Lawrence A. Shirley

Microwave ablation for hepatic malignancies: a multiinstitutional analysis.

Objective:This study hypothesized that tumor size, number of tumors, surgical approach, and tumor histology significantly affected microwave ablation (MWA) success and recurrence-free survival. Background:Although many hepatobiliary centers have adopted MWA, the factors that influence local control are not well described. Methods:Consecutive patients with hepatic malignancy treated by MWA were included from 4 high-volume institutions (2003–2011) and grouped by histology: hepatocellular carcinoma (HCC), colorectal liver metastases, neuroendocrine liver metastases, and other cancers. Independent significance of outcome variables was established with logistic regression and Cox proportional hazards models. Results:Four hundred fifty patients were treated with 473 procedures (139 HCC, 198 colorectal liver metastases, 61 neuroendocrine liver metastases, and 75 other) for a total of 875 tumors. Median follow-up was 18 months. Concurrent hepatectomy was performed in 178 patients (38%), and when performed was associated with greater morbidity. Complete ablation was confirmed for 839 of 865 tumors (97.0%) on follow-up cross-sectional imaging (10 were unevaluable). A surgical approach (open, laparoscopic, or percutaneous) had no significant impact on complication rates, recurrence, or survival. The local recurrence rate was 6.0% overall and was highest for HCC (10.1%, P = 0.045) and percutaneously treated lesions (14.1%, P = 0.014). In adjusted models, tumor size 3 cm or more predicted poorer recurrence-free survival (hazard ratio: 1.60, 95% CI: 1.02–2.50, P = 0.039). Conclusions:In this large data set, patients with 3 cm or more tumors showed a propensity for early recurrence, regardless of histology. Higher rates of local recurrence were noted in HCC patients, which may reflect underlying liver disease. There were no significant differences in morbidity or survival based on the surgical approach; however, local recurrence rates were highest for percutaneously ablated tumors.

Targeting the Warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells

Gemcitabine resistance remains a significant clinical challenge. Here, we used a novel glucose transporter (Glut) inhibitor, CG-5, as a proof-of-concept compound to investigate the therapeutic utility of targeting the Warburg effect to overcome gemcitabine resistance in pancreatic cancer. The effects of gemcitabine and/or CG-5 on viability, survival, glucose uptake and DNA damage were evaluated in gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cell lines. Mechanistic studies were conducted to determine the molecular basis of gemcitabine resistance and the mechanism of CG-5-induced sensitization to gemcitabine. The effects of CG-5 on gemcitabine sensitivity were investigated in a xenograft tumor model of gemcitabine-resistant pancreatic cancer. In contrast to gemcitabine-sensitive pancreatic cancer cells, the resistant Panc-1 and Panc-1(GemR) cells responded to gemcitabine by increasing the expression of ribonucleotide reductase M2 catalytic subunit (RRM2) through E2F1-mediated transcriptional activation. Acting as a pan-Glut inhibitor, CG-5 abrogated this gemcitabine-induced upregulation of RRM2 through decreased E2F1 expression, thereby enhancing gemcitabine-induced DNA damage and inhibition of cell survival. This CG-5-induced inhibition of E2F1 expression was mediated by the induction of a previously unreported E2F1-targeted microRNA, miR-520f. The addition of oral CG-5 to gemcitabine therapy caused greater suppression of Panc-1(GemR) xenograft tumor growth in vivo than either drug alone. Glut inhibition may be an effective strategy to enhance gemcitabine activity for the treatment of pancreatic cancer.

Regulation of oncogenic KRAS signaling via a novel KRAS-integrin-linked kinase-hnRNPA1 regulatory loop in human pancreatic cancer cells

Integrin-linked kinase (ILK) is a mediator of aggressive phenotype in pancreatic cancer. On the basis of our finding that knockdown of either KRAS or ILK has a reciprocal effect on the other’s expression, we hypothesized the presence of an ILK-KRAS regulatory loop that enables pancreatic cancer cells to regulate KRAS expression. This study aimed to elucidate the mechanism by which this regulatory circuitry is regulated and to investigate the translational potential of targeting ILK to suppress oncogenic KRAS signaling in pancreatic cancer. Interplay between KRAS and ILK and the roles of E2F1, c-Myc and heterogeneous nuclear ribonucleoprotein as intermediary effectors in this feedback loop was interrogated by genetic manipulations through small interfering RNA/short hairpin RNA knockdown and ectopic expression, western blotting, PCR, promoter-luciferase reporter assays, chromatin immunoprecipitation and pull-down analyses. In vivo efficacy of ILK inhibition was evaluated in two murine xenograft models. Our data show that KRAS regulated the expression of ILK through E2F1-mediated transcriptional activation, which, in turn, controlled KRAS gene expression via hnRNPA1-mediated destabilization of the G-quadruplex on the KRAS promoter. Moreover, ILK inhibition blocked KRAS-driven epithelial–mesenchymal transition and growth factor-stimulated KRAS expression. The knockdown or pharmacological inhibition of ILK suppressed pancreatic tumor growth, in part, by suppressing KRAS signaling. These studies suggest that this KRAS-E2F1-ILK-hnRNPA1 regulatory loop enables pancreatic cancer cells to promote oncogenic KRAS signaling and to interact with the tumor microenvironment to promote aggressive phenotypes. This regulatory loop provides a mechanistic rationale for targeting ILK to suppress oncogenic KRAS signaling, which might foster new therapeutic strategies for pancreatic cancer.

Therapeutic Endoscopic Ultrasonography: Intratumoral Injection for Pancreatic Adenocarcinoma

Pancreatic adenocarcinoma is an aggressive disease that has poor outcomes despite maximal traditional therapies. Thus, treatment of this cancer demands innovative strategies to be used in addition to standing therapies in order to provide new avenues of care. Here, we describe the technique of using endoscopic ultrasound in order to directly inject both novel and conventional therapies into pancreatic tumors. We detail the rationale behind this strategy and the many benefits it provides. We then describe our technique in detail, including our experience injecting the AdV-tk adenoviral vector to create an in situ vaccine effect.

An indeterminate nodule in the cirrhotic liver discovered by surveillance imaging is a prelude to malignancy.

Surveillance imaging often shows indeterminate lesions in the cirrhotic liver, which may represent early hepatocellular carcinoma (HCC), dysplastic or regenerative nodules, or vascular shunts. The risk of HCC after identification of an indeterminate nodule is not well described.

The Role of Central Neck Lymph Node Dissection in the Management of Papillary Thyroid Cancer

Papillary thyroid cancer (PTC) is the most common thyroid malignancy, and cervical nodal metastases are frequent at presentation. The most common site for nodal metastases from PTC is the central compartment of the ipsilateral neck in the paratracheal and pretracheal regions. The decision to resect these lymph nodes at the time of thyroidectomy often depends on if nodes with suspected malignancy can be identified preoperatively. If nodal spread to the central neck nodes is known, then the consensus is to remove all nodes in this area. However, there remains significant controversy regarding the utility of removing central neck lymph nodes for prophylactic reasons. Herein, we review the potential utility of central neck lymph node dissection as well as the risks of performing this procedure. As well, we review the potential of molecular testing to stratify patients who would most benefit from this procedure. We advocate a selective approach in which patients undergo clinical neck examination coupled with ultrasound to detect any concerning lymph nodes that warrant additional evaluation with either fine needle aspiration or excisional biopsy in the operating room. In lieu of clinical lymphadenopathy, we suggest the use of patient and disease characteristics as identified by multiple groups, such as the American Thyroid Association and European Society of Endocrine Surgeons, which include extremes of ages, large primary tumor size, and male gender, when deciding to perform central neck lymph node dissection. Patients should be educated on the potential long-terms risks versus the lack of known long-term benefits.

Fundamentals of Incisions and Skin Closures

This chapter will address the principles that guide the decision of where to place and how to close common incisions utilized in routine general surgical procedures. A strong understanding of anatomy, wound behavior, and healing will herald successful outcomes. The major goal in choosing the optimal surgical incision is assuring adequate visualization. There are a wide range of general surgery operative sites and incisions. Common abdominal incisions include the vertical midline, paramedian, transverse, oblique, and thoracoabdominal. Additionally, the retroperitoneum, cervical area, and breast are specialized sites that will be discussed in this chapter. The principles of wound closure can be summarized into three major components: achieving primary skin closure, minimizing wound-healing complications, and optimizing cosmesis. Additional elements of incision closure including primary closure, delayed closure, wound complications, and cosmesis will also be discussed.

The prognostic significance of adrenocortical carcinomas identified incidentally: ROSSFELD et al.

Little is known regarding the difference in prognosis among patients who have an incidentally discovered adrenocortical carcinoma (ACC) vs those who present with signs or symptoms. We aimed to explore differences in the outcomes of these two populations.

Practices and Perceptions Among Surgical Oncologists in the Perioperative Care of Obese Cancer Patients

BackgroundObesity and cancer are two common diseases in the United States. Although there is an interaction of obesity and cancer, little is known about surgeon perceptions and practices in the care of obese cancer patients. We sought to characterize perceptions and practices of surgical oncologists regarding the perioperative care of obese patients being treated for cancer.MethodsA cross-sectional survey was designed, pilot tested, and utilized to assess perceptions and practices of surgeons treating cancer patients. Surgical oncologists were identified using a commercially available database, and Qualtrics® was used to distribute and manage the survey. Statistical analyses were completed by using SPSS.ResultsOf the 1731 electronic invitations, 172 recipients initiated the survey, and 157 submitted responses (91.2%). Many surgeons (65.7%) believed that obese patients are more likely to present with more advanced cancers and were more likely than system factors to explain this delayed treatment [t(87) = 4.84; p < 0.001]. Nearly two-thirds of providers (64.5%) reported that obesity had no impact on the timing of surgery; however, one-third of respondents (34.2%) were more likely to recommend preoperative nonsurgical therapy rather than upfront surgery among obese patients. For operations of the chest/abdomen and breast/soft tissue, surgeons perceived obesity to be more related to risk of postoperative than intraoperative complications (chest/abdomen mean 4.13 vs. 3.26; breast/soft tissue 4.11 vs. 2.60; p < 0.001).ConclusionsOne in three surgeons reported that patient obesity would change the timing/sequence of when resection would be offered. Many surgeons perceived that obesity was related to a wide array of intra- and postoperative adverse outcomes.

Phase I trial of gene-mediated cytotoxic immunotherapy combined with resection for pancreatic adenocarcinoma.

241 Background: While surgical resection of pancreatic adenocarcinoma provides the only chance of cure, long-term survival is still poor. Immunotherapy approaches may improve outcomes. Gene Mediated Cytotoxic Immunotherapy (GMCI) generates a systemic anti-tumor vaccine effect through intra-tumoral delivery of an adenoviral vector expressing the HSV-thymidine kinase gene (AdV-tk) followed by anti-herpetic prodrug administration. This is the first application of GMCI in pancreatic cancer. METHODS This study evaluated 4 dose levels of AdV-tk (3x1010 to 1x1012 vector particles) injected into pancreatic tumors via EUS 2 weeks before resection. Patients then underwent attempt at resection. If resection was undertaken, AdV-tk was injected into the resection bed. If resection was not possible, AdV-tk was injected into the primary tumor. The prodrug, Valacyclovir, was given for 14 days after each injection. Postoperative therapy was not protocol-driven. RESULTS The study accrued 14 patients with 12 completing therapy: 3 at each of the 4 planned dose levels. One patient died of an unrelated myocardial infarction 2 days after initial injection and one patient dropped out mid-treatment after metastases were found at surgery. Median age was 67 years (range 40-81). Of 12 patients explored, 4 were not resected due to distant metastases (N=3) or locally advanced disease (N=1). Three patients had Grade 3 possibly-related adverse events: 2 abdominal pain and one dehydration with renal insufficiency. There were no dose limiting toxicities and no grade 4 clinical adverse events. Grade 3-4 laboratory abnormalities were AST/ALT, bilirubin, alkaline phosphatase and lipase, all in patients with obstructive jaundice. Post-operative complications included 2 patients who developed abscesses requiring drainage. Six of 12 patients are alive 5-34 months after start of treatment including 5 resected patients and one unresected. CONCLUSIONS AdV-tk can be safely injected into potentially resectable pancreatic tumors prior to planned resection. Early results are encouraging and justify further evaluation in a Phase 2 study.