Kevin F. Staveley-O'Carroll

Assessment of K-ras mutation: A step toward personalized medicine for patients with colorectal cancer

Some of the most significant therapeutic advances in the treatment of cancer have occurred in the management of colorectal metastases. The introduction of new cytotoxic chemotherapeutic and biologic agents has changed the approach to these patients from both an oncologic and a surgical perspective. In addition, an understanding of the molecular mechanisms by which these agents affect tumors is developing. This molecular information will be critical in the future in designing therapeutic regimens based on an individual tumors genetic profile rather than treatment for a specific tumor type. The rapidly evolving treatment of colon cancer has provided several interesting genetic biomarkers/pathways/genes‐/kinases that have been targeted or seem to play an important role. Of particular interest is the blockade of epidermal growth factor receptor (EGFR) with monoclonal antibodies. This treatment is efficacious when used alone or combined with chemotherapy. However, recent data revealed that patients with tumors positive for the K‐ras mutation do not benefit from EGFR blockade. Compelling evidence has indicated that mutated K‐ras is an important oncogene involved at the early stage of the development of colorectal cancer. Furthermore, mutations in the K‐ras gene have been associated with aggressive tumor biology. K‐ras mutational analysis is an important step in the overarching goal of developing personalized medicine. New treatment strategies are needed to more effectively treat patients with the K‐ras mutation. Cancer 2009.

Indications and approach to surgical resection of lung metastases.

Pulmonary metastasectomy is a curative option for selected patients with cancer spread to the lungs. Complete surgical removal of pulmonary metastases can improve survival and is recommended under certain criteria. Specific issues that require consideration in a multidisciplinary setting when planning pulmonary metastasectomy include: adherence to established indications for resection, the surgical strategy including the use of minimally invasive techniques, pulmonary parenchyma preservation, and the role of lymphadenectomy. J. Surg. Oncol. 2010;102:187–195.

Nanoliposomal ceramide prevents in vivo growth of hepatocellular carcinoma

Background and objectives Hepatocellular carcinoma (HCC) affects an increasing number of people worldwide. The poor survival rate of patients with HCC is manifested by an aggressive and metastatic phenotype, as well as a poor response to common therapeutic strategies. The purpose of this study was to evaluate the efficacy of nanoliposomal C6-ceramide as an antineoplastic agent in an in vivo model of human HCC. Methods The growth-arresting and pro-apoptotic properties of nanoliposomal C6-ceramide were first evaluated in vitro in human SK-HEP-1 cells by assessing cellular viability, caspase 3/7 activity, annexin-V expression, DNA fragmentation, cell cycle distribution and AKT phosphorylation. SK-HEP-1 cells were then engrafted subcutaneously into athymic nude mice and nanoliposomal C6-ceramide was administered by tail vein injection. Tumour size was monitored over time, followed by excision of tumours to evaluate tumour vascularisation, proliferation, apoptosis and cellular signalling. Results Nanoliposomal C6-ceramide, but not ghost (no ceramide) nanoliposomes, induced apoptotic cell death of SK-HEP-1 cells in vitro, concomitant with an accumulation of cells in the G2 phase of the cell cycle and decreased phosphorylation of AKT. Systemic administration of nanoliposomal C6-ceramide to mice engrafted with SK-HEP-1 tumours reduced tumour vascularisation and proliferation, induced tumour cell apoptosis, decreased phosphorylation of AKT and ultimately blocked tumour growth. Conclusions These studies show that nanoliposomal ceramide is an efficacious antineoplastic agent for the treatment of in vitro and in vivo models of human HCC.

Combinatorial therapies improve the therapeutic efficacy of nanoliposomal ceramide for pancreatic cancer

Poor prognosis cancers, such as pancreatic cancer, represent inherent challenges for ceramide-based nanotherapeutics due to metabolic pathways, which neutralize ceramide to less toxic or pro-oncogenic metabolites. We have recently developed a novel 80 nanometer diameter liposomal formulation that incorporates 30 molar percent C6-ceramide, a bioactive lipid that is pro-apoptotic to many cancer cells, but not to normal cells. In this manuscript, we evaluated the efficacy of combining nanoliposomal C6-ceramide (Lip-C6) with either gemcitabine or an inhibitor of glucosylceramide synthase. We first assessed the biological effect of Lip-C6 in PANC-1 cells, a gemcitabine-resistant human pancreatic cancer cell line, and found that low doses alone did not induce cell toxicity. However, cytotoxicity was achieved by combining Lip-C6 with either non-toxic sub-therapeutic concentrations of gemcitabine or with the glucosylceramide synthase inhibitor D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP). Furthermore, these combinations with Lip-C6 cooperatively inhibited PANC-1 tumor growth in vivo. Mechanistically, Lip-C6 inhibited pro-survival Akt and Erk signaling, whereas the nucleoside analog gemcitabine did not. Furthermore, by including PDMP within the nanoliposomes, which halted ceramide neutralization as evidenced by LC-MS3, the cytotoxic effects of Lip-C6 were enhanced. Collectively, we have demonstrated that nanoliposomal ceramide can be an effective anti-pancreatic cancer therapeutic in combination with gemcitabine or an inhibitor of ceramide neutralization.

Diagnosis and management of retroperitoneal ancient schwannomas

BackgroundAncient schwannomas are degenerate peripheral nerve sheath tumors that very rarely occur in the retroperitoneum. They generally reach large proportions before producing symptoms due to mass effect. We describe three cases of retroperitoneal ancient schwannomas and discuss the diagnosis and management of these tumors.Case presentationsThree female patients with retroperitoneal ancient schwannomas were reviewed. One patient presented with several weeks of upper abdominal pain and lower chest discomfort, whereas back pain and leg pain with associated weakness were predominant symptoms in the remaining two. Abdominal imaging findings demonstrated heterogeneous masses in the retroperitoneum with demarcated margins, concerning for malignancy. The patients successfully had radical excision of their tumors. Histological examination showed encapsulated tumors that displayed alternating areas of dense cellularity and areas of myxoid matrix consistent with a diagnosis of ancient schwannoma.ConclusionA diagnosis of ancient schwannoma should be entertained for any heterogeneous, well encapsulated mass in the retroperitoneum. In these cases less radical surgical resection should be considered as malignant transformation of these tumors is extremely rare and recurrence is uncommon following excision.

The opioid growth factor-opioid growth factor receptor axis regulates cell proliferation of human hepatocellular cancer

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide, with a mortality rate approximating its incidence. Understanding the biology of these tumors, as well as treatment modalities, has been challenging. The opioid growth factor (OGF; [Met(5)]-enkephalin) and the OGF receptor (OGFr) form an endogenous growth-regulating pathway in homeostasis and neoplasia. In this investigation, we examined the relationship of the OGF-OGFr axis in HCC and define its presence, function, and mechanism. Using SK-HEP-1, Hep G2, and Hep 3B human HCC cell lines, we found that OGF and OGFr were present and functional. Exogenous OGF was observed to have a dose-dependent, reversible, and receptor-mediated inhibitory action on cell proliferation. Endogenous OGF was found to be constitutively produced and tonically active on cell replicative activities, with neutralization of this peptide accelerating cell proliferation. Silencing of OGFr using siRNA stimulated cell replication, even when exogenous OGF was added to the cultures, documenting its importance in mediating OGF activity. The mechanism of OGF-OGFr action on cell number was related to inhibition of DNA synthesis and not to apoptotic or necrotic pathways. Both OGF and OGFr were detected in surgical specimens of HCC, and no quantitative differences were recorded in peptide or receptor between pathological and normal specimens. These data are the first to report that the OGF-OGFr system is a native biological regulator of cell proliferation in HCC. The findings may provide important insight in designing treatment strategies for this deadly disease.

Multidisciplinary management of malignant pleural effusion.

Approximately 50% of patients with metastatic disease develop a malignant pleural effusion (MPE). Prompt clinical evaluation and treatment to achieve successful palliation are the main goals of management of MPE. Optimal treatment is still controversial and there is no universal standard approach. Management options include observation, thoracentesis, indwelling pleural catheter (IPC) or chest tube placement, pleurodesis, and surgical pleurectomy. The treatment for each patient should be based on symptoms, general condition, and life expectancy. J. Surg. Oncol. 2012; 105:731–738.

Regression of established hepatocellular carcinoma is induced by chemoimmunotherapy in an orthotopic murine model.

The high rate of mortality and frequent incidence of recurrence associated with hepatocellular carcinoma (HCC) reveal the need for new therapeutic approaches. In this study we evaluated the efficacy of a novel chemoimmunotherapeutic strategy to control HCC and investigated the underlying mechanism that increased the antitumor immune response. We developed a novel orthotopic mouse model of HCC through seeding of tumorigenic hepatocytes from SV40 T antigen (Tag) transgenic MTD2 mice into the livers of syngeneic C57BL/6 mice. These MTD2‐derived hepatocytes form Tag‐expressing HCC tumors specifically within the liver. This approach provides a platform to test therapeutic strategies and antigen‐specific immune‐directed therapy in an immunocompetent murine model. Using this model we tested the efficacy of a combination of oral sunitinib, a small molecule multitargeted receptor tyrosine kinase (RTK) inhibitor, and adoptive transfer of tumor antigen‐specific CD8+ T cells to eliminate HCC. Sunitinib treatment alone promoted a transient reduction in tumor size. Sunitinib treatment combined with adoptive transfer of tumor antigen‐specific CD8+ T cells led to elimination of established tumors without recurrence. In vitro studies revealed that HCC growth was inhibited through suppression of STAT3 signaling. In addition, sunitinib treatment of tumor‐bearing mice was associated with suppression of STAT3 and a block in T‐cell tolerance. Conclusion: These findings indicate that sunitinib inhibits HCC tumor growth directly through the STAT3 pathway and prevents tumor antigen‐specific CD8+ T‐cell tolerance, thus defining a synergistic chemoimmunotherapeutic approach for HCC. (HEPATOLOGY 2012;55:141–152)

Multivisceral and extended resections during pancreatoduodenectomy increase morbidity and mortality

BACKGROUND Improvements in outcomes after pancreatoduodenectomy (PD) have permitted more complex resections. Complete extirpation at PD may require multivisceral resection (MVR-PD); however, descriptions of morbidity of MVR-PD are limited to small, single-institution series. METHODS The National Surgical Quality Improvement Project database (2005-2011) was used to compare 30-day postoperative morbidity of PD with MVR-PD. Concurrent resection of colon, small bowel, stomach, kidney, or adrenal gland defined MVR-PD. RESULTS Of 9,927 PDs, MVR-PD was performed in 273 patients (3%). MVR included colon (58%), small bowel (30%), and gastric (12%) resections. Preoperative comorbidities were similar between groups. Pancreatic, duodenal, or periampullary cancer was present in 75% of patients. Mortality (8.8% vs 2.9%) and major morbidity (56.8% vs 30.8%) were much greater for MVR-PD versus PD alone (P < .001). MVR-PD patients also experienced greater rates of wound, pulmonary, cardiac, thromboembolic, renal, and septic complications. On multivariable regression, MVR was an independent predictor of death (odds ratio [OR], 3.4; P < .001), overall morbidity (OR, 3.01; P < .001), major morbidity (OR, 3.21; P < .001), and minor morbidity (OR, 1.65; P = .03). Among patients undergoing PD+MVR, colectomy was an independent predictor of increased overall morbidity (OR, 1.96; P = .03) and major morbidity (OR, 1.90; P = .02). CONCLUSION Margin-negative resection may require MVRs at the time of PD. MVR at is associated with 3-fold mortality and substantial morbidity after adjusting for comorbidities. Colectomy independently predicted major morbidity. At PD, the morbidity of MVR should be approached with caution when attempting margin-negative resection.

Pancreaticoduodenectomy in the presence of superior mesenteric venous obstruction

The study goal was to determine the technical feasibility and outcomes associated with pancreaticoduodenectomy for periampullary malignancies with near (>80%) or complete (100%) superior mesenteric venous (SMV) obstruction. A retrospective examination of 11 patients with high-grade or complete SMV obstruction who underwent pancreaticoduodenectomy at five academic medical centers is reviewed. Pancreaticoduodenectomy for locally advanced periampullary malignancies causing highgrade or complete SMV obstruction is technically feasible. Operative approaches and outcomes are presented. One 30-day death was observed. Median survival of the cohort is 18 months. Survivals exceeding 2 years post-resection have been observed. In a number of cases, significant palliation of pain and of biliary and duodenal obstruction were achieved. Based on this initial series, pancreaticoduodenectomy in the presence of near or total SMV obstruction is feasible, may result in an R0 resection, and may be beneficial in select patients with a periampullary malignancy. We suggest such an approach be considered particularly following completion of neoadjuvant therapy without systemic progression. Further studies and more long-term follow-up at high-volume centers are required, however, to better determine the indications and potential benefit of such an undertaking.