This in-vitro study assessed the effect of an underdrilling implant placement protocol on the insertion torque, implant surface temperature and surface roughness (Sa) topography of the cervical ...microthreads of implants. Three groups of 25 implants (3.75 mm × 10 mm) were placed in osteotomies prepared in an artificial bone disc with final diameters of 3.65 mm according to the manufacturer’s instructions and in osteotomies prepared in accordance with an underdrilling protocol with final drill diameters of 3.2 and 2.8 mm (groups D3.65, D3.2, D2.8, respectively). Implants were inserted at a constant rate of 30 rpm. The surface temperature of the implants was measured with a thermal camera and temperature amplitude (Temp-Amp) was calculated by subtracting the room temperature from the measured implant surface temperature. Upon implant retrieval, coronal surface topography was assessed using a Nanofocus µsurf explorer and compared to a set of 25 new implants (control group). The differences between groups were compared using one-way ANOVA (p < 0.05). Significantly higher insertion torque, surface temperature values and significantly smaller average Sa values were measured in the implants inserted in undersized preparations. The highest temperature, insertion torque and Temp-Amp values and the largest decrease in Sa were measured in the D2.8 group. The lowest values were measured in the D3.65 group.
Background
Biliary tract malignancies, in particular cholangiocarcinomas (CCA), are rare tumors that carry a poor prognosis. BRCA2 mutation carriers have an increased risk of developing CCA with a ...reported relative risk of ∼5 according to the Breast Cancer Linkage Consortium. In addition to this risk, there are potential therapeutic implications in those harboring somatic and/or germline (GL) BRCA mutations. Therefore, it is important to define the clinical characteristics of GL/somatic BRCA1/2 variants in CCA patients.
Materials and Methods
We performed a multicenter retrospective analysis of CCA patients diagnosed between January 2000 and December 2013 with GL or somatic variants in BRCA1/2 genes detected by GL mutations testing and/or by tumor next generation sequencing. Cases were identified from clinical databases at participating institutions. Data including demographics, clinical history, surgical procedures, and systemic chemotherapy or radiation were extracted from patients' records.
Results
Overall, 18 cases were identified: 5 carriers of GL BRCA1/2 mutations (4 BRCA2; 1 BRCA1) and 13 harboring somatic variations (7 BRCA1; 6 BRCA2). Mean age at diagnosis was 60, SD ± 10 years (range 36–75 years), with male and female prevalence rates of 61.2% and 38.8%, respectively. Stage at diagnosis was I (n = 4), II (n = 3), III (n = 3), and IV (n = 8). Six patients had extrahepatic CCA and the rest intrahepatic CCA. Thirteen patients received platinum‐based therapy and four were treated with poly ADP ribose polymerase inhibitors, of whom one experienced sustained disease response with a progression‐free survival of 42.6 months. Median overall survival from diagnosis for patients with stage I/II in this study was 40.3 months (95% confidence interval CI, 6.73–108.15) and with stages III/IV was 25 months (95% CI, 15.23–40.57).
Conclusion
BRCA‐associated CCA is uncommon. This multicenter retrospective study provides a thorough clinical analysis of a BRCA‐associated CCA cohort, which can serve as a benchmark for future development and design of expanded analyses and clinical trials.
Implications for Practice
BRCA‐associated CCA is uncommon but a very important subtype of hepatic malignancies, due to its rising prevalence. Better clinical characterization of this subtype might allow application of targeted therapy for CCA patients with germline or somatic mutations in BRCA1/2 genes, especially due to previously reported success of such therapies in other BRCA‐associated malignancies. Thus this study, first of its kind, provides a basis for future multi‐centered analyses in larger cohorts, as well as clinical trials. Additionally, this study emphasizes the importance of both germline and somatic genotyping for all CCA patients.
摘要
背景. 胆道恶性肿瘤, 尤其是胆管癌（CCA）是一类预后不良的罕见肿瘤。BRCA2突变携带者罹患CCA的风险增加, 乳腺癌联合协作组报告的相对风险约为5。除上述风险以外, 这对于携带体细胞和/或胚系（GL）BRCA突变的患者而言还具有潜在治疗意义。因此, 确定CCA患者中GL/体细胞BRCA1/2变异体的临床特征至关重要。
材料和方法. 我们针对2000年1月至2013年12月期间诊断的携带GL或体细胞BRCA1/2基因变异体（通过GL突变检测方法和/或新一代肿瘤测序技术检测）的CCA患者进行了一项多中心回顾性分析。从参与机构的临床数据库中检索病例。研究数据包括人口统计学、临床病史、手术方式以及全身化疗或放疗, 以上信息摘自患者记录。
结果. 共计检索到18例病例：5例携带GL BRCA1/2突变（4例BRCA2；1例BRCA1）, 13例携带体细胞变异（7例BRCA1；6例BRCA2）。诊断时的平均年龄为60岁, SD±10岁（范围：36‐75岁）, 男性和女性的患病率分别为61.2%和38.8%。诊断时的疾病分期包括I期（n=4）、II期（n=3）、III期（n=3）和IV期（n=8）。6例患者为肝外CCA, 其余为肝内CCA。13例患者接受以铂类药物为基础的治疗, 4例患者接受多聚ADP核糖聚合酶抑制剂（PARPi）治疗, 其中1例患者获得了持久性疾病缓解, 无进展生存期为42.6个月。在本研究中, 自诊断时起, I/II期患者的中位总生存期为40.3个月95%置信区间（CI）：6.73‐108.15, III/IV期患者的中位总生存期为25个月（95% CI：15.23‐40.57）。
结论. BRCA相关性CCA并不常见。本项多中心回顾性研究针对一个BRCA相关性CCA队列进行了全面的临床分析, 在日后开发和设计扩展分析和临床试验时可以此作为基准。
It is unknown if and to what extent the clinical course and therapeutic response of BRCA‐associated cholangiocarcinomas are distinct from non‐BRCA carriers. To gain insight, this multicenter retrospective study on BRCA‐associated cases was initiated and is reported here.
Homologous recombination deficiency (HRD) in pancreatic ductal adenocarcinoma (PDAC), remains poorly defined beyond germline (g) alterations in BRCA1, BRCA2, and PALB2.
We interrogated whole genome ...sequencing (WGS) data on 391 patients, including 49 carriers of pathogenic variants (PVs) in gBRCA and PALB2. HRD classifiers were applied to the dataset and included (1) the genomic instability score (GIS) used by Myriad’s MyChoice HRD assay; (2) substitution base signature 3 (SBS3); (3) HRDetect; and (4) structural variant (SV) burden. Clinical outcomes and responses to chemotherapy were correlated with HRD status.
Biallelic tumor inactivation of gBRCA or PALB2 was evident in 43 of 49 germline carriers identifying HRD-PDAC. HRDetect (score ≥0.7) predicted gBRCA1/PALB2 deficiency with highest sensitivity (98%) and specificity (100%). HRD genomic tumor classifiers suggested that 7% to 10% of PDACs that do not harbor gBRCA/PALB2 have features of HRD. Of the somatic HRDetecthi cases, 69% were attributed to alterations in BRCA1/2, PALB2, RAD51C/D, and XRCC2, and a tandem duplicator phenotype. TP53 loss was more common in BRCA1- compared with BRCA2-associated HRD-PDAC. HRD status was not prognostic in resected PDAC; however in advanced disease the GIS (P = .02), SBS3 (P = .03), and HRDetect score (P = .005) were predictive of platinum response and superior survival. PVs in gATM (n = 6) or gCHEK2 (n = 2) did not result in HRD-PDAC by any of the classifiers. In 4 patients, BRCA2 reversion mutations associated with platinum resistance.
Germline and parallel somatic profiling of PDAC outperforms germline testing alone in identifying HRD-PDAC. An additional 7% to 10% of patients without gBRCA/PALB2 mutations may benefit from DNA damage response agents.
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•Pancreatic cancer patients demonstrate a limited response to chemotherapy.•Pancreatic cancer subtype: unstable tumors co-segregated with inactivation of DNA damage repair genes e.g. ...BRCA1/2.•BRCA-associated PDAC demonstrates a response to platinum chemotherapy/PARP inhibitors, however resistance develops.•BRCA-associated PDAC PDX model recapitulating the clinical scenario, i.e., sensitivity or resistance to treatment.•BRCA-associated PDAC PDX models may potentially identify novel therapeutic strategies for tumors resistant to treatment.
Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease. The majority of patients diagnosed at an advanced, metastatic stage, and poor overall survival rates. The most clinically meaningful subtype obtained from PDAC genomic classification is represented by unstable genomes, and co-segregated with inactivation of DNA damage repair genes, e.g., Breast cancer 1/2 (BRCA1/2).
The FDA and EMA has recently approved olaparib, a Poly (ADP-ribose) polymerase (PARP) inhibitor, as a maintenance strategy for platinum-sensitive advanced PDAC patients with BRCA mutations. However, susceptibility to treatment varies, and resistance may develop. Resistance can be defined as innate or acquired resistance to platinum/PARP-inhibition.
Patient-derived xenograft (PDX) models have been utilized in cancer research for many years. We generated a unique PDX model, obtained from BRCA-associated PDAC patients at distinct time points of the disease recapitulating the different clinical scenario.
In this review we discuss the relevant PDX-derived models for investigating BRCA-associated PDAC and drug development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Brain white matter hyperintensities (WMHs) commonly observed on brain imaging of older adults are associated with balance and gait impairment and have also been linked to cognitive deficits. ...Parkinson's disease (PD) is traditionally sub-classified into the postural instability gait difficulty (PIGD) sub-type, and the tremor dominant (TD) sub-type. Considering the known association between WMHs and axial symptoms like gait disturbances and postural instability, one can hypothesize that WMHs might contribute to the disparate clinical sub-types of patients with PD.
110 patients with PD underwent a clinical evaluation and a 3T MRI exam. Based on the Unified Parkinson Disease Rating Scale, the patients were classified into motor sub-types, i.e., TD or PIGD, and scores reflecting PIGD and TD symptoms were computed. We compared white matter burden using three previously validated methods: one using a semi-quantitative visual rating scale in specific brain regions and two automated methods.
Overall, MRI data were obtained in 104 patients. The mean WMHs scores and the percent of subjects with lesions in specific brain regions were similar in the two subtypes, p = 0.678. The PIGD and the TD scores did not differ even when comparing patients with a relatively high burden of WMHs to patients with a relatively low burden. Across most of the brain regions, mild to moderate correlations between WMHs and age were found (r = 0.23 to 0.41; p<0.021). Conversely, no significant correlations were found between WMHs and the PIGD score or disease duration. In addition, depressive symptoms and cerebro-vascular risk factors were similar among the two subtypes.
In contrast to what has been reported previously among older adults, the present study could not demonstrate any association between WMHs and the PIGD or TD motor sub-types in patients with PD.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Surveillance of high‐risk individuals for pancreatic ductal adenocarcinoma (PDAC) is recommended. This study aimed to determine the prevalence and outcomes of PDAC and its precursor ...lesions in BRCA1/2 pathogenic variants (PVs) carriers undergoing pancreatic surveillance.
Methods
A retrospective multicenter cohort study of pancreatic surveillance outcomes in Israeli BRCA1/2 carriers preferably with a family history of PDAC.
Results
A total of 180 asymptomatic carriers participated in the screening programs, including 57 (31.7%) with BRCA1 PVs, 121 (67.2%) with BRCA2 PVs, and 12 (6.6%) with PVs in BRCA1/2 and other genes, for a median follow‐up period of 4 years. Ninety‐one individuals (50.5%) fulfilled the International Cancer of the Pancreas Screening (CAPS) criteria for surveillance whereas 116 (64.4%) fulfilled the American College of Gastroenterology (ACG) criteria. There were four cases of adenocarcinoma and four cases of grade 1‐neuroendocrine tumor (G1‐NET). All were BRCA2 carriers, and two had no family history of PDAC. Three cancer patients were at resectable stages (IA, IIA, IIB) whereas one had a stage IIIB tumor. Of the G1‐NET cases, one had surgery and the others were only followed. Success rate for detection of confined pancreatic carcinoma was thus 1.6% (three of 180) in the whole cohort, 1.6% (two of 116) among individuals who fulfilled ACG criteria and 2.2% (two of 91) in those fulfilling CAPS criteria for surveillance.
Conclusions
Despite the low detection rate of PDAC and its' high‐risk neoplastic precursor lesions among BRCA1/2 carriers undergoing pancreatic surveillance, 75% of cancer cases were detected at a resectable stage.
In a surveillance program of 180 BRCA1/2 carriers for pancreatic cancer, four cases of cancer were detected. Despite this overall low detection rate (2.2%), 75% of them were successfully detected at relatively early, resectable stage.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Syndecan-1 (SDC1) has multiple functions in tumorigenesis in general and specifically in pancreatic cancer. We aimed to evaluate SDC1 as a diagnostic and prognostic biomarker in patients with ...pancreatic ductal adenocarcinoma (PDAC).
In this case-control study, patients newly diagnosed with a biopsy-proven PDAC were enrolled alongside healthy individuals in a derivation-validation cohort design. Serum SDC1 was measured by enzyme-linked immunoassay. The diagnostic accuracy of SDC1 levels for diagnosing PDAC was computed. A unified cohort enriched with additional early-stage patients with PDAC was used to evaluate the association of SDC1 with survival outcomes and patient characteristics.
In the derivation cohort, serum SDC1 levels were significantly higher in patients with PDAC (n = 39) compared with healthy controls (n = 20) (40.1 ng/mL, interquartile range 29.8-95.3 vs 25.6 ng/mL, interquartile range 17.1-29.8, respectively; P < 0.001). The receiver operating characteristic analysis area under the curve was 0.847 (95% confidence interval 0.747-0.947, P < 0.001). These results were replicated in a separate age-matched validation cohort (n = 38 PDAC, n = 38 controls; area under the curve 0.844, 95% confidence interval 0.757-0.932, P < 0.001). In the combined-enriched PDAC cohort (n = 110), using a cutoff of 35 ng/mL, the median overall 5-year survival between patients below and above this cutoff was not significantly different, although a trend for better survival after 1 year was found in the lower level group (P = 0.06). There were 12 of the 110 patients with PDAC (11%) who had normal CA 19-9 in the presence of elevated SDC1.
These findings suggest serum SDC1 as a promising novel biomarker for early blood-based diagnosis of pancreatic cancer.
Each tumour contains diverse cellular states that underlie intratumour heterogeneity (ITH), a central challenge of cancer therapeutics
. Dozens of recent studies have begun to describe ITH by ...single-cell RNA sequencing, but each study typically profiled only a small number of tumours and provided a narrow view of transcriptional ITH
. Here we curate, annotate and integrate the data from 77 different studies to reveal the patterns of transcriptional ITH across 1,163 tumour samples covering 24 tumour types. Among the malignant cells, we identify 41 consensus meta-programs, each consisting of dozens of genes that are coordinately upregulated in subpopulations of cells within many tumours. The meta-programs cover diverse cellular processes including both generic (for example, cell cycle and stress) and lineage-specific patterns that we map into 11 hallmarks of transcriptional ITH. Most meta-programs of carcinoma cells are similar to those identified in non-malignant epithelial cells, suggesting that a large fraction of malignant ITH programs are variable even before oncogenesis, reflecting the biology of their cell of origin. We further extended the meta-program analysis to six common non-malignant cell types and utilize these to map cell-cell interactions within the tumour microenvironment. In summary, we have assembled a comprehensive pan-cancer single-cell RNA-sequencing dataset, which is available through the Curated Cancer Cell Atlas website, and leveraged this dataset to carry out a systematic characterization of transcriptional ITH.
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IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
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