Distal HVS was defined as hyperintensity on fluid-attenuated inversion recovery image, located distal to the Sylvian fissure. The extent of distal HVS was divided into absent, subtle and prominent. RESULTS: Amongst a total of 325 participants, END was found in 103 (32%) patients. END was associated with age, atrial fibrillation, initial NIHSS score, initial infarct volume, severe leukoaraiosis, hemorrhagic infarction and distal HVS. In multivariate analysis, distal HVS remained an independent predictor of END [adjusted odds ratio (aOR) 2.86, 95% confidence interval (CI) 1.65-4.97, P < 0.001]. Initial infarct volume (aOR = 1.01, 95% CI 1.01-1.02, P < 0.001) and severe leukoaraiosis (aOR = 3.16, 95% CI 1.77-5.65, P < 0.001) were also associated with END, independently of distal HVS. In the analysis of the burden of distal HVS and stroke outcomes, prominent distal HVS was associated with stroke severity and infarct volume in a dose-response manner. CONCLUSIONS: Distal HVS is associated with END in acute ischaemic stroke patients with large vessel steno-occlusion.

Gene regulatory network identification from the yeast cell cycle based on a neuro-fuzzy system.

Many studies exist for reconstructing gene regulatory networks (GRNs). In this paper, we propose a method based on an advanced neuro-fuzzy system, for gene regulatory network reconstruction from microarray time-series data. This approach uses a neural network with a weighted fuzzy function to model the relationships between genes. Fuzzy rules, which determine the regulators of genes, are very simplified through this method. Additionally, a regulator selection procedure is proposed, which extracts the exact dynamic relationship between genes, using the information obtained from the weighted fuzzy function. Time-series related features are extracted from the original data to employ the characteristics of temporal data that are useful for accurate GRN reconstruction. The microarray dataset of the yeast cell cycle was used for our study. We measured the mean squared prediction error for the efficiency of the proposed approach and evaluated the accuracy in terms of precision, sensitivity, and F-score. The proposed method outperformed the other existing approaches.

Cotunneling Drag Effect in Coulomb-Coupled Quantum Dots.

In Coulomb drag, a current flowing in one conductor can induce a voltage across an adjacent conductor via the Coulomb interaction. The mechanisms yielding drag effects are not always understood, even though drag effects are sufficiently general to be seen in many low-dimensional systems. In this Letter, we observe Coulomb drag in a Coulomb-coupled double quantum dot and, through both experimental and theoretical arguments, identify cotunneling as essential to obtaining a correct qualitative understanding of the drag behavior.