GDPR Compliance for Blockchain Applications in Healthcare

The transparent and decentralized characteristics associated with blockchain can be both appealing and problematic when applied to a healthcare use-case. As health data is highly sensitive, it is also highly regulated to ensure the privacy of patients. At the same time, access to health data and interoperability is in high demand. Regulatory frameworks such as GDPR and HIPAA are, amongst other objectives, meant to contribute to mitigating the risk of privacy violations in health data. Blockchain features can likely improve interoperability and access control to health data, and at the same time, preserve or even increase, the privacy of patients. Blockchain applications should address compliance with the current regulatory framework to increase real-world feasibility. This exploratory work indicates that published proof-of-concepts in the health domain comply with GDRP, to an extent. Blockchain developers need to make design choices to be compliant with GDPR since currently, none available blockchain platform can show compliance out of the box

Surgery for colorectal liver metastases: the impact of resection margins on recurrence and overall survival

Background: Several reports have presented conflicting results regarding the association between resection margins (RMs) and outcome after surgery for colorectal liver metastases (CLM), especially in the era of modern chemotherapy. The purpose of this study was to evaluate the impact of RMs on overall survival (OS), time to recurrence (TTR) and local recurrence (LR) status, particularly for patients treated with preoperative chemotherapy. Methods: A combined retrospective (1998 to 2008) and prospective (2008 to 2010) cohort study of consecutive patients with CLM without extrahepatic disease treated with primary resection at a medium volume centre. Results: A total of 253 patients with known R status and 242 patients with defined margin width were included in the study. Patients were stratified according to margin width; A: R1, <1 mm (n = 48, 19%), B: 1 to 4 mm (n = 77), C: 5 to 9 mm (n = 46) and D: ≥10 mm (n = 71). Median time to recurrence was 12.8 months, and after five years 21.5% had no recurrence. LR (inclusive combined recurrence in other hepatic sites or extrahepatic) occurred in 40 (16.5%) cases, most frequently seen with RMs below 5 mm. Five-year OS was 42.5% in R0 and 16.1% in R1 resections (P = 0.011). Patients were also stratified according to preoperative chemotherapy (n = 88), and the difference in five-year OS between R0 (45.1%) and R1 (14.7%) was maintained (P = 0.037). By multiple Cox regression analysis R1 resections tended to an adverse outcome (P = 0.067), also when adjusting for preoperative chemotherapy (P = 0.081). Conclusions: R1 resections for colorectal liver metastases predict adverse outcome. RMs below 5 mm increased the risk for LR and shortened the time to recurrence. Preoperative chemotherapy did not alter an adverse outcome in R1 vs. R0 patients

Performance comparison of three BRAF V600E detection methods in malignant melanoma and colorectal cancer specimen

Personalized cancer care requires reliable biomarkers. While the BRAF V600E mutation is implemented in the clinic, no method for its detection has so far been established as reference. We aimed to perform a comprehensive comparison of three methods currently being used for V600E detection in clinical samples. We analysed genomic DNA from 127 malignant melanomas (77 patients) and 389 tumours from 141 colorectal cancer patients (383 liver metastases and 6 primary tumours) by Sanger sequencing and a single probe-based high-resolution melting assay (LightMix). Formalin-fixed paraffin-embedded (FFPE) tissue from a subset of these lesions (n = 77 and 304, respectively) was analysed by immunohistochemistry (IHC) using the V600E-specific antibody VE1. In a dilution series of V600E-mutated DNA in wild-type DNA, the detection limit for the LightMix assay was 1:1000 mutated alleles while it was 1:10 for Sanger sequencing. In line with this, we detected 15 additional mutated melanoma samples and two additional mutated metastatic colorectal cancer samples by the LightMix assay compared to Sanger sequencing. For the melanoma samples, we observed high concordance between DNA-based methods and analysis by IHC. However, in colorectal samples, IHC performed poorly with 12 samples being scored as V600E positive exclusively by IHC and nine samples being scored as V600E negative exclusively by IHC. In conclusion, the VE1 antibody is not recommendable for clinical tests of colorectal cancer samples. For melanoma samples, IHC may be useful as a screening tool guiding further analytical approaches. This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited

GDPR Compliance for Blockchain Applications in Healthcare

The transparent and decentralized characteristics associated with blockchain can be both appealing and problematic when applied to a healthcare use-case. As health data is highly sensitive, it is therefore, highly regulated to ensure the privacy of patients. At the same time, access to health data and interoperability are in high demand. Regulatory frameworks such as GDPR and HIPAA are, amongst other objectives, meant to contribute to mitigating the risk of privacy violations of health data. Blockchain features can likely improve interoperability and access control to health data, and at the same time, preserve or even increase, the privacy of patients. Blockchain applications should address compliance with the current regulatory framework to increase real-world feasibility. This exploratory work indicates that published proof-of-concepts in the healthcare domain comply with GDPR, to an extent. Blockchain developers need to make design choices to be compliant with GDPR since currently, none available blockchain platform can show compliance out of the box

Predictive factors for time to recurrence, treatment and post-recurrence survival in patients with initially resected colorectal liver metastases

Background: Despite progress in resection for colorectal liver metastases (CLM), the majority of patients experience recurrence. We aimed to evaluate factors influencing time to recurrence (TTR), treatment and post-recurrence survival (PRS) related to site of recurrence. Methods: This is a retrospective population-based cohort study (1998–2012) of consecutive patients without extrahepatic disease treated with resection for CLM in a referral centre. Results: A total of 311 patients underwent resection for CLM. After a median follow-up of 4.2 years (range 1.2–15.2), 209 (67.4 %) patients developed recurrence, hepatic 90, extrahepatic 59 and both 60. Median TTR was 14.0 months, and 5-year recurrence-free status was 25.7 %. Five- and 10-year overall survival (OS) was 38.8 and 22.0 %, respectively. Median OS was 45 months. A multivariate analysis displayed synchronous disease (hazard ratio (HR) 1.50), American Society of Anaesthesiologists (ASA) score (HR 1.40), increasing number (HR 1.24) and size of metastases (HR 1.08) to shorten TTR (all p < 0.05). Perioperative chemotherapy (n = 59) increased overall TTR (HR 0.63) and overall survival (OS; HR 0.55). Hepatic TTR was correlated to synchronous disease (HR 2.07), number of lesions (HR 1.20), R1 resection (HR 2.00) and ASA score (HR 1.69), whereas extrahepatic TTR was correlated to N stage of the primary (HR 1.79), number (HR 1.27) and size of metastases (HR 1.16). Single-site recurrence was most common (135 of 209, 64.5 %), while 58 patients had double- and 16 triple-site relapses. Median PRS was 24.3 months. There was a difference in median PRS (months) according to site of relapse: liver 30.5, lung 32.3, abdominal 22.0, liver and lung 14.3, others 14.8 (p = 0.002). Repeated liver resections were performed in n = 57 patients resulting in 40.6 months median OS and 36.8 % 5-year OS. Conclusions: An adverse overall TTR was correlated to number and size of metastases, ASA score and synchronous disease. Perioperative chemotherapy increased TTR and OS after surgery for CLM. Patients with solitary post-resection relapse in the liver or lungs had the potential for longevity due to multimodal treatment

Impact of KRAS, BRAF, PIK3CA, TP53 status and intraindividual mutation heterogeneity on outcome after liver resection for colorectal cancer metastases

We determined prognostic impact of KRAS, BRAF, PIK3CA and TP53 mutation status and mutation heterogeneity among 164 colorectal cancer (CRC) patients undergoing liver resections for metastatic disease. Mutation status was determined by Sanger sequencing of a total of 422 metastatic deposits. In univariate analysis, KRAS (33.5%), BRAF (6.1%) and PIK3CA (13.4%) mutations each predicted reduced median time to relapse (TTR) (7 vs. 22, 3 vs. 16 and 4 vs. 17 months; p < 0.001, 0.002 and 0.023, respectively). KRAS and BRAF mutations also predicted a reduced median disease-specific survival (DSS) (29 vs. 51 and 16 vs. 49 months; p <0.001 and 0.008, respectively). No effect of TP53 (60.4%) mutation status was observed. Postoperative, but not preoperative chemotherapy improved both TTR and DSS (p < 0.001 for both) with no interaction with gene mutation status. Among 94 patients harboring two or more metastatic deposits, 13 revealed mutation heterogeneity across metastatic deposits for at least one gene. Mutation heterogeneity predicted reduced median DSS compared to homogeneous mutations (18 vs. 37 months; p = 0.011 for all genes; 16 vs. 26 months; p < 0.001 analyzing BRAF or KRAS mutations separately). In multivariate analyses, KRAS or BRAF mutations consistently predicted poor TRR and DSS. Mutation heterogeneity robustly predicted DSS but not TTR, while postoperative chemotherapy improved both TTR and DSS. Our findings indicate that BRAF and KRAS mutations as well as mutation heterogeneity predict poor outcome in CRC patients subsequent to liver resections and might help guide treatment decisions

Intra-patient Inter-metastatic Genetic Heterogeneity in Colorectal Cancer as a Key Determinant of Survival after Curative Liver Resection

<div><p>Chromosomal instability is a well-defined hallmark of tumor aggressiveness and metastatic progression in colorectal cancer. The magnitude of genetic heterogeneity among distinct liver metastases from the same patient at the copy number level, as well as its relationship with chemotherapy exposure and patient outcome, remains unknown. We performed high-resolution DNA copy number analyses of 134 liver metastatic deposits from 45 colorectal cancer patients to assess: (i) intra-patient inter-metastatic genetic heterogeneity using a heterogeneity score based on pair-wise genetic distances among tumor deposits; and (ii) genomic complexity, defined as the proportion of the genome harboring aberrant DNA copy numbers. Results were analyzed in relation to the patients’ clinical course; previous chemotherapy exposure and outcome after surgical resection of liver metastases. We observed substantial variation in the level of intra-patient inter-metastatic heterogeneity. Heterogeneity was not associated with the number of metastatic lesions or their genomic complexity. In metachronous disease, heterogeneity was higher in patients previously exposed to chemotherapy. Importantly, intra-patient inter-metastatic heterogeneity was a strong prognostic determinant, stronger than known clinicopathological prognostic parameters. Patients with a low level of heterogeneity (below the median level) had a three-year progression-free and overall survival rate of 23% and 66% respectively, <i>versus</i> 5% and 18% for patients with a high level (hazard ratio0.4, 95% confidence interval 0.2–0.8, P = 0.01; and hazard ratio0.3,95% confidence interval 0.1–0.7, P = 0.007). A low patient-wise level of genomic complexity (below 25%) was also a favorable prognostic factor; however, the prognostic association of intra-patient heterogeneity was independent of genomic complexity in multivariable analyses. In conclusion, intra-patient inter-metastatic genetic heterogeneity is a pronounced feature of metastatic colorectal cancer, and the strong prognostic association reinforces its clinical relevance and places it as a key feature to be explored in future patient cohorts.</p></div

Variation in intra-patient genetic heterogeneity in liver metastases.

<p>(A) Summarized patient-wise, the DNA copy number profiles of liver metastases (n = 134 from 45 patients) show high-frequency gains (vertical axis; red) on chromosome arms 7p,7q, 8q, 13q, and 20q, and losses (blue) on 1p, 4p, 4q, 8p, 17p, and 18q. In this plot, chromosome numbers are indicated on the horizontal axes, and chromosomes and chromosome arms are separated by vertical lines. (B) Hierarchical clustering of metastatic deposits collected at first liver resection (n = 123 from 45 patients)based on DNA copy numbers. In 23 patients, the metastatic deposits clustered in a patient-wise manner (different tones of grey distinguish among metastases from individual patients plotted adjacent to each other). Four patients had solitary metastases. In 18 patients, the metastatic deposits were separated in multiple clusters (individual color for each patient), indicating intra-patient heterogeneity. Clustering was done by complete linkage, based on Euclidean distance metrics. (C)Intra-patient inter-metastatic genetic heterogeneity was measured as the average pair-wise Euclidean distance of genome-wide copy numbers among all metastases from each patient (illustrated for a patient with three liver metastases). (D) Violin plot (left) showing the distribution of intra-patient inter-metastatic genetic heterogeneity among the 41 patients with multiple metastatic deposits collected at first liver resection (range 1.7 to 9.7; median 4.7). The right panel shows representative individual copy number segmentation profiles of two metastases from a patient with a level of heterogeneity above (5.0; blue) and below (2.6; red) the median level.</p

High intra-patient inter-metastatic genetic heterogeneity after chemotherapy exposure.

<p>Twenty-two of the 26 patients (vertically in the left panel) with metachronous metastases had two or more liver deposits (horizontally in the left panel) at first liver resection (the symbols are the same as described in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006225#pgen.1006225.g001" target="_blank">Fig 1</a>). The right panel shows the intra-patient inter-metastatic genetic heterogeneity in chemonaïve patients (n = 9; indicated by light grey boxes in the left part of the right panel) <i>versus</i> patients treated with chemotherapy (n = 13; indicated by dark grey boxes), respectively, demonstrating higher intra-patient inter-metastatic heterogeneity after chemotherapy exposure (P = 0.03 by independent samples t-test; however, not statistically significant after correcting for multiple testing).</p

Low intra-patient inter-metastatic genetic heterogeneity and genomic complexity are associated with favorable patient outcome.

<p>(A) A low level of intra-patient inter-metastatic genetic heterogeneity (below median) was strongly associated with a higher three-year progression-free and overall survival rate, measured from start of treatment for the metastases. Median progression-free survival was 17 and 8 months and the three-year overall survival rate was 66% and 18%for patients with heterogeneity below and above the median level respectively. Hazard ratios (HR) at three years of follow-up were calculated by Cox’s regression and P-values from Wald’s tests of predictive potential. (B) Patients with a low level of both intra-patient inter-metastatic heterogeneity (below median) and average genomic complexity (below 25%) had a significantly higher three-year progression-free (P = 0.002) and overall (P = 0.001) survival rate than patients with a low level of only one, or neither, of the two characteristics. Median progression-free survival was 23, 12 and 7 months for the three patient groups respectively, and the three-year overall survival rate was 100%, 41% and 16% respectively. P-values were calculated by the log-rank test of linear trend among the three patient groups.</p