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.

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.

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.

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.

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.

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.

Malignant progression in IPMN: a cohort analysis of patients initially selected for resection or observation.

BACKGROUND: Intraductal papillary mucinous neoplasms (IPMN) may represent a field defect of pancreatic ductal instability. The relative risk of carcinoma in regions remote from the radiographically identified cyst remains poorly defined. This study describes the natural history of IPMN in patients initially selected for resection or surveillance. METHODS: Patients with IPMN submitted to resection or radiographic surveillance were identified from a prospectively maintained database. Comparisons were made between these two groups. RESULTS: From 1995 to 2010, a total of 356 of 1,425 patients evaluated for pancreatic cysts fulfilled inclusion criteria. Median follow-up for the entire cohort was 36 months. Initial resection was selected for 186 patients (52 %); 114 had noninvasive lesions and 72 had invasive disease. A total of 170 patients underwent initial nonoperative management. Median follow-up for this surveillance group was 40 months. Ninety-seven patients (57 % of those under surveillance) ultimately underwent resection, with noninvasive disease in 79 patients and invasive disease in 18. Five of the 18 (28 %) invasive lesions developed in a region remote from the monitored lesion. Ninety invasive carcinomas were identified in the entire population (25 %), ten of which developed the invasive lesion separate from the index cyst, representing 11 % with invasive disease. CONCLUSIONS: Invasive disease was identified in 39 % of patients with IPMN selected for initial resection and 11 % of patients selected for initial surveillance. Ten patients developed carcinoma in a region separate from the radiographically identified IPMN, representing 2.8 % of the study population. Diagnostic, operative, and surveillance strategies for IPMN should consider risk not only to the index cyst but also to the entire gland.

Ankle fusion in patients with haemophilia.

Ankle fusion in patients with haemophilia is a well-accepted treatment for end-stage arthropathy. However, current published outcome data are based on small sample sizes and generally short-term follow-up. The aim of this study was to evaluate the long-term results of ankle fusion in a large group of haemophilic patients treated at a single institution. The results of 57 ankle fusions performed on 45 patients between 1971 and 2010 were reviewed retrospectively. Data were gathered for type and severity of haemophilia, HIV status, fixation technique, postoperative complications and requirement of additional surgeries. A modified American Orthopaedic Foot & Ankle Society (AOFAS) hindfoot score was calculated for 20 ankles available for follow-up. Patients were followed for a mean of 6.6 years. There were no intra-operative or immediate postoperative complications related to fusion of the ankle. The overall non-union rate was 10.4% for tibio-talar fusion and 8.3% for sub-talar fusion. This rate was reduced to 3.7% and 5.6%, respectively, after the introduction of newer surgical techniques in 1995. None of these non-unions required revision surgery. The modified AOFAS scale demonstrated that 75% had no pain in the operated ankle a mean of 7.2 years following surgery. The remaining 25% scored their average pain as 3 of 10. The functional portion of the score suggested that patients have good alignment, minimal activity limitations or gait abnormalities, and can walk long distances. We conclude that ankle fusion successfully relieves pain and provides a good functional outcome. It is an appropriate treatment for end-stage haemophilic arthropathy of the ankle.

Downstaging in pancreatic cancer: a matched analysis of patients resected following systemic treatment of initially locally unresectable disease.

BACKGROUND: Patients with locally unresectable pancreatic cancer (AJCC stage III) have a median survival of 10-14 months. The objective of this study was to evaluate outcome of initially unresectable patients who respond to multimodality therapy and undergo resection. METHODS: Using a prospectively collected database, patients were identified who were initially unresectable because of vascular invasion and had sufficient response to nonoperative treatment to undergo resection. Overall survival (OS) was compared with a matched group of patients who were initially resectable. Case matching was performed using a previously validated pancreatic cancer nomogram. RESULTS: A total of 36 patients with initial stage III disease were identified who underwent resection after treatment with either systemic therapy or chemoradiation. Initial unresectability was determined by operative exploration (n = 15, 42%) or by cross-sectional imaging (n = 21, 58%). Resection consisted of pancreaticoduodenectomy (n = 31, 86%), distal pancreatectomy (n = 4, 11%), and total pancreatectomy (n = 1, 3%). Pathology revealed T3 lesions in 26 patients (73%), node positivity in 6 patients (16%), and a negative margin in 30 patients (83%). The median OS in this series was 25 months from resection and 30 months since treatment initiation. There was no difference in OS from time of resection between the initial stage III patients and those who presented with resectable disease (P = .35). CONCLUSIONS: In this study, patients who were able to undergo resection following treatment of initial stage III pancreatic cancer experienced survival similar to those who were initially resectable. Resection is indicated in this highly select group of patients.

A robust bayesian random effects model for nonlinear calibration problems.

In the context of a bioassay or an immunoassay, calibration means fitting a curve, usually nonlinear, through the observations collected on a set of samples containing known concentrations of a target substance, and then using the fitted curve and observations collected on samples of interest to predict the concentrations of the target substance in these samples. Recent technological advances have greatly improved our ability to quantify minute amounts of substance from a tiny volume of biological sample. This has in turn led to a need to improve statistical methods for calibration. In this article, we focus on developing calibration methods robust to dependent outliers. We introduce a novel normal mixture model with dependent error terms to model the experimental noise. In addition, we propose a reparameterization of the five parameter logistic nonlinear regression model that allows us to better incorporate prior information. We examine the performance of our methods with simulation studies and show that they lead to a substantial increase in performance measured in terms of mean squared error of estimation and a measure of the average prediction accuracy. A real data example from the HIV Vaccine Trials Network Laboratory is used to illustrate the methods.

Predicting stroke evolution: comparison of susceptibility-weighted MR imaging with MR perfusion.

OBJECTIVES: To investigate the ability of susceptibility-weighted imaging (SWI) to predict stroke evolution in comparison with perfusion-weighted imaging (PWI). METHODS: In a retrospective analysis of 15 patients with non-lacunar ischaemic stroke studied no later than 24 h after symptom onset, we used the Alberta Stroke Program Early CT Score (ASPECTS) to compare lesions on initial diffusion-weighted images (DWI), SWI, PWI and follow-up studies obtained at least 5 days after symptom onset. The National Institutes of Health Stroke Scale scores at entry and stroke risk factors were documented. The clinical-DWI, SWI-DWI and PWI-DWI mismatches were calculated. RESULTS: SWI-DWI and mean transit time (MTT)-DWI mismatches were significantly associated with higher incidence of infarct growth (P = 0.007 and 0.028) and had similar ability to predict stroke evolution (P = 1.0). ASPECTS values on initial DWI, SWI and PWI were significantly correlated with those on follow-up studies (P ≤ 0.026) but not associated with infarct growth. The SWI ASPECTS values were best correlated with MTT ones (ρ = 0.8, P < 0.001). CONCLUSIONS: SWI is an alternative to PWI to assess penumbra and predict stroke evolution. Further prospective studies are needed to evaluate the role of SWI in guiding thrombolytic therapy. Key Points • SWI can provide perfusion information comparable to MTT • SWI-DWI mismatch can indicate ischaemic penumbra • SWI-DWI mismatch can be a predictor for stroke evolution.

Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association.

BACKGROUND: The purpose of this statement is to provide an overview of cerebral venous sinus thrombosis and to provide recommendations for its diagnosis, management, and treatment. The intended audience is physicians and other healthcare providers who are responsible for the diagnosis and management of patients with cerebral venous sinus thrombosis. METHODS AND RESULTS: Members of the panel were appointed by the American Heart Association Stroke Council's Scientific Statement Oversight Committee and represent different areas of expertise. The panel reviewed the relevant literature with an emphasis on reports published since 1966 and used the American Heart Association levels-of-evidence grading algorithm to rate the evidence and to make recommendations. After approval of the statement by the panel, it underwent peer review and approval by the American Heart Association Science Advisory and Coordinating Committee. CONCLUSIONS: Evidence-based recommendations are provided for the diagnosis, management, and prevention of recurrence of cerebral venous thrombosis. Recommendations on the evaluation and management of cerebral venous thrombosis during pregnancy and in the pediatric population are provided. Considerations for the management of clinical complications (seizures, hydrocephalus, intracranial hypertension, and neurological deterioration) are also summarized. An algorithm for diagnosis and management of patients with cerebral venous sinus thrombosis is described.

A population-based study on trend in incidence of distal radial fractures in adults in Taiwan in 2000-2007.

UNLABELLED: This population-based study was conducted using claims data obtained from the National Health Insurance to investigate the trend in incidence of distal radial fractures in adults in Taiwan from 2000 to 2007. Our results revealed an increasing trend, particularly among women >50 years of age. INTRODUCTION: This population-based study used insurance claims data from 2000 to 2007 obtained from the National Health Research Institute to investigate the longitudinal trend in distal radial fractures in adults ≥20 years old in Taiwan. METHODS: We estimated the age- and gender-specific annual incidence rates of distal radial fracture and compared the differences in distribution by sociodemographic status between patients with and those without distal radial fracture and the differences in incidence rates between 2000 and 2007. RESULTS: The incidence of fracture was higher in women than in men. The overall female-to-male rate ratios were 1.52 in 2000 (12.3 vs 8.06 per 10,000 persons) and 1.89 in 2007 (18.9 vs 10.0 per 10,000 persons). There was marked increase in age-specific incidence beginning in the 50-54-year age group, particularly among women. CONCLUSION: These results imply the need for more effective intervention for the prevention of subsequent fracture and disability, particularly for perimenopausal women.

Changes of CCAAT enhancer-binding proteins (CEBPs) in the lung of streptozotocin-induced diabetic rats.

CCAAT enhancer-binding proteins (CEBPs) play key roles in the metabolic regulation, cell transformation, and inflammation. However, the expression and/or functions of CEBPs in rats with hyperglycemia are still unclear. In the present study, we investigated the changes of CEBPs protein in lung of the diabetic rats. The levels of C/EBPß and C/EBPδ protein were decreased in the lung isolated from streptozotocin-induced diabetic rats (STZ-diabetic rats) as compared with that of normal rats. Exogenous insulin at the dose sufficient to normalize the plasma glucose of STZ-diabetic rats reversed the protein levels of C/EBPß and C/EBPδ in lung after a 4-day treatment. Similar results were also observed in STZ-diabetic rats that received the treatment of phlorizin to reverse the plasma glucose level for 4 days. Otherwise, the protein level of C/EBPα in lung of the STZ-diabetic rats was similar as the normal rats. Also, the level of C/EBPα protein in lung of the STZ-diabetic rat was not significantly changed by correction of plasma glucose by exogenous insulin or phlorizin. In addition, we also cultured human lung cells (A-549) and rat lung cells (L2) in varies concentration of D-glucose and L-glucose to identify the effect of glucose in expression of C/EBPs. The obtained results suggest that increase of plasma glucose is related to the lower expression of C/EBPß and C/EBPδ proteins in the lung of STZ-diabetic rats. The changes of expression of C/EBPß and C/EBPδ are not caused by changes of osmolarity but by D-glucose itself.

Positron emission tomography imaging for herpes virus infection: Implications for oncolytic viral treatments of cancer.

Molecular therapy using viruses would benefit greatly from a non-invasive modality for assessing dissemination of viruses. Here we investigated whether positron emission tomography (PET) scanning using [(124)I]-5-iodo-2'-fluoro-1-beta-d-arabinofuranosyl-uracil (FIAU) could image cells infected with herpes simplex viruses (HSV). Using replication-competent HSV-1 oncolytic viruses with thymidine kinase (TK) under control of different promoters, we demonstrate that viral infection, proliferation and promoter characteristics all interact to influence FIAU accumulation and imaging. In vivo, as few as 1 x 107 viral particles injected into a 0.5-cm human colorectal tumor can be detected by [(124)I]FIAU PET imaging. PET signal intensity is significantly greater at 48 hours compared with that at 8 hours after viral injection, demonstrating that PET scanning can detect changes in TK activity resulting from local viral proliferation. We also show the ability of FIAU-PET scanning to detect differences in viral infectivity at 0.5 log increments. Non-invasive imaging might be useful in assessing biologically relevant distribution of virus in therapies using replication-competent HSV.

Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation.

Cachexia is a potentially lethal syndrome of unknown etiology characterized by anorexia, weight loss, and protein wasting that frequently complicates the treatment of chronic inflammation and cancer. Cachectin/TNF was isolated during the search for a humoral mediator of cachexia and found to stimulate the breakdown of energy stores from adipocytes and myocytes in vitro, but the chronic effects of the monokine in vivo are not known. Sublethal doses of recombinant human cachectin administered twice daily for 7-10 d caused cachexia in rats, as evidenced by reduced food intake, weight loss, and depletion of whole-body lipid and protein stores. Significant anemia is also observed and found to be the result of decreased red blood cell mass, not expanded plasma volume. Leukocytosis and histopathological evidence of tissue injury and inflammation are observed in several organs, including omentum, liver, spleen, and heart. These data suggests that the exposure of the normal host to cachectin is capable of inducing a pathophysiological syndrome of cachexia, anemia, and inflammation similar to that observed during inflammatory states or malignancy.

Antibodies to cachectin/tumor necrosis factor reduce interleukin 1 beta and interleukin 6 appearance during lethal bacteremia.

Cytokines secreted in response to invading micro-organisms are important mediators of detrimental hemodynamic and metabolic changes in the host. To test whether cachectin/TNF plays a role in triggering release of other cytokines in the setting of infection, anesthetized baboons were passively immunized against systemic cachectin/TNF before infusion of a LD100 dose of live Escherichia coli. Bacteremia led to significant increases in circulating levels of cachectin/TNF, IL-1 beta, and IL-6. Although bacterial endotoxin/lipopolysaccharide is a potent stimulus for the synthesis and release of IL-1 and IL-6 in vitro, specific neutralization of cachectin/TNF in vivo with mAb pretreatment significantly attenuated both the IL-1 beta and the IL-6 responses despite fulminant overwhelming bacteremia. These data suggest that cachectin/TNF is essential for the initiation or amplification of IL-1 and IL-6 release during lethal gram-negative septic shock syndrome.

Synergistic action of oncolytic herpes simplex virus and radiotherapy in pancreatic cancer cell lines.

BACKGROUND: Despite much research in chemotherapy and radiotherapy, pancreatic adenocarcinoma remains a fatal disease, highly resistant to all treatment modalities. Recent developments in the field of herpes simplex virus (HSV) engineering have allowed the generation of a number of promising virus vectors for treatment of many cancers, including pancreatic tumours. This study examined the use of one such virus, NV1023, in combination with radiation therapy in pancreatic cancer cell lines. METHODS: HSV therapy in combination with radiotherapy was investigated in pancreatic cancer cell lines Hs766T, Panc-1 and MIA PaCa-2. Multiple therapy effect analysis was performed by computerized simulation. Mechanisms underlying synergy, such as virus replication and apoptosis, were investigated. RESULTS: The combination of NV1023 and radiation yielded a synergistic oncolytic effect in all tested pancreatic cancer cell lines, with the greatest effect achieved in MIA PaCa-2. This effect was not mediated by an increase in rapid viral replication, but by a substantial increase in apoptosis. CONCLUSION: The synergistic oncolytic actions of HSV and radiotherapy observed in pancreatic cancer cell lines encourage further testing of this multimodality treatment.

ONCOLYTIC HERPES SIMPLEX VIRUS 1 (HSV-1) VECTORS: INCREASING TREATMENT EFFICACY AND RANGE THROUGH STRATEGIC VIRUS DESIGN.

Viruses have long been considered potential anticancer treatments. Wild-type viruses have been tested as anticancer agents in clinical trials since the 1960s. The possibility of viral oncolysis as an alternate cancer therapy was transformed by the emergence of modern genetic engineering. The herpes simplex virus (HSV) family offers particular advantages for use as a viral oncolytic. The engineered vectors that make up oncolytic HSVs (oHSVs) have demonstrated remarkable safety in clinical trials, with some evidence of efficacy. The past decade has seen a focus on increasing the efficacy of oncolytic vectors by adding exogenous transgenes to enhance tumor destruction. The current paper describes the various strategies for engineering HSV for increased cancer tissue specificity and efficacy. Presented are the rationale, preclinical data and clinical data where available. This is meant to illustrate a basic framework for the development of a novel therapy meant to exploit the viral life cycle for the killing of cancer.