Area Deprivation Index is not predictive of worse outcomes after open lower extremity revascularization.

OBJECTIVE: Prior research has shown that socioeconomic status (SES) is associated with higher rates of diabetes, peripheral vascular disease, and amputation. We sought to determine whether SES or insurance type increases the risk of mortality, major adverse limb events (MALE), or hospital length of stay (LOS) after open lower extremity revascularization. METHODS: We conducted a retrospective analysis of patients who underwent open lower extremity revascularization at a single tertiary care center from January 2011 to March 2017 (n = 542). SES was determined using state Area Deprivation Index (ADI), a validated metric determined by income, education, employment, and housing quality by census block group. Patients undergoing amputation in this same time period (n = 243) were included to compare rates of revascularization to amputation by ADI and insurance status. For patients undergoing revascularization or amputation procedures on both limbs, each limb was treated individually for this analysis. We performed a multivariate analysis of the association between ADI and insurance type with mortality, MALE, and LOS using Cox proportional hazard models, including confounding variables such as age, gender, smoking status, body mass index, hyperlipidemia, hypertension, and diabetes. The cohort with an ADI quintile of 1, meaning least deprived, and the Medicare cohort were used for reference. P values of <.05 were considered statistically significant. RESULTS: We included 246 patients undergoing open lower extremity revascularization and 168 patients undergoing amputation. Controlling for age, gender, smoking status, body mass index, hyperlipidemia, hypertension, and diabetes, ADI was not an independent predictor of mortality (P = .838), MALE (P = .094), or hospital LOS (P = .912). Controlling for the same confounders, uninsured status was independently predictive of mortality (P = .033), but not MALE (P = .088) or hospital LOS (P = .125). There was no difference in the distribution of revascularizations or amputations by ADI (P = .628), but there was higher proportion of uninsured patients undergoing amputation compared with revascularization (P < .001). CONCLUSIONS: This study suggests that ADI is not associated with an increased risk of mortality or MALE in patients undergoing open lower extremity revascularization, but that uninsured patients are at higher risk of mortality after revascularization. These findings indicate that individuals undergoing open lower extremity revascularization at this single tertiary care teaching hospital received similar care, regardless of their ADI. Further study is warranted to understand the specific barriers that uninsured patients face.

Concomitant Aorto-Caval Reconstruction for Inferior Vena Cava Leiomyosarcoma.

BACKGROUND: Leiomyosarcoma of the inferior vena cava (IVC) is a rare smooth muscle neoplasm typically presenting in the fifth to sixth decades of life with both intraluminal and extraluminal growth patterns. Surgical resection remains the gold standard for nonmetastatic disease and often requires vascular reconstruction. We present an atypical case of leiomyosarcoma involving both the IVC and infrarenal abdominal aorta necessitating reconstruction with intraoperative veno-venous bypass. METHODS: A 63-year-old man initially presenting with back pain was found to have a large mass adjacent to the IVC on MRI, subsequently confirmed to be leiomyosarcoma by biopsy. After 6 months of neoadjuvant chemotherapy, the patient was taken for resection. However, intraoperatively the tumor was found to involve the aorta necessitating combined aorto-caval reconstruction. To facilitate en-bloc resection of the tumor, the aorta was reconstructed first followed by the inferior vena cava using veno-venous bypass. RESULTS: Postoperatively, the patient was taken to the intensive care unit for resuscitation and had an uncomplicated hospital course. He was discharged to rehab 6 days postoperatively and at one year remains free of significant tumor burden with patent aorto-caval bypass grafts. CONCLUSIONS: Primary leiomyosarcoma of the IVC is estimated to have aortic involvement in <10% of cases and concurrent aorto-caval reconstruction can be a well-tolerated option in good surgical candidates. Furthermore, veno-venous bypass can be a useful tool for accomplishing successful oncologic resections. With interdisciplinary collaboration between surgical oncologists, urologists, and vascular surgeons, difficult pathologies can be addressed with good patient outcomes.

Modern mortality risk stratification scores accurately and equally predict real-world postoperative mortality after ruptured abdominal aortic aneurysm.

OBJECTIVE: It is often unclear which patients presenting with a ruptured abdominal aortic aneurysm (rAAA) are likely to survive after surgery. The Harborview Medical Center (HMC), Dutch Aneurysm Score (DAS), and Vascular Study Group of New England (VSGNE) risk scores have been recent attempts at predicting mortality in this setting. We compared the prognostic value of these scoring systems for patients at our institution with rAAA. METHODS: A retrospective chart review was performed for all patients who received surgery at our institution for rAAA between January 1, 2011, and November 27, 2019. The χ2, Fisher's exact, and t-tests were used to screen preoperative variables against in-hospital mortality. HMC, DAS, and VSGNE scores were calculated for each patient and tested against in-hospital mortality. Logistic regression and receiver operating characteristic curves were used to assess performance of each scoring system. RESULTS: Sixty-four patients were identified during the study period. Fifteen patients were excluded because 4 patients chose comfort care and an additional 11 patients were missing key variables. The final cohort for analysis included 49 patients who underwent surgery, including 33 patients receiving endovascular repair and 16 patients receiving open repair. The in-hospital mortality was 37% (24% for endovascular repair vs 63% for open repair). Individual variables associated with in-hospital mortality were lowest preoperative systolic blood pressure (P = .036), creatinine greater than 2.0 mg/dL (P = .020), first recorded intraoperative pH (P = .007), and use of suprarenal aortic control (P = .025), and preoperative cardiac arrest approached significance (P = .051). Plots of the HMC and VSGNE scores vs in-hospital mortality rate produced linear relationships (R2 = 0.97 and R2 = 0.93, respectively), in which a higher score was associated with a greater likelihood of mortality. On logistic regression analysis using HMC score components, creatinine greater than 2.0 mg/dL produced a significant association with in-hospital mortality (odds ratio, 12.3; 95% confidence interval [CI], 1.1-131.7). Similar analysis using VSGNE components produced a significant association between suprarenal aortic control and in-hospital mortality (odds ratio, 5.5; 95% CI, 1.2-25.5). receiver operating characteristic curves produced an area under the curve of 0.74 (95% CI, 0.60-0.88), 0.73 (95% CI, 0.58-0.87), and 0.67 (95% CI, 0.51-0.83) for the HMC, VSGNE, and DAS, respectively. CONCLUSIONS: The HMC, VSGNE, and DAS scores performed similarly and adequately predicted in-hospital mortality after rAAA. The HMC score holds the added benefit of using preoperative variables, setting it apart as a valid prognostic indicator in the preoperative setting.

Tunneling nanotubes: an alternate route for propagation of the bystander effect following oncolytic viral infection.

Tunneling nanotubes (TNTs) are ultrafine, filamentous actin-based cytoplasmic extensions which form spontaneously to connect cells at short and long-range distances. We have previously described long-range intercellular communication via TNTs connecting mesothelioma cells in vitro and demonstrated TNTs in intact tumors from patients with mesothelioma. Here, we investigate the ability of TNTs to mediate a viral thymidine kinase based bystander effect after oncolytic viral infection and administration of the nucleoside analog ganciclovir. Using confocal microscopy we assessed the ability of TNTs to propagate enhanced green fluorescent protein (eGFP), which is encoded by the herpes simplex virus NV1066, from infected to uninfected recipient cells. Using time-lapse imaging, we observed eGFP expressed in infected cells being transferred via TNTs to noninfected cells; additionally, increasing fluorescent activity in recipient cells indicated cell-to-cell transmission of the eGFP-expressing NV1066 virus had also occurred. TNTs mediated cell death as a form of direct cell-to-cell transfer following viral thymidine kinase mediated activation of ganciclovir, inducing a unique long-range form of the bystander effect through transmission of activated ganciclovir to nonvirus-infected cells. Thus, we provide proof-of-principle demonstration of a previously unknown and alternative mechanism for inducing apoptosis in noninfected recipient cells. The conceptual advance of this work is that TNTs can be harnessed for delivery of oncolytic viruses and of viral thymidine kinase activated drugs to amplify the bystander effect between cancer cells over long distances in stroma-rich tumor microenvironments.

Recombinant vaccinia virus GLV-1h68 is a promising oncolytic vector in the treatment of cholangiocarcinoma.

Although early stage cholangiocarcinoma (CC) can be cured by surgical extirpation, the options for treatment of advanced stage CC are very few and suboptimal. Oncolytic virotherapy using replication-competent vaccinia virus (VACV) is a promising new strategy to treat human cancers. The ability of oncolytic VACV GLV-1h68 to infect, replicate in, and lyse three human CC cell lines was assayed in vitro and in subcutaneous flank xenografts in athymic nude mice. In this study, we have demonstrated that GLV-1h68 effectively infects and lyses three CC cell lines (KMC-1, KMBC, and KMCH-1) in vitro. Expression of the viral marker gene ruc-gfp facilitated real-time monitoring of infection and replication. Furthermore in athymic nude mice, a single dose of GLV-1h68 significantly suppressed tumor growth. The treatment was well tolerated in all animals. Recombinant VACV GLV-1h68 has significant oncolytic ability against CC both in vitro and in vivo. GLV-1h68 has the potential to be used clinically as a therapeutic agent against CC.

Oncolytic gene therapy with recombinant vaccinia strain GLV-2b372 efficiently kills hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) commonly presents at a late stage when surgery is no longer a curative option. As such, novel therapies for advanced HCC are needed. Oncolytic viruses are a viable option for cancer therapy owing to their ability to specifically infect, replicate within, and kill cancer cells. In this study, we have investigated the ability of GLV-2b372, a novel light-emitting recombinant vaccinia virus derived from a wild-type Lister strain, to kill HCC. METHODS: Four human HCC cell lines were assayed in vitro for infectivity and cytotoxicity. Viral replication was quantified via standard viral plaque assays. Flank HCC xenografts generated in athymic nude mice were treated with intratumoral GLV-2b372 to assess for tumor growth inhibition and viral biodistribution. RESULTS: Infectivity occurred in a time- and concentration-dependent manner with 70% cell death in all cell lines by day 5. All cell lines supported efficient viral replication. At 25 days after infection, flank tumor volumes decreased by 50% whereas controls increased by 400%. Tumor tissue demonstrated substantial GLV-2b372 infection at 24 hours, 48 hours, and 2 weeks. CONCLUSION: We demonstrate that GLV-2b372 efficiently kills human HCC in vitro and in vivo and is a viable treatment option for patients with HCC.

Gene therapy using therapeutic and diagnostic recombinant oncolytic vaccinia virus GLV-1h153 for management of colorectal peritoneal carcinomatosis.

BACKGROUND: Peritoneal carcinomatosis (PC) is a terminal progression of colorectal cancer (CRC). Poor response to cytoreductive operation and chemotherapy coupled with the inability to reliably track disease progression by the use of established diagnostic methods, make this a deadly disease. We examined the effectiveness of the oncolytic vaccinia virus GLV-1h153 as a therapeutic and diagnostic vehicle. We believe that viral expression of the human sodium iodide transporter (hNIS) provides both real-time monitoring of viral therapy and effective treatment of colorectal peritoneal carcinomatosis (CRPC). METHODS: Infectivity and cytotoxic effect of GLV-1h153 on CRC cell lines was assayed in vitro. Viral replication was examined by standard viral plaque assays. Orthotopic CRPC xenografts were generated in athymic nude mice and subsequently administered GLV-1h153 intraperitoneally. A decrease in tumor burden was assessed by mass. Orthotopic tumors were visualized by single-photon emission computed tomography/computed tomography after Iodine ((131)I) administration and by fluorescence optical imaging. RESULTS: GLV-1h153 infected and killed CRC cells in a time- and concentration-dependent manner. Viral replication demonstrated greater than a 2.35 log increase in titer over 4 days. Intraperitoneal treatment of orthotopic CRPC xenografts resulted in a substantial decrease in tumor burden. Infection of orthotopic xenografts was therapeutic and facilitated monitoring by (131)I-single-photon emission computed tomography/computed tomography via expression of hNIS in infected tissue. CONCLUSION: GLV-1h153 kills CRC in vitro effectively and decreases tumor burden in vivo. We demonstrate that GLV-1h153 can be used as an agent to provide accurate delineation of tumor burden in vivo. These findings indicate that GLV-1h153 has potential for use as a therapeutic and diagnostic agent in the treatment of CRPC.

Imaging for infection: from visualization of inflammation to visualization of microbes.

BACKGROUND: With the development of high-resolution cross-sectional imaging, anatomic identification of most areas of infection has become routine. Imaging a site of infection allows for diagnosis and treatment. In the past, molecular imaging for infection involved mainly the use of radiolabeled leukocytes for functional targeting at infection sites. With the recent development of functional nuclear imaging, bacterial and viral metabolism can also be imaged directly for potential identification of early infection. METHODS: Review of pertinent English-language literature. RESULTS: Cross-sectional imaging is used routinely to identify and treat sources of infection in patients with fever, leukocytosis, or unexplained hemodynamic instability. Although ultrasound is preferred for the identification of biliary or hepatic sepsis, computed tomography (CT) has proved to be accurate for the identification and treatment of intra-abdominal fluid collections and abscesses. Biologic imaging is a non-invasive technique that identifies sites of infection in cases in which no definite abnormality is identified via cross-sectional imaging. This is made possible by imaging the accumulation of radioisotopes that have been attached to white blood cells or glucose. Biologic imaging is useful for the identification of anatomic sites where there is inflammation or high metabolic demand. However, a drawback of biologic imaging is that it is not specific for infection. Techniques that image microbes directly increase the specificity of imaging results significantly and can be used to quantify and track infectious processes. For example, radiolabeling of antimicrobial proteins and antibiotics is one technique that has been demonstrated to identify areas of infection accurately in animals but is not currently being used clinically in humans. With the advent of gene therapy, many researchers are inserting the herpes viral thymidine kinase gene into both viruses and bacteria. This allows for tracking of the infectious process by imaging the accumulation of radiolabeled thymidine analogues. CONCLUSION: This review summarizes standard imaging for infection as it is currently practiced clinically. We will also explore the promising new methods of microbial imaging that are likely to become standards in clinical care in the near future.

Intercellular communication in malignant pleural mesothelioma: properties of tunneling nanotubes.

Malignant pleural mesothelioma is a particularly aggressive and locally invasive malignancy with a poor prognosis despite advances in understanding of cancer cell biology and development of new therapies. At the cellular level, cultured mesothelioma cells present a mesenchymal appearance and a strong capacity for local cellular invasion. One important but underexplored area of mesothelioma cell biology is intercellular communication. Our group has previously characterized in multiple histological subtypes of mesothelioma a unique cellular protrusion known as tunneling nanotubes (TnTs). TnTs are long, actin filament-based, narrow cytoplasmic extensions that are non-adherent when cultured in vitro and are capable of shuttling cellular cargo between connected cells. Our prior work confirmed the presence of nanotube structures in tumors resected from patients with human mesothelioma. In our current study, we quantified the number of TnTs/cell among various mesothelioma subtypes and normal mesothelial cells using confocal microscopic techniques. We also examined changes in TnT length over time in comparison to cell proliferation. We further examined potential approaches to the in vivo study of TnTs in animal models of cancer. We have developed novel approaches to study TnTs in aggressive solid tumor malignancies and define fundamental characteristics of TnTs in malignant mesothelioma. There is mounting evidence that TnTs play an important role in intercellular communication in mesothelioma and thus merit further investigation of their role in vivo.

Oncolytic immunotherapy using recombinant vaccinia virus GLV-1h68 kills sorafenib-resistant hepatocellular carcinoma efficiently.

BACKGROUND: Sorafenib is the standard systemic therapy for unresectable or recurrent hepatocellular carcinoma (HCC) but adds minimal increase in survival. Therefore, there is a great need to develop novel therapies for advanced or recurrent HCC. One emerging field of cancer treatment involves oncolytic viruses that specifically infect, replicate within, and kill cancer cells. In this study, we examined the ability of GLV-1h68, a recombinant vaccinia virus derived from the vaccine strain that was used to eradicate smallpox, to kill sorafenib-resistant (SR) HCC cell lines. METHODS: Four SR HCC cell lines were generated by repeated passage in the presence of sorafenib. Median inhibitory concentration was determined for all cell lines. The infectivity, viral replication, and cytotoxicity of GLV-1h68 were assayed for both parental and SR HCC cells. RESULTS: Infectivity increased in a time and concentration-dependent manner in all cell lines. All cell lines supported efficient replication of virus. No difference between the rates of cell death between the parental and SR cell lines was observed. CONCLUSION: Our results demonstrate that the oncolytic vaccinia virus GLV-1h68 kills both parental and SR HCC cell lines efficiently. This study indicates that patients who have failed treatment with sorafenib remain viable candidates for oncolytic therapy.

Oncolytic viral therapy for pancreatic cancer: current research and future directions.

The development of targeted agents and chemotherapies for pancreatic cancer has only modestly affected clinical outcome and not changed 5-year survival. Fortunately the genetic and molecular mechanisms underlying pancreatic cancer are being rapidly uncovered and are providing opportunities for novel targeted therapies. Oncolytic viral therapy is one of the most promising targeted agents for pancreatic cancer. This review will look at the current state of the development of these self-replicating nanoparticles in the treatment of pancreatic cancer.

An oncolytic vaccinia virus expressing the human sodium iodine symporter prolongs survival and facilitates SPECT/CT imaging in an orthotopic model of malignant pleural mesothelioma.

BACKGROUND: The purpose of this work was to examine the ability of an oncolytic vaccinia virus expressing the human sodium iodine transporter (hNIS) to provide real time monitoring of viral therapy and effective treatment of malignant pleural mesothelioma (MPM). METHODS: Infectivity and cytotoxic effects of GLV-1h153 on mesothelioma cell lines of all histologic subtypes were assayed in vitro. Viral replication was examined by standard viral plaque assay. Orthotopic MPM xenografts were generated in athymic nude mice, treated with intrapleural GLV-1h153, and assessed for effect on tumor burden and survival. Orthotopic tumors were also imaged on single photon emission computed tomography (SPECT)/computed tomography (CT) after (131)I administration. RESULTS: GLV-1h153-infected and killed all cell lines in a time- and concentration-dependent manner. Viral replication demonstrated a >2.5-log increase in titer over 4 days. Intrapleural treatment of orthotopic MPM xenografts resulted in a significant decrease in tumor burden 1 week after treatment and an improvement in survival. Infection of orthotopic xenografts was both therapeutic and facilitated monitoring by (131)I-SPECT/CT via expression of hNIS in infected tissue. CONCLUSION: Our results suggest that GLV-1h153 may be a promising therapeutic agent for MPM and warrants further investigation.