Assessing associations between the AURKAHMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood appr

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Renal involvement in human rabies: clinical manifestations and autopsy findings of nine cases from northeast of Brazil Envolvimento renal na raiva em humanos: manifestações clínicas e achados de autópsia de nove casos do nordeste do Brasil

A retrospective study was conducted in nine patients with rabies admitted to a hospital of Fortaleza, Brazil. Autopsy was performed in all cases. The ages ranged from three to 81 years and six were males. They all were bitten by dogs. The time between the accident and the hospital admission ranged from 20 to 120 days (mean 45 &plusmn; 34 days). The time until death ranged from one to nine days (mean 3.3 &plusmn; 5.5 days). The signs and symptoms presented were fever, hydrophobia, aerophobia, agitation, disorientation, dyspnea, sialorrhea, vomiting, oliguria, sore throat, pain and hypoesthesia in the site of the bite, headache, syncope, cough, hematemesis, mydriasis, hematuria, constipation, cervical pain and priapism. In three out of six patients, there was evidence of acute renal failure, defined as serum creatinine > 1.4 mg/dL. The post-mortem findings in the kidneys were mild to moderate glomerular congestion and mild to intense peritubular capillary congestion. Acute tubular necrosis was seen in only two cases. This study shows some evidence of renal involvement in rabies. Histopathologic findings are nonspecific, so hemodynamic instability, caused by autonomic dysfunction, hydrophobia and dehydration must be responsible for acute renal failure in rabies.<br>Foi realizado estudo retrospectivo de nove casos de raiva internados em um hospital de Fortaleza, Brasil. Autópsia foi realizada em todos os casos. As idades variaram de 3 a 81 anos. Todos foram agredidos por cães. O tempo entre o acidente e a admissão hospitalar variou de 20 a 120 dias (média de 45 &plusmn; 34 dias). O tempo de internamento variou de 1 a 9 dias (média de 5.5 &plusmn; 3.1 dias). Os sinais e sintomas observados foram febre, hidrofobia, aerofobia, agitação, desorientação, dispnéia, sialorréia, vômitos, oligúria, faringite, dor e hipoestesia no local da mordida, cefaléia, síncope, tosse, hematêmese, midríase, hematúria, constipação, dor cervical e priapismo. Em três de seis pacientes (50%) foi encontrada evidência de insuficiência renal aguda, definida como creatinina > 1.4 mg/dL. Os achados de autópsia do tecido renal foram congestão glomerular leve a moderada e congestão capilar peritubular leve a intensa. Necrose tubular aguda foi encontrada em dois casos. Estes achados são inespecíficos, de modo que a instabilidade hemodinâmica, causada por disfunção autonômica, hidrofobia e desidratação podem ser considerados como responsáveis pela insuficiência renal aguda na raiva

Impact of maximal extent of resection on postoperative deficits, patient functioning, and survival within clinically important glioblastoma subgroups

BACKGROUND: The impact of extent of resection (EOR), residual tumor volume (RTV), and gross-total resection (GTR) in glioblastoma subgroups is currently unknown. This study aimed to analyze their impact on patient subgroups in relation to neurological and functional outcomes. METHODS: Patients with tumor resection for eloquent glioblastoma between 2010 and 2020 at 4 tertiary centers were recruited from a cohort of 3919 patients. RESULTS: One thousand and forty-seven (1047) patients were included. Higher EOR and lower RTV were significantly associated with improved overall survival (OS) and progression-free survival (PFS) across all subgroups, but RTV was a stronger prognostic factor. GTR based on RTV improved median OS in the overall cohort (19.0 months, P < .0001), and in the subgroups with IDH wildtype tumors (18.5 months, P = .00055), MGMT methylated tumors (35.0 months, P < .0001), aged <70 (20.0 months, P < .0001), NIHSS 0-1 (19.0 months, P = .0038), KPS 90-100 (19.5 months, P = .0012), and KPS ≤80 (17.0 months, P = .036). GTR was significantly associated with improved OS in the overall cohort (HR 0.58, P = .0070) and improved PFS in the NIHSS 0-1 subgroup (HR 0.47, P = .012). GTR combined with preservation of neurological function (OFO 1 grade) yielded the longest survival times (median OS 22.0 months, P < .0001), which was significantly more frequently achieved in the awake mapping group (50.0%) than in the asleep group (21.8%) (P < .0001). CONCLUSIONS: Maximum resection was especially beneficial in the subgroups aged <70, NIHSS 0-1, and KPS 90-100 without increasing the risk of postoperative NIHSS or KPS worsening. These findings may assist surgical decision making in individual glioblastoma patients

Effect of awake craniotomy in glioblastoma in eloquent areas (GLIOMAP): a propensity score-matched analysis of an international, multicentre, cohort study

Background: Awake mapping has been associated with decreased neurological deficits and increased extent of resection in eloquent glioma resections. However, its effect within clinically relevant glioblastoma subgroups remains poorly understood. We aimed to assess the benefit of this technique in subgroups of patients with glioblastomas based on age, preoperative neurological morbidity, and Karnofsky Performance Score (KPS). Methods: In this propensity score-matched analysis of an international, multicentre, cohort study (GLIOMAP), patients were recruited at four tertiary centres in Europe (Erasmus MC, Rotterdam and Haaglanden MC, The Hague, Netherlands, and UZ Leuven, Leuven, Belgium) and the USA (Brigham and Women's Hospital, Boston, MA). Patients were eligible if they were aged 18–90 years, undergoing resection, had a histopathological diagnosis of primary glioblastoma, their tumour was in an eloquent or near-eloquent location, and they had a unifocal enhancing lesion. Patients either underwent awake mapping during craniotomy, or asleep resection, as per treating physician or multidisciplinary tumour board decision. We used propensity-score matching (1:3) to match patients in the awake group with those in the asleep group to create a matched cohort, and to match patients from subgroups stratified by age (<70 years vs ≥70 years), preoperative National Institute of Health Stroke Scale (NIHSS) score (score of 0–1 vs ≥2), and preoperative KPS (90–100 vs ≤80). We used Cox proportional hazard regressions to analyse the effect of awake mapping on the primary outcomes including postoperative neurological deficits (measured by deterioration in NIHSS score at 6 week, 3 months, and 6 months postoperatively), overall survival, and progression-free survival. We used logistic regression to analyse the predictive value of awake mapping and other perioperative factors on postoperative outcomes. Findings: Between Jan 1, 2010, and Oct 31, 2020, 3919 patients were recruited, of whom 1047 with tumour resection for primary eloquent glioblastoma were included in analyses as the overall unmatched cohort. After propensity-score matching, the overall matched cohort comprised 536 patients, of whom 134 had awake craniotomies and 402 had asleep resection. In the overall matched cohort, awake craniotomy versus asleep resection resulted in fewer neurological deficits at 3 months (26 [22%] of 120 vs 107 [33%] of 323; p=0·019) and 6 months (30 [26%] of 115 vs 125 [41%] of 305; p=0·0048) postoperatively, longer overall survival (median 17·0 months [95% CI 15·0–24·0] vs 14·0 months [13·0–16·0]; p=0·00054), and longer progression-free survival (median 9·0 months [8·0–11·0] vs 7·3 months [6·0–8·8]; p=0·0060). In subgroup analyses, fewer postoperative neurological deficits occurred at 3 months and at 6 months with awake craniotomy versus asleep resection in patients younger than 70 years (3 months: 22 [21%] of 103 vs 93 [34%] of 272; p=0·016; 6 months: 24 [24%] of 101 vs 108 [42%] of 258; p=0·0014), those with an NIHSS score of 0–1 (3 months: 22 [23%] of 96 vs 97 [38%] of 254; p=0·0071; 6 months: 27 [28%] of 95 vs 115 [48%] of 239; p=0·0010), and those with a KPS of 90–100 (3 months: 17 [19%] of 88 vs 74 [35%] of 237; p=0·034; 6 months: 24 [28%] of 87 vs 101 [45%] of 223, p=0·0043). Additionally, fewer postoperative neurological deficits were seen in the awake group versus the asleep group at 3 months in patients aged 70 years and older (two [13%] of 16 vs 15 [43%] of 35; p=0·033; no difference seen at 6 months), with a NIHSS score of 2 or higher (3 months: three [13%] of 23 vs 21 [36%] of 58; p=0·040) and at 6 months in those with a KPS of 80 or lower (five [18%] of 28 vs 34 [39%] of 88; p=0·043; no difference seen at 3 months). Median overall survival was longer for the awake group than the asleep group in the subgroups younger than 70 years (19·5 months [95% CI 16·0–31·0] vs 15·0 months [13·0–17·0]; p<0·0001), an NIHSS score of 0–1 (18·0 months [16·0–31·0] vs 14·0 months [13·0–16·5]; p=0·00047), and KPS of 90–100 (19·0 months [16·0–31·0] vs 14·5 months [13·0–16·5]; p=0·00058). Median progression-free survival was also longer in the awake group than in the asleep group in patients younger than 70 years (9·3 months [95% CI 8·0–12·0] vs 7·5 months [6·5–9·0]; p=0·0061), in those with an NIHSS score of 0–1 (9·5 months [9·0–12·0] vs 8·0 months [6·5–9·0]; p=0·0035), and in those with a KPS of 90–100 (10·0 months [9·0–13·0] vs 8·0 months [7·0–9·0]; p=0·0010). No difference was seen in overall survival or progression-free survival between the awake group and the asleep group for those aged 70 years and older, with NIHSS scores of 2 or higher, or with a KPS of 80 or lower. Interpretation: These data might aid neurosurgeons with the assessment of their surgical strategy in individual glioblastoma patients. These findings will be validated and further explored in the SAFE trial (NCT03861299) and the PROGRAM study (NCT04708171). Funding: None