Magnetically guided surgery after primary systemic therapy for breast cancer: implications for enhanced axillary mapping.

BACKGROUND: Superparamagnetic iron nanoparticles perform comparably to radioisotope ± blue dye for sentinel lymph node detection in breast cancer, even when injected up to 8 weeks before surgery. Using superparamagnetic iron nanoparticles for sentinel lymph node detection after primary systemic therapy, and the maximum time frame of superparamagnetic iron nanoparticle administration have not been investigated. METHODS: This cohort study included cN0/1-to-ycN0 patients undergoing sentinel lymph node detection or targeted axillary dissection. All patients received superparamagnetic iron nanoparticles either before primary systemic therapy or before surgery, and radioisotope on the day of surgery. RESULTS: For 113 patients analysed, superparamagnetic iron nanoparticles were injected a median of 3 (range 0-248) days before surgery, with a 97.4% detection rate compared with 91.2% for radioisotope (P = 0.057). Concordance for radioisotope was 97.1% and this was not affected by timing of superparamagnetic iron nanoparticle injection (Kendall's tau 0.027; P = 0.746). The median sentinel lymph node yield was 3 (interquartile range (i.q.r.) 2-3) for superparamagnetic iron nanoparticles and 2 (i.q.r. 2-3) for radioisotope (P < 0.001). In targeted axillary dissection, detection was 100% for superparamagnetic iron nanoparticles and 81.8% for radioisotope (P = 0.124). The index node was magnetic in 93.9% and radioactive in 66.7% (P = 0.007), an outcome that was not affected by any factors. For patients with metastases, superparamagnetic iron nanoparticle detection was 100% and radioisotope-based detection was 84.2% (P = 0.083), with superparamagnetic iron nanoparticles detecting more metastatic sentinel lymph nodes (median of 1 (i.q.r. 1-2) for superparamagnetic iron nanoparticles compared with a median of 1 (i.q.r. 0-1) for radioisotope; P = 0.005). CONCLUSION: Injection before primary systemic therapy is feasible and does not affect concordance with radioisotope. Superparamagnetic iron nanoparticles perform comparably to radioisotope, but detect more sentinel lymph nodes and have a higher rate of detection of metastatic sentinel lymph nodes.

Clinical Significance of the TK1-Specific Activity in the Early Detection of Ovarian Cancer.

INTRODUCTION: Ovarian cancer is the eighth most common cause of cancer death in women. One of the major concerns is almost two-thirds of cases are typically diagnosed in the late stage as the symptoms are unspecific in the early stage of ovarian cancer. It is known that the combination of TK1 protein with CA 125 or HE4 showed better performance than either of them alone. That is why, the aim of the study was to investigate whether the TK1-specific activity (TK1 SA) could function as a complement marker for early-stage diagnosis of ovarian cancer. METHODS: The study included a set of 198 sera consisting of 134 patients with ovarian tumors (72 benign and 62 malignant) and 64 healthy age-matched controls. The TK1 SA was determined using TK1 activity by TK-Liaison and TK1 protein by AroCell TK 210 ELISA. Further, CA 125, HE4, as well as risk of ovarian malignancy algorithm index were also determined in the same set of clinical samples. RESULTS: The TK1 SA was significantly different between healthy compared to ovarian cancer patients (p < 0.0001). Strikingly, TK1 SA has higher sensitivity (55%) compared to other biomarkers in the detection of benign ovarian tumors. Further, the highest sensitivity was achieved by the combination of TK1 SA with CA 125 and HE4 for the detection of benign tumors as well as malignant ovarian tumors (72.2% and 88.7%). In addition, TK1 SA could significantly differentiate FIGO stage I/II from stage III/IV malignancies (p = 0.026). Follow-up of patients after surgery and chemotherapy showed a significant difference compared to TK1 SA at the time of diagnosis. CONCLUSIONS: These results indicate that TK1 SA is a promising blood-based biomarker that could complement CA 125 and HE4 for the detection of early stages of ovarian cancer.

Delayed Sentinel Lymph Node Dissection in Patients with a Preoperative Diagnosis of Ductal Cancer In Situ by Preoperative Injection with Superparamagnetic Iron Oxide (SPIO) Nanoparticles: The SentiNot Study.

BACKGROUND: Difficulty in preoperatively assessing the risk for occult invasion or surgery that precludes future accurate axillary mapping in patients with ductal cancer in situ (DCIS) account for overutilization of SLND. METHODS: Prospective, multicenter, cohort study, including women with any DCIS planned for mastectomy or DCIS grade 2 and > 20 mm, any DCIS grade 3, any mass-forming DCIS and any planned surgery. Patients received an interstitial SPIO injection during breast surgery, but no upfront SLND was performed. If invasion was identified on final pathology, delayed SLND (d-SLND) was performed separately with the coadministration of isotope ± blue dye (BD). Study outcomes were proportion of upfront SLNDs that were avoided, detection rates during d-SLND, and impact on healthcare costs. RESULTS: In total, 78.7% of study participants (N = 254, mean age 60 years, mean DCIS size 37.8 mm) avoided upfront SLND. On d-SLND (median 28 days, range 9-46), SPIO outperformed Tc99 with (98.2% vs. 63.6%, p < 0.001) or without BD (92.7% vs. 50.9%, p < 0.001) and had higher nodal detection rate (86.9% vs. 32.3%, p < 0.001) and with BD (93.9% vs. 41.4%, p < 0.001). Only 27.9% of all SLNs retrieved were concordant for Tc99 and SPIO. Type of breast procedure (WLE vs. oncoplastic BCT vs. mastectomy) affected these outcomes and accounted for the low performance of Tc99 (p < 0.001). d-SLND resulted in a 28.1% total cost containment for women with pure DCIS on final pathology (4190 vs. 5828 USD, p < 0.001). CONCLUSIONS: Marking the SLN with SPIO may avoid overtreatment and allow for accurate d-SLND in patients with DCIS.

Evolution and refinement of magnetically guided sentinel lymph node detection in breast cancer: meta-analysis.

BACKGROUND: Superparamagnetic iron oxide nanoparticles (SPIO) have been used as a tracer for sentinel lymph node (SLN) localization in breast cancer, demonstrating comparable performance to the combination of radioisotope (RI) and blue dye (BD). METHODS: A systematic literature search and meta-analysis with subgroup and meta-regression analysis were undertaken to update the available evidence, assess technique evolution, and define knowledge gaps. Recommendations were made using the GRADE approach. RESULTS: In 20 comparative studies, the detection rate was 97.5 per cent for SPIO and 96.5 per cent for RI ± BD (risk ratio 1.006, 95 per cent c.i. 0.992 to 1.019; P = 0.376, high-certainty evidence). Neoadjuvant therapy, injection site, injection volume or nodal metastasis burden did not affect the detection rate, but injection over 24 h before surgery increased the detection rate on meta-regression. Concordance was 99.0 per cent and reverse concordance 97.1 per cent (rate difference 0.003, 95 per cent c.i. -0.009 to 0.015; P = 0.656, high-certainty evidence). Use of SPIO led to retrieval of slightly more SLNs (pooled mean 1.96 versus 1.89) with a higher nodal detection rate (94.1 versus 83.5 per cent; RR 1.098, 1.058 to 1.140; P < 0.001; low-certainty evidence). In meta-regression, injection over 24 h before surgery increased the SPIO nodal yield over that of RI ± BD. The skin-staining rate was 30.8 per cent (very low-certainty evidence), and possibly prevented with use of smaller doses and peritumoral injection. CONCLUSION: The performance of SPIO is comparable to that of RI ± BD. Preoperative injection increases the detection rate and nodal yield, without affecting concordance. Whether skin staining and MRI artefacts are reduced by lower dose and peritumoral injection needs to be investigated.

Differential expression of enzymes in thymidylate biosynthesis in zebrafish at different developmental stages: implications for dtymk mutation-caused neurodegenerative disorders.

BACKGROUND: Deoxythymidine triphosphate (dTTP) is an essential building block of DNA, and defects in enzymes involved in dTTP synthesis cause neurodegenerative disorders. For instance, mutations in DTYMK, the gene coding for thymidylate kinase (TMPK), cause severe microcephaly in human. However, the mechanism behind this is not well-understood. Here we used the zebrafish model and studied (i) TMPK, an enzyme required for both the de novo and the salvage pathways of dTTP synthesis, and (ii) thymidine kinases (TK) of the salvage pathway in order to understand their role in neuropathology. RESULTS: Our findings reveal that maternal-stored dNTPs are only sufficient for 6 cell division cycles, and the levels of dNTPs are inversely correlated to cell cycle length during early embryogenesis. TMPK and TK activities are prominent in the cytosol of embryos, larvae and adult fish and brain contains the highest TMPK activity. During early development, TMPK activity increased gradually from 6 hpf and a profound increase was observed at 72 hpf, and TMPK activity reached its maximal level at 96 hpf, and remained at high level until 144 hpf. The expression of dtymk encoded Dtymk protein correlated to its mRNA expression and neuronal development but not to the TMPK activity detected. However, despite the high TMPK activity detected at later stages of development, the Dtymk protein was undetectable. Furthermore, the TMPK enzyme detected at later stages showed similar biochemical properties as the Dtymk enzyme but was not recognized by the Dtymk specific antibody. CONCLUSIONS: Our results suggest that active dNTP synthesis in early embryogenesis is vital and that Dtymk is essential for neurodevelopment, which is supported by a recent study of dtymk knockout zebrafish with neurological disorder and lethal outcomes. Furthermore, there is a novel TMPK-like enzyme expressed at later stages of development.

Outcome of ERCP related to case-volume.

BACKGROUND AND AIMS: In some studies, high endoscopic retrograde cholangiopancreatography (ERCP) case-volume has been shown to correlate to high success rate in terms of successful cannulation and fewer adverse events. The aim of this study was to analyze the association between ERCP success and complications, and endoscopist and centre case-volumes. METHODS: Data were obtained from the Swedish National Register for Gallstone Surgery and ERCP (GallRiks) on all ERCPs performed for Common Bile Duct Stone (CBDS) (n = 17,873) and suspected or confirmed malignancy (n = 6152) between 2009 and 2018. Successful cannulation rate, procedure time, intra- and postoperative complication rates and post-ERCP pancreatitis (PEP) rate, were compared with endoscopist and centre ERCP case-volumes during the year preceding the procedure as predictor. RESULTS: In multivariable analyses of the CBDS group adjusting for age, gender and year, a high endoscopist case-volume was associated with higher successful cannulation rate, lower complication and PEP rates, and shorter procedure time (p < 0.05). Centres with a high annual case-volume were associated with high successful cannulation rate and shorter procedure time (p < 0.05), but not lower complication and PEP rates. When indication for ERCP was malignancy, a high endoscopist case-volume was associated with high successful cannulation rate and low PEP rates (p < 0.05), but not shorter procedure time or low complication rate. Centres with high case-volume were associated with high successful cannulation rate and low complication and PEP rates (p < 0.05), but not shorter procedure time. CONCLUSIONS: The results suggest that higher endoscopist and centre case-volumes are associated with safer ERCP and successful outcome.

Cardiovascular complications after common bile duct stone extractions.

BACKGROUND: Common bile duct stone (CBDS) is a common condition the rate of which increases with age. Decision to treat in particular elderly and frail patients with CBDS is often complex and requires careful assessment of the risk for treatment-related cardiovascular complications. The aim of this study was to compare the rate of postoperative cardiovascular events in CBDS patients treated with the following: ERCP only; cholecystectomy only; cholecystectomy followed by delayed ERCP; cholecystectomy together with ERCP; or ERCP followed by delayed cholecystectomy. METHODS: The study was based on data from procedures for gallstone disease registered in the Swedish National Quality Register for Cholecystectomy and Endoscopic Retrograde Cholangiopancreatography (GallRiks) 2006-2014. ERCP and cholecystectomy procedures performed for confirmed or suspected CBDS were included. Postoperative events were registered by cross-matching GallRiks with the National Patient Register (NPR). A postoperative cardiovascular event was defined as an ICD-code in the discharge notes indicating myocardial infarct, pulmonary embolism or cerebrovascular disease within 30 days after surgery. In cases where a patient had undergone ERCP and cholecystectomy on separate occasions, the 30-day interval was timed from the first intervention. RESULTS: A total of 23,591 underwent ERCP or cholecystectomy for CBDS during the study period. A postoperative cardiovascular event was registered in 164 patients and death within 30 days in 225 patients. In univariable analysis, adverse cardiovascular event and death within 30 days were more frequent in patients who underwent primary ERCP (p < 0.05). In multivariable analysis, adjusting for history of cardiovascular disease or events, neither risk for cardiovascular complication nor death within 30 days remained statistically significant in the ERCP group. CONCLUSIONS: Primary ERCP as well as cholecystectomy may be performed for CBDS with acceptable safety. More studies are required to provide reliable guidelines for the management of CBDS.

Feline thymidine kinase 1: molecular characterization and evaluation of its serum form as a diagnostic biomarker.

BACKGROUND: Thymidine kinase 1 (TK1) catalyzes the initial phosphorylation of thymidine in the salvage pathway synthesis of dTTP, an essential building block of DNA. TK1 is a cytosolic enzyme with its highest level during the S-phase of the cell cycle. In cancer cells TK1 is upregulated and excess TK1 is leaked into the blood. Therefore, serum TK1 has been used as biomarker for cancer diagnosis and prognosis in human medicine. Feline TK1 shows high sequence similarity to TK1 from other species. The aim of this study was to characterize feline TK1 and evaluate if serum TK1 can be used as a diagnostic biomarker. RESULTS: Feline TK1 was cloned, expressed and affinity purified. The purified feline TK1 phosphorylated not only pyrimidine deoxyribonucleosides but also pyrimidine ribonucleosides and to some extent purine deoxynucleosides. A number of anticancer and antiviral nucleoside analogs also served as substrates with fairly high efficiency. ATP and dATP were the preferred phosphate donor. Serum TK1 activity in felines with malignant diseases was significantly higher than that in healthy individuals. ROC analysis revealed an area under the curve (AUC) of 0.98 with a sensitivity of 0.83 and a specificity of 0.95 for felines with lymphoma. Serum TK1 activity in felines with IBD or inflammatory disease was within the same range as healthy ones. Furthermore, in felines with lymphoma serum TK1 activity returned to normal levels in response to treatment. CONCLUSION: Feline TK1 has high specific activity and a broader substrate specificity in comparison with TK1 from other species. Serum TK1 activity in felines with malignant diseases is significantly higher than that in normal felines and in felines with inflammatory diseases. These results suggest that serum TK1 may be a promising biomarker for the diagnosis and monitoring of malignant diseases and for the differential diagnosis of certain inflammatory disease.

Effects on walking performance and lower body strength by short message service guided training after stroke or transient ischemic attack (The STROKEWALK Study): a randomized controlled trial.

OBJECTIVE: To evaluate whetherdaily mobile-phone delivered messages with training instructions during three months increase physical activity and overall mobility in patients soon after stroke or transient ischemic attack. DESIGN: Randomised controlled trial with intention-to-treat analyses. SETTING: University hospital. Data collection from November 2016 until December2018. SUBJECTS: Seventy-nine patients (mean (SD) age 63.9 (10.4) years, 29 were women) were allocated to either intervention (n = 40) or control group (n = 39). Participants had to be independent (modified Ranking Scale ⩽2) and able to perform the six-minute walking test at discharge from the hospital. INTERVENTIONS: The intervention group received standard care and daily mobile phone instructional text messages to perform regular outdoor walking and functional leg exercises. The control group received standard care; that is, primary care follow-up. MAIN MEASURES: Walking performance by six-minute walking test (m), lower body strength by five times chair-stand test (s), the short physical performance battery (0-12 points) and 10-metres walk test (m/s) were assessed at baseline and after three months. RESULTS: The estimated median difference in the six-minute walking test was in favour of the intervention group by 30 metres (95% CI, 55 to 1; effect size 0.64; P = 0.037) and in the chair-stand test by 0.88 seconds (95% CI, 0.02 to 1.72; effect size 0.64; P = 0.034). There were no differences between groups on the short physical performance battery or in 10-metres walking time. CONCLUSIONS: Three months of daily mobile phone text messages with guided training instructions improved composite mobility measures; that is, walking performanceand lower body strength. CLINICAL TRIAL REGISTRY: The study is registered with ClinicalTrials.gov, number NCT02902367.

Postoperative rendezvous endoscopic retrograde cholangiopancreaticography as an option in the management of choledocholithiasis.

BACKGROUND: Rendezvous endoscopic retrograde cholangiopancreaticography (ERCP) is a well-established method for treatment of choledocholithiasis. The primary aim of this study was to determine how different techniques for management of common bile duct stone (CBDS) clearance in patients undergoing cholecystectomy have changed over time at tertiary referral hospitals (TRH) and county/community hospitals (CH). The secondary aim was to see if postoperative rendezvous ERCP is a safe, effective and feasible alternative to intraoperative rendezvous ERCP in the management of CBDS. METHODS: Data were retrieved from the Swedish registry for cholecystectomy and ERCP (GallRiks) 2006-2016. All cholecystectomies, where CBDS were found at intraoperative cholangiography, and with complete 30-day follow-up (n = 10,386) were identified. Data concerning intraoperative and postoperative complications, readmission and reoperation within 30 days were retrieved for patients where intraoperative ERCP (n = 2290) and preparation for postoperative ERCP were performed (n = 2283). RESULTS: Intraoperative ERCP increased (7.5% 2006; 43.1% 2016) whereas preparation for postoperative ERCP decreased (21.2% 2006; 17.2% 2016) during 2006-2016. CBDS management differed between TRHs and CHs. Complications were higher in the postoperative rendezvous ERCP group: Odds Ratio [OR] 1.69 (95% confidence interval [CI] 1.16-2.45) for intraoperative complications and OR 1.50 (CI 1.29-1.75) for postoperative complications. Intraoperative bleeding OR 2.46 (CI 1.17-5.16), postoperative bile leakage OR 1.89 (CI 1.23-2.90) and postoperative infection with abscess OR 1.55 (CI 1.05-2.29) were higher in the postoperative group. Neither post-ERCP pancreatitis, postoperative bleeding, cholangitis, percutaneous drainage, antibiotic treatment, ICU stay, readmission/reoperation within 30 days nor 30-day mortality differed between groups. CONCLUSIONS: Techniques for management of CBDS found at cholecystectomy have changed over time and differ between TRH and CH. Rendezvous ERCP is a safe and effective method. Even though intraoperative rendezvous ERCP is the preferred method, postoperative rendezvous ERCP constitutes an acceptable alternative where ERCP resources are lacking or limited.

The combination of AroCell TK 210 ELISA with Prostate Health Index or prostate-specific antigen density can improve the ability to differentiate prostate cancer from noncancerous conditions.

BACKGROUND: Prostate-specific antigen (PSA) is an established tumour marker for prostate cancer (PCa). Serum thymidine kinase 1 is a possible new marker for the detection of PCa. The aim of the study was to investigate the diagnostic value of the AroCell TK 210 enzyme-linked immunosorbent assay (ELISA) together with free PSA, [-2]proPSA, and Prostate Health Index (PHI) in differentiating PCa from benign urological conditions. METHODS: Serum samples from 140 patients with PSA values in the range between 2 and 10 µg/L were collected at the Ljubljana University Medical Centre and the Maribor University Medical Centre. Thymidine kinase (TK1) protein levels were determined using the AroCell TK 210 ELISA and PSA-related parameters analysed with commercial assays. RESULTS: Serum TK1 protein, total and free PSA, proPSA, PSA density (PSAD), and PHI levels in patients with confirmed PCa were significantly higher than in patients with benign urological conditions (P < 0.05). Overall, the AroCell TK 210 ELISA results showed a significant correlation with PHI ( r = 0.25, P = 0.0031). Receiver-operating characteristic curve analyses were used to compare the area under the curve (AUC) of TK 210 ELISA, PHI, and PSA density. For PHI, the AUC was 0.73, comparable to those of TK 210 ELISA (0.67) and PSAD (0.66), with no significant differences in pairwise comparisons (PHI vs TK 210 ELISA P = 0.32, PHI vs PSAD P = 0.24, and TK 210 ELISA vs PSAD P = 0.95). The AUC for the combination of TK1 plus PSAD was significantly higher than those for the individual PSA-related biomarkers and marginally PHI, while the AUC for the combination of TK1 plus PHI was significantly higher than those for the individual PSA-related biomarkers except for PHI and marginally for PSAD. Total PSA concentration was the only marker, that was significantly higher in patients with an increasing Gleason grade. CONCLUSIONS: These results suggest that TK1 protein determinations together with PHI or PSAD could be a valuable additional tool in PCa management.

A small difference in recovery between total knee arthroplasty with and without tourniquet use the first 3 months after surgery: a randomized controlled study.

PURPOSE: When a tourniquet is used during surgery on the extremities, the pressure applied to the muscles, nerves and blood vessels can cause neuromuscular damage that contributes to postoperative weakness. The hypothesis was that the rehabilitation-related results would be improved if total knee arthroplasty (TKA) is performed without the use of a tourniquet. METHODS: 81 patients with osteoarthritis of the knee who underwent TKA surgery were randomized to surgery with or without tourniquet. Active flexion and extension of the knee, pain by visual analog scale (VAS), swelling by knee circumference, quadriceps function by straight leg raise, and timed up and go (TUG) test results were measured before and up to 3 months after surgery. RESULTS: ANCOVA revealed no between-groups effect for flexion of the knee at day 3 postsurgery. Compared with the tourniquet group, the nontourniquet group experienced elevated pain at 24 h, with a mean difference of 16.6 mm, p = 0.005. The effect on mobility (TUG test) at 3 months was better in the nontourniquet group, with a mean difference of -1.1 s, p = 0.029. CONCLUSIONS: The hypothesis that the rehabilitation-related results would be improved without a tourniquet is not supported by the results. When the results in this study for surgery performed with and without tourniquet are compared, no clear benefit for either procedure was observed, as the more pain exhibited by the nontourniquet group was only evident for a short period and the improved mobility in this group was not at a clinically relevant level. LEVEL OF EVIDENCE: Inconsistent results, Level II.

One-Year Adherence to the Otago Exercise Program With or Without Motivational Interviewing in Community-Dwelling Older Adults.

This study investigated if behavioral factors, treatment with behavioral support, readiness to change, fall self-efficacy, and activity habits could predict long-term adherence to an exercise program. Included in this study were 114 community-dwelling older adults who had participated in one of two home-based exercise interventions. Behavioral factors associated with adherence to the exercise program over 52 weeks were analyzed. The behavioral factors, specifically activity habits at baseline, significantly predicted adherence to the exercise program, with an odds ratio = 3.39, 95% confidence interval [1.38, 8.32], for exercise and an odds ratio = 6.11, 95% confidence interval [2.34, 15.94], for walks. Being allocated to a specific treatment including motivational interviewing was also significantly predictive: odds ratio = 2.47, 95% confidence interval [1.11, 5.49] for exercise adherence. In conclusion, activity habits and exercise in combination with motivational interviewing had a significant association with adherence to the exercise program at a 1-year follow-up.

Thymidine kinase 1 expression in ovarian serous adenocarcinoma is superior to Ki-67: A new prognostic biomarker.

Cancer is a disease with abnormally proliferating cells and therefore proliferation rate is an important index for assessing tumour growth. Ki-67 is a commonly used proliferation marker considered to be an unfavourable prognostic marker in some tumors, while Thymidine kinase 1 (TK1) is an interesting proliferation marker because its levels are highly dependent on the growth stage of cells. To define the immunohistochemistry (IHC) expression of the TK1 in patients with ovarian serous adenocarcinoma and establish its potential role as a new biomarker for progressive disease, we analyzed the expression patterns of TK1 and Ki-67 in 109 patients with ovarian serous adenocarcinoma. TK1 and Ki-67 expression both showed a statistically significant correlation to MD Anderson Cancer Center (MDACC) grade, but not to age, tumour size, lymph node metastasis or pathological TNM (pTNM) stages. TK1 expression, MDACC grades, pathological stages and lymph node metastasis correlate to relapse incident rate and overall survival, but Ki-67 does not. Although TK1 expression, MDACC grade, pTNM stage and lymph node metastasis significantly correlate to relapse in the Cox univariate analysis, in the multivariate Cox analysis only TK1 expression and lymph node metastasis were independent prognostic factors. The overall survival also correlated significantly to TK1 expression, MDACC grade, pTNM stage and lymph node metastasis in the Cox univariate analysis. However, only the pTNM stage was found to be an independent prognostic factor for survival in the Cox multivariate analysis. Therefore, though TK1 expression was an independent prognostic factor for relapse, but not for survival, TK1 is a more informative expression than Ki-67 for LI, relapse and overall survival rates. Thus, when TK1 is combined with MDACC grading, pTNM staging and lymph node metastasis, IHC determination of TK1 expression may improve the overall prediction of prognosis in patients with ovarian cancer.

The Nordic SentiMag trial: a comparison of super paramagnetic iron oxide (SPIO) nanoparticles versus Tc(99) and patent blue in the detection of sentinel node (SN) in patients with breast cancer and a meta-analysis of earlier studies.

The aim of the study is to compare the efficacy of SPIO as a tracer in sentinel node biopsy (SNB) in breast cancer with Tc and patent blue in a multicentre prospective study and perform a meta-analysis of all published studies. It also aims to follow skin discoloration after SPIO injection and describe when and how it resolves. Totally 206 patients with early breast cancer were recruited. Tc and patent blue were administered in standard fashion. Patients were injected with SPIO (Sienna+) preoperatively. SNB was performed and detection rates were recorded for both methods. Skin discoloration was followed and documented postoperatively. Data extraction and subsequent meta-analysis of all previous studies were also performed. SN detection rates were similar between standard technique succeeded and SPIO both per patient (97.1 vs. 97.6 %, p = 0.76) as well as per node (91.3 vs. 93.3 %, p = 0.34), something which was not affected by the presence of malignancy. Concordance rates were also consistently high (98.0 % per patient and 95.9 % per node). Discoloring was present in 35.5 % of patients postoperatively, almost exclusively in breast conservation. It fades slowly and is still detectable in 8.6 % of patients after 15 months. Meta-analysis depicted similar detection rates (p = 0.71) and concordance rates (p = 0.82) per patient. However, it seems that SPIO is characterized by higher nodal retrieval (p < 0.001). SPIO is an effective method for the detection of SN in patients with breast cancer. It is comparable to the standard technique and seems to simplify logistics. Potential skin discoloration is something of consideration in patients planned for breast conservation.

The potential for chemical mixtures from the environment to enable the cancer hallmark of sustained proliferative signalling.

The aim of this work is to review current knowledge relating the established cancer hallmark, sustained cell proliferation to the existence of chemicals present as low dose mixtures in the environment. Normal cell proliferation is under tight control, i.e. cells respond to a signal to proliferate, and although most cells continue to proliferate into adult life, the multiplication ceases once the stimulatory signal disappears or if the cells are exposed to growth inhibitory signals. Under such circumstances, normal cells remain quiescent until they are stimulated to resume further proliferation. In contrast, tumour cells are unable to halt proliferation, either when subjected to growth inhibitory signals or in the absence of growth stimulatory signals. Environmental chemicals with carcinogenic potential may cause sustained cell proliferation by interfering with some cell proliferation control mechanisms committing cells to an indefinite proliferative span.

Breast and prostate cancer patients differ significantly in their serum Thymidine kinase 1 (TK1) specific activities compared with those hematological malignancies and blood donors: implications of using serum TK1 as a biomarker.

BACKGROUND: Thymidine kinase 1 (TK1) is a cellular enzyme involved in DNA precursor synthesis, and its activity has been used as a proliferation marker for monitoring malignant diseases. Here, for the first time, we evaluated both TK1 activity and protein levels in sera from patients with different malignancies. METHODS: Serum samples from patients with myelodysplastic syndrome (MDS, n = 22), breast cancer (n = 42), prostate cancer (n = 47) and blood donors (n = 30) were analyzed for TK1 protein and activity levels, using a serum TK1 (STK1) protein assay based on antibodies and an activity assay that measured [(3)H]-deoxythymidine (dThd) phosphorylation. The molecular forms of TK1 in sera from some of these patients were analyzed using size-exclusion chromatography. RESULTS: Mean STK1 activities in sera from MDS, breast and prostate cancer were 11 ± 17.5, 6.7 ± 19 and 1.8 ± 1.4 pmol/min/mL, differing significantly from blood donors (mean ± standard deviation (SD) = 1.1 ± 0.9 pmol/min/mL). Serum TK1 protein (25 kDa polypeptide) levels were also significantly higher in MDS, breast, prostate cancer compared to blood donors (mean ± SD = 19 ± 9, 22 ± 11, 20 ± 12, and 5 ± 3.5 ng/mL, respectively). The STK1 specific activities of sera from patients with MDS and blood donors were significantly higher when compared with activities in sera from breast and prostate cancer patients. Size-exclusion analysis of sera from breast and prostate cancer showed that the detected active TK1 was primarily a high molecular weight complex, similar to the forms found in sera from MDS patients and blood donors. However, Western blotting demonstrated high TK1 25 kDa protein levels in fractions lacking TK1 activity in sera from cases with breast and prostate cancer. CONCLUSIONS: These results demonstrate that there are differences in the specific activities and the subunit compositions of STK1 in hematological malignancies compared with breast and prostate cancer. This fact has several important implications for the use of STK1 as a tumor biomarker. One is that STK1 protein assays may differentiate early-stage tumor development in breast and prostate cancer more effectively than STK1 activity assays.

Zidovudine induces downregulation of mitochondrial deoxynucleoside kinases: implications for mitochondrial toxicity of antiviral nucleoside analogs.

Mitochondrial thymidine kinase 2 (TK2) and deoxyguanosine kinase (dGK) catalyze the initial phosphorylation of deoxynucleosides in the synthesis of the DNA precursors required for mitochondrial DNA (mtDNA) replication and are essential for mitochondrial function. Antiviral nucleosides are known to cause toxic mitochondrial side effects. Here, we examined the effects of 3'-azido-2',3'-dideoxythymidine (AZT) (zidovudine) on mitochondrial TK2 and dGK levels and found that AZT treatment led to downregulation of mitochondrial TK2 and dGK in U2OS cells, whereas cytosolic deoxycytidine kinase (dCK) and thymidine kinase 1 (TK1) levels were not affected. The AZT effects on mitochondrial TK2 and dGK were similar to those of oxidants (e.g., hydrogen peroxide); therefore, we examined the oxidative effects of AZT. We found a modest increase in cellular reactive oxygen species (ROS) levels in the AZT-treated cells. The addition of uridine to AZT-treated cells reduced ROS levels and protein oxidation and prevented the degradation of mitochondrial TK2 and dGK. In organello studies indicated that the degradation of mitochondrial TK2 and dGK is a mitochondrial event. These results suggest that downregulation of mitochondrial TK2 and dGK may lead to decreased mitochondrial DNA precursor pools and eventually mtDNA depletion, which has significant implications for the regulation of mitochondrial nucleotide biosynthesis and for antiviral therapy using nucleoside analogs.

Down-regulation of mitochondrial thymidine kinase 2 and deoxyguanosine kinase by didanosine: implication for mitochondrial toxicities of anti-HIV nucleoside analogs.

Mitochondrial thymidine kinase 2 (TK2) and deoxyguanosine kinase (dGK) catalyze the initial rate limiting phosphorylation of deoxynucleosides and are essential enzymes for mitochondrial function. Chemotherapy using nucleoside analogs is often associated with mitochondrial toxicities. Here we showed that incubation of U2OS cells with didanosine (ddI, 2',3'-dideoxyinosine), a purine nucleoside analog used in the highly active antiretroviral therapy (HAART), led to selective degradation of both mitochondrial TK2 and dGK while the cytosolic deoxycytidine kinase (dCK) and thymidine kinase 1 (TK1) were not affected. Addition of guanosine to the ddI-treated cells prevented the degradation of mitochondrial TK2 and dGK. The levels of intracellular reactive oxygen species and protein oxidation in ddI-treated and control cells were also measured. The results suggest that down-regulation of mitochondrial TK2 and dGK may be a mechanism of mitochondrial toxicity caused by antiviral and anticancer nucleoside analogs.