Anatomical relationships between medullary veins and three types of deep-seated malignant brain tumors as detected by susceptibility-weighted imaging.

BACKGROUND: Deep-seated brain tumors can be difficult to differentiate. Three tumor types (primary central nervous system lymphoma [PCNSL], high-grade glioma, and metastatic brain tumors), identified by susceptibility-weighted imaging, have different relationships with small medullary veins, and these relationships can be used to enhance diagnostic accuracy. METHODS: Records of patients with pathology confirmed malignant brain tumors who received susceptibility-weighted imaging between 2009 and 2015 were reviewed. A total of 29 patients with deep-seated malignant brain tumors in the territory of small medullary veins were enrolled in this study. The sensitivity, specificity, and diagnostic accuracy of medullary vein blockage (MVB), defined as a small medullary vein terminating at the margin of the tumor, for indicating malignant brain tumors were analyzed. RESULTS: Of 11 patients with PCNSLs, 5 with high-grade gliomas, and 13 with metastases, only the latter presented MVBs. The sensitivity, specificity, and accuracy of using MVBs for diagnosing metastatic tumors were 76.9%, 100%, and 89.7%, respectively. CONCLUSION: An MVB is an accurate sign for differentiating metastatic brain tumors from two other common malignancies and thus provides a useful tool for preoperative planning.

Designing de Novo Small Molecules That Control Heat Shock Protein 70 (Hsp70) and Heat Shock Organizing Protein (HOP) within the Chaperone Protein-Folding Machinery.

Protein-protein interactions (PPIs) regulate all signaling pathways for cellular function. Developing molecules that modulate PPIs through the interface of their protein surfaces has been a significant challenge and there has been little success controlling PPIs through standard molecular library screening approaches. PPIs control the cell's protein-folding machinery, and this machinery relies on a multiprotein complex formed with heat shock protein 70 (Hsp70). Described is the design, synthesis, and biological evaluation of molecules aimed to regulate the interaction between two proteins that are critical to the protein-folding machinery: heat shock protein 70 (Hsp70) and cochaperone heat shock organizing protein (HOP). We report the first class of compounds that directly regulate these two protein-protein interactions and inhibit protein folding events.

Propensity score-matched comparison of oncological outcomes between laparoscopic and open distal pancreatic resection.

BACKGROUND: Selected studies have reported improved outcomes in laparoscopic compared with open distal pancreatic resection. Concerns regarding failure to achieve proper oncological resection and compromised long-term outcomes remain. This study investigated whether postoperative outcomes and long-term survival after laparoscopic distal pancreatectomy are comparable to those after an open procedure. METHODS: This retrospective case-control study included patients who underwent distal pancreatectomy for resectable pancreatic adenocarcinoma between 2010 and 2013, identified from the National Cancer Database. Propensity score nearest-neighbour 1 : 1 matching was performed between patients undergoing laparoscopic or open distal pancreatectomy based on all relevant co-variables. The primary outcome was overall survival. RESULTS: Of 1947 eligible patients, 605 (31·1 per cent) underwent laparoscopic distal pancreatectomy. After propensity score matching, two well balanced groups of 563 patients each were analysed. There was no difference in overall survival at 3 years after laparoscopic versus open distal pancreatectomy (41·6 versus 36·0 per cent; hazard ratio 0·93, 95 per cent c.i. 0·77 to 1·12; P = 0·457). The overall conversion rate was 27·3 per cent (165 of 605). Patients who underwent laparoscopic distal pancreatectomy had outcomes comparable to those of patients who had an open procedure with regard to median time to chemotherapy (50 versus 50 days; P = 0·342), median number of nodes examined (12 versus 12; P = 0·759); 30-day mortality (1·2 versus 0·9 per cent; P = 0·562); 90-day mortality (2·8 versus 3·7 per cent; P = 0·403), 30-day readmission rate (9·6 versus 9·2 per cent; P = 0·838) and positive margin rate (14·9 versus 18·5 per cent; P = 0·110). However, median duration of hospital stay was shorter in the laparoscopic group (6 versus 7 days; P < 0·001). CONCLUSION: Laparoscopic distal pancreatectomy is an acceptable alternative to open distal pancreatectomy with no detriment to survival.

Genome-wide DNA methylation profiling reveals cancer-associated changes within early colonic neoplasia.

Colorectal cancer (CRC) is characterized by genome-wide alterations to DNA methylation that influence gene expression and genomic stability. Less is known about the extent to which methylation is disrupted in the earliest stages of CRC development. In this study, we have combined laser-capture microdissection with reduced representation bisulfite sequencing to identify cancer-associated DNA methylation changes in human aberrant crypt foci (ACF), the earliest putative precursor to CRC. Using this approach, methylation profiles have been generated for 10 KRAS-mutant ACF and 10 CRCs harboring a KRAS mutation, as well as matched samples of normal mucosa. Of 811 differentially methylated regions (DMRs) identified in ACF, 537 (66%) were hypermethylated and 274 (34%) were hypomethylated. DMRs located within intergenic regions were heavily enriched for AP-1 transcription factor binding sites and were frequently hypomethylated. Furthermore, gene ontology analysis demonstrated that DMRs associated with promoters were enriched for genes involved in intestinal development, including homeobox genes and targets of the Polycomb repressive complex 2. Consistent with their role in the earliest stages of colonic neoplasia, 75% of the loci harboring methylation changes in ACF were also altered in CRC samples, though the magnitude of change at these sites was lesser in ACF. Although aberrant promoter methylation was associated with altered gene expression in CRC, this was not the case in ACF, suggesting the insufficiency of methylation changes to modulate gene expression in early colonic neoplasia. Altogether, these data demonstrate that DNA methylation changes, including significant hypermethylation, occur more frequently in early colonic neoplasia than previously believed, and identify epigenomic features of ACF that may provide new targets for cancer chemoprevention or lead to the development of new biomarkers for CRC risk.

A practical guide to development of a successful robotic abdominal surgery program: The path to implementation.

The authors describe current situation in robotic assisted operations. The most important aspects of establishing a successful robotic program are patience and flexibility. The improved patient satisfaction, return to function, and decreased perioperative pain for patients and surgeons will be seen, but the road is long and requires careful navigation.Key Words: robot abdominal surgery - program development.

In vitro detection of cholangiocarcinoma cells using a fluorescent protein-expressing oncolytic herpes virus.

Pathological confirmation is desired prior to high-risk surgery for suspected perihilar cholangiocarcinoma (PHC), but preoperative tissue diagnosis is limited by poor sensitivity of available techniques. This study aimed to validate whether a tumor-specific enhanced green fluorescent protein (eGFP)-expressing oncolytic virus could be used for cholangiocarcinoma (CC) cell detection. Extrahepatic CC cell lines SK-ChA-1, EGI-1, TFK-1 and control cells (primary human liver cells) were exposed to the oncolytic herpes simplex type 1 virus NV1066 for up to 24 h in adherent culture. The technique was validated for cells in suspension and cultured cells that had been exposed to crude patient bile. Optimal incubation time of the CC cells with NV1066 at a multiplicity of infection of 0.1 was determined at 6-8 h, yielding 15% eGFP-expressing cells, as measured by flow cytometry. Cells were able to survive 2-h crude bile exposure and remained capable of producing eGFP following NV1066 infection. Detection of malignant cells was possible at the highest dilution tested (10 CC cells among 2 × 105 control cells), though hampered by non-target cell autofluorescence. The technique was not applicable to cells in suspension due to insufficient eGFP production. Accordingly, as yet the technique is not suitable for standardized clinical diagnostics in PHC.

Predicting Mortality in Patients With "Malignant" Middle Cerebral Artery Infarction Using Susceptibility-Weighted Magnetic Resonance Imaging: Preliminary Findings.

To evaluate malignant middle cerebral artery (MCA) infarction (defined as space-occupying edema in more than 50% to 75% of the MCA territory) on magnetic resonance imaging (MRI) with susceptibility-weighted imaging (SWI) sequence and assess the usefulness of SWI findings, diffusion-weighted imaging (DWI) findings, and apparent diffusion coefficient (ADC) as predictors of clinical outcome.Data from 16 patients with large MCA infarction previously admitted to our institution between December 2009 and October 2012 were retrospectively collected and analyzed. Within 7 days after stroke onset, 1 neurologist and 1 neuroradiologist estimated the area of infarction on DWI/ADC and extent of prominent vessel sign (PVS) on SWI images using the Stroke Program Early MR Score (SPEMRS). The PVS on SWI was defined as a local prominence of hypointense vessels with either increased vessel number or diameter in the target area, when compared with the number or diameter of the contralateral MCA territory vessels.Six patients died and 10 survived. Although the DWI/ADC-SPEMRS and clinical profiles were similar between the nonsurvivor and survivor groups, SWI-SPEMRS was significantly lower in the nonsurvivor group (P < 0.001).The area of deoxygenation on SWI in patients with malignant MCA infarction can predict mortality. Lower SWI-SPEMRS is a potentially better predictor of poor outcome than lower DWI-SPEMRS. A larger prospective study is needed to clarify the role of SWI as a therapeutic guide in malignant MCA.

In men at risk of HIV infection, IgM, IgG1, IgG3, and IgA reach the human foreskin epidermis.

We profiled the humoral response in the penis, an area that has been minimally explored but may be relevant for protecting insertive men against HIV and other sexually acquired infections. Comparing paired tissue samples from 20 men at risk of HIV infection, foreskin contains less immunoglobulin A (IgA) and more IgG2 than colon. Using foreskin dermal and epidermal explants and paired plasma from 17 men, we examined Ig accumulation by normalizing Ig to human serum albumin (HSA) transudation. Dermal IgM, IgG2, IgA, and IgE ratios were greater than that in plasma, suggesting there is local antibody secretion at the dermis. Local Ig transcription was concentrated at the inner rather than the outer foreskin, and inner foreskin Ig ratios did not correlate with blood, indicating that localized production can contribute to the foreskin response. IgM, IgG1, IgG3, and IgA have preferential access to the foreskin epidermis, whereas IgG2, IgG4, and IgE are restricted to the dermis. Lastly, Ad5-specific IgA was selectively present in the colon, whereas foreskin Ad5 IgG was mainly derived from blood, and reached the inner epidermis at higher ratios than the outer (P<0.002). In summary, the foreskin antibody response combines local and systemic sources, and there is selective isotype accumulation in the epidermis.

Temperature monitoring during microwave ablation in ex vivo porcine livers.

OBJECTIVE: The aim of the present study was to assess the temperature map and its reproducibility while applying two different MWA systems (915 MHz vs 2.45 GHz) in ex vivo porcine livers. MATERIALS AND METHODS: Fifteen fresh pig livers were treated using the two antennae at three different settings: treatment time of 10 min and power of 45 W for both systems; 4 min and 100 W for the 2.45 GHz system. Trends of temperature were recorded during all procedures by means of fiber optic-based probes located at five fixed distances from the antenna, ranging between 10 mm and 30 mm. Each trial was repeated twice to assess the reproducibility of temperature distribution. RESULTS: Temperature as function of distance from the antenna can be modeled by a decreasing exponential trend. At the same settings, temperature obtained with the 2.45 GHz system was higher than that obtained with the 915 MHz thus resulting into a wider area of ablation (diameter 17 mm vs 15 mm). Both systems showed good reproducibility in terms of temperature distribution (root mean squared difference for both systems ranged between 2.8 °C and 3.4 °C). CONCLUSIONS: When both MWA systems are applied, a decreasing exponential model can predict the temperature map. The 2.45 GHz antenna causes higher temperatures as compared to the 915 MHz thus, resulting into larger areas of ablation. Both systems showed good reproducibility although better results were achieved with the 2.45 GHz antenna.

Prominent vessel sign on susceptibility-weighted imaging in acute stroke: prediction of infarct growth and clinical outcome.

BACKGROUND AND PURPOSE: Predicting the risk of further infarct growth in stroke patients is critical to therapeutic decision making. We aimed to predict early infarct growth and clinical outcome from prominent vessel sign (PVS) identified on the first susceptibility-weighted image (SWI) after acute stroke. MATERIALS AND METHODS: Twenty-two patients with middle cerebral artery (MCA) infarction had diffusion-weighted imaging, SWI, MR angiography, and clinical evaluation using the National Institutes of Health Stroke Scale at 7-60 hours and 5-14 days after stroke onset. Late-stage clinical evaluation at 1 and 3 months used the modified Rankin Scale. The infarct area and growth were scored from 10 (none) to 0 (infarct or growth in all 10 zones) using the Alberta Stroke Program Early CT Score (ASPECTS) system. RESULTS: Infarct growth on the second MRI occurred in 13 of 15 patients with PVS on the first MRI and not in any patient without PVS (n=7; r=0.86, P<0.001). The extent of PVS was significantly correlated with infarct growth (r=0.82, P<0.001) and early-stage outcome (P=0.02). No between-group difference in late-stage clinical outcome was found. CONCLUSION: PVS on the first SWI after acute MCA territory stroke is a useful predictor of early infarct growth. Extensive PVS within the large MCA territory is related to poor early-stage outcome and could be useful for clinical assessment of stroke.

The Nottingham Prognostic Index: five- and ten-year data for all-cause survival within a screened population.

INTRODUCTION: The Nottingham Prognostic Index (NPI) is an established prognostication tool in the management of breast cancers (BCs). Latest ten-year survival data have demonstrated an improved outlook for each NPI category and the latest UK five- and ten-year survival from BC has been reported to be 85% and 77%, respectively. We compared survival of each NPI category for BCs diagnosed within the national breast screening service in Wales (Breast Test Wales (BTW)) to the latest data, and reviewed its validity in unselected cases within a screened population. METHODS: All women screened between 1998 and 2001 within BTW were included. The NPI score for each cancer was calculated using the size, nodal status, and grade of the primary tumour. Survival data (all-cause) were calculated after ten years of follow-up. RESULTS: In the three-year screening period, 199,082 women were screened. A total of 1,712 cancers were diagnosed, and 1,546 had data available for calculating the NPI. Overall five-year and ten-year survival was 94% and 82%, respectively. CONCLUSIONS: Overall five-year and ten-year survival (all-cause) has improved even when compared with UK data for BC-specific survival. We found that the NPI remains valid for BC treatment, and that our data provide a reference for updating the all-cause survival of women diagnosed with BCs within a screened population.

Long-term outcomes following microwave ablation for liver malignancies.

BACKGROUND: Microwave ablation has emerged as a promising treatment for liver malignancies, but there are scant long-term follow-up data. This study evaluated long-term outcomes, with a comparison of 915-MHz and 2.4-GHz ablation systems. METHODS: This was a retrospective review of patients with malignant liver tumours undergoing operative microwave ablation with or without liver resection between 2008 and 2013. Regional or systemic (neo)adjuvant therapy was given selectively. Local recurrence was analysed using competing-risk methods with clustering, and overall survival was determined from Kaplan-Meier curves. RESULTS: A total of 176 patients with 416 tumours were analysed. Colorectal liver metastases (CRLM) comprised 81.0 per cent of tumours, hepatocellular carcinoma 8.4 per cent, primary biliary cancer 1.7 per cent and non-CRLM 8.9 per cent. Median follow-up was 20.5 months. Local recurrence developed after treatment of 33 tumours (7.9 per cent) in 31 patients (17.6 per cent). Recurrence rates increased with tumour size, and were 1.0, 9.3 and 33 per cent for lesions smaller than 1 cm, 1-3 cm and larger than 3 cm respectively. On univariable analysis, the local recurrence rate was higher after ablation of larger tumours (hazard ratio (HR) 2.05 per cm; P < 0.001), in those with a perivascular (HR 3.71; P = 0.001) or subcapsular (HR 2.71; P = 0.008) location, or biliary or non-CRLM histology (HR 2.47; P = 0.036), and with use of the 2.4-GHz ablation system (HR 3.79; P = 0.001). Tumour size (P < 0.001) and perivascular position (P = 0.045) remained significant independent predictors on multivariable analysis. Regional chemotherapy was associated with decreased local recurrence (HR 0.49; P = 0.049). Overall survival at 4 years was 58.3 per cent for CRLM and 79.4 per cent for other pathology (P = 0.360). CONCLUSION: Microwave ablation of liver malignancies, either combined or not combined with liver resection, and selective regional and systemic therapy resulted in good long-term survival. Local recurrence rates were low after treatment of tumours smaller than 3 cm in diameter, and those remote from vessels.

Intracranial venous hemodynamics and rupture of cerebral aneurysm.

Many uncertain and inconsistent etiologies of cerebral aneurysmal rupture including a wide spectrum of factors have been reported. Our recent observation discloses the potential new factor of cerebral aneurysm rupture with cerebral venous pressure gradient. We retrospectively reviewed 52 cases treated with coil embolization with or without cerebral aneurysmal rupture. Seventeen males and 30 females were recruited in this study. Quantitative color-coded cerebral angiography was performed during coil therapeutic procedures to measure cerebral venous circulation. Ruptured cases had shorter and symmetrical cerebral venous circulation time (P <0.05). In addition, an asymmetrical venous outflow pattern was critical for aneurysmal rupture. Non-ruptured cases tended to have slower and asymmetrical cerebral venous circulation compared with rupture cases. Symmetrical and shorter cerebral venous circulation in the dysplasia venous outlet may be a potential new factor for cerebral aneurysm rupture.

Role of MAPK in oncolytic herpes viral therapy in triple-negative breast cancer.

Triple-negative breast cancers (TNBCs) have poor clinical outcomes owing to a lack of targeted therapies. Activation of the MEK/MAPK pathway in TNBC has been associated with resistance to conventional chemotherapy and biologic agents and has a significant role in poor clinical outcomes. NV1066, a replication-competent herpes virus, infected, replicated in and killed all TNBC cell lines (MDA-MB-231, HCC1806, HCC38, HCC1937, HCC1143) tested. Greater than 90% cell kill was achieved in more-sensitive lines (MDA-MB-231, HCC1806, HCC38) by day 6 at a multiplicity of infection (MOI) of 0.1. In less-sensitive lines (HCC1937, HCC1143), NV1066 still achieved >70% cell kill by day 7 (MOI 1.0). In vivo, mean volume of flank tumors 14 days after treatment with NV1066 was 57 versus 438 mm(3) in controls (P=0.002). NV1066 significantly downregulated p-MAPK activation by 48 h in all cell lines in vitro and in MDA-MB-231 xenografts in vivo. NV1066 demonstrated synergistic effects with a MEK inhibitor, PD98059 in vitro. We demonstrate that oncolytic viral therapy (NV1066) effectively treats TNBC with correlation to decreased MEK/MAPK signaling. These findings merit future studies investigating the potential role of NV1066 as a sensitizing agent for conventional chemotherapeutic and biologic agents by downregulating the MAPK signaling pathway.

Hepatic arterial infusion pump chemotherapy in the management of colorectal liver metastases: expert consensus statement.

Despite significant improvements in systemic therapy for patients with colorectal liver metastases (crlms), response rates in the first-line setting are not optimal, and response rates in the second-line setting remain disappointing. Hepatic arterial infusion pump (haip) chemotherapy has been extensively studied in patients with crlms, but it remains infrequently used. We convened an expert panel to discuss the role of haip in the contemporary management of patients with crlm. Using a consensus process, we developed these statements: haip chemotherapy should be given in combination with systemic chemotherapy.haip chemotherapy should be offered in the context of a multidisciplinary program that includes expertise in hepatobiliary surgery, medical oncology, interventional radiology, nursing, and nuclear medicine.haip chemotherapy in combination with systemic therapy should be considered in patients with unresectable crlms who have progressed on first-line systemic treatment. In addition, haip chemotherapy is acceptable as first-line treatment in patients with unresectable colorectal liver metastases.haip chemotherapy is not recommended in the setting of extrahepatic disease outside the context of a clinical trial.haip chemotherapy in combination with systemic therapy is an option for select patients with resected colorectal liver metastases. These consensus statements provide a framework that clinicians who treat patients with crlm can use when considering treatment with haip.

The incidence and 10-year survival of interval breast cancers in Wales.

AIM: To evaluate the number of interval cancers (IC) within one screening cycle and the overall 10-year survival of IC, including its four main classifications, and compare that to screen-detected cancers (SDC). MATERIALS AND METHODS: Within Breast Test Wales (BTW), all SDC between the years 1998 and 2001 were included. IC that occurred between 1998 and 2003 that had undergone screening between the years 1998 and 2001 were also included. These IC were classified into true interval (TI), false negative (FN), occult cancer (OCC), and unclassified cancer (UCC). BTW received notification of all deaths of women that had undergone screening; thus, the 10-year all-cause survival rate was calculated from the date of diagnosis and death. RESULTS: During the study period, 199,082 women attended screening. Of these, 1020 (0.51%) women had SDC and 692 (0.38%) women developed IC. Of the 692 IC, 391 (57.8%) were TI, 120 (17.7%) were FN, 68 (10%) were OCC, and 98 (14.5%) were UCC; 15 (2.2%) were not classified. After a 10-year follow-up period, the 10-year survival rate (all-cause) for SDC was 81.6%, overall for all of IC was 72.4% (OR = 1.67, p < 0.001), TI was 77.5% (OR = 1.00, p = 0.99), FN was 55% (OR = 2.36, p < 0.001), OCC was 54.4% (OR = 3.17, p < 0.001), and UCC was 87.8% (OR = 0.61, p = 0.19). CONCLUSIONS: The overall 10-year survival of IC was significantly different to SDC. However, within this, the prognosis of TI was similar to SDC, whereas FN and OCC had significantly worse long-term survival. Further research is required to identify the underlying cause of poor survival of FN and OCC.

Oncolytic vaccinia virus in combination with radiation shows synergistic antitumor efficacy in pancreatic cancer.

Combining oncolytic viruses with conventional therapy such as radiation is an innovative option for pancreatic cancer. We demonstrated that combination of GLV-1h151 and radiation yielded a synergistic cytotoxic effect, with the greatest effect achieved in the AsPC-1cell line. Combination treatment significantly increased apoptosis compared with either single treatment or the control group. In mice bearing human pancreatic tumor xenografts, combination treatment resulted in significantly enhanced inhibition of tumor growth. No evidence of toxicity was observed in mice. These results indicate that the combination of GLV-1h151 and radiation has great potential for translation into clinic practice.

Advanced MR imaging of gliomas: an update.

Recent advances in the treatment of cerebral gliomas have increased the demands on noninvasive neuroimaging for the diagnosis, therapeutic planning, tumor monitoring, and patient outcome prediction. In the meantime, improved magnetic resonance (MR) imaging techniques have shown much potentials in evaluating the key pathological features of the gliomas, including cellularity, invasiveness, mitotic activity, angiogenesis, and necrosis, hence, further shedding light on glioma grading before treatment. In this paper, an update of advanced MR imaging techniques is reviewed, and their potential roles as biomarkers of tumor grading are discussed.

Perioperative complications influence recurrence and survival after resection of hepatic colorectal metastases.

BACKGROUND: Perioperative outcomes, such as blood loss, transfusions, and morbidity, have been linked to cancer-specific survival, but this is largely unsupported by prospective data. METHODS: Patients from a previous, randomized trial that evaluated acute normovolemic hemodilution during major hepatectomy (≥3 segments) were reevaluated and those with metastatic colorectal cancer (n = 90) were selected for analysis. Survival data were obtained from the medical record. Disease extent was measured using a clinical-risk score (CRS). Log-rank test and Cox proportional hazard model were used to evaluate recurrence-free survival (RFS) and overall survival (OS). RESULTS: Median follow-up was 71 months. The CRS was ≥3 in 45 % of patients; 59 % had extrahepatic procedures. Morbidity and mortality were 33 and 2 %, respectively. Postoperative chemotherapy was given to 87 % of patients (78/90) starting at a median of 6 weeks. RFS and OS were 29 and 60 months, respectively. Postoperative morbidity significantly reduced RFS (23 vs. 69 months; P < 0.001) and OS (28 vs. 74 months; P < 0.001) on uni- and multi-variate analysis; positive resection margins and high CRS also were significant factors. Delayed initiation of postoperative chemotherapy (≥8 weeks) was common in patients with complications (37 vs. 12 %; P = 0.01). CONCLUSIONS: In this selected cohort of patients from a previous RCT, perioperative morbidity was strongly (and independently) associated with cancer-specific outcome. It also was associated with delayed initiation of postoperative chemotherapy, the impact of which on survival is unclear.