Eric T. Kimchi

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.

A Reduction in Delayed Gastric Emptying by Classic Pancreaticoduodenectomy with an Antecolic Gastrojejunal Anastomosis and a Retrogastric Omental Patch

BackgroundDelayed gastric emptying (DGE) continues to be a major cause of morbidity following pancreaticoduodenectomy (PD). A change in the method of reconstruction following PD was instituted in an attempt to reduce the incidence DGE.MethodsPatients undergoing PD from January 2002 to December 2008 were reviewed and outcomes determined. Pylorus-preserving pancreaticoduodenectomy (PPPD) with a retrocolic duodenojejunal anastomosis (n = 79) or a classic PD with a retrocolic gastrojejunostomy (n = 36) was performed prior to January 2008. Thereafter, a classic PD with an antecolic gastrojejunal anastomosis and placement of a retrogastric vascular omental patch was undertaken (n = 36).ResultsA statistically significant decrease in DGE was noted in the antecolic group compared to the entire retrocolic group (14% vs 40%; p = 0.004) and compared to patients treated by classic PD with a retrocolic anastomosis alone (14% vs 39%; p = 0.016). On multivariate analysis, the only modifiable factor associated with reduced DGE was the antecolic technique with an omental patch, odds ratio (OR) 0.3 (confidence interval (CI) 0.1–0.8) p = 0.022. Male gender was associated with an increased risk of DGE with OR 2.3 (CI 1.1–4.8) p = 0.026.ConclusionA classic PD combined with an antecolic anastomosis and retrogastric vascular omental patch results in a significant reduction in DGE.

Circulating Tumor Cells in Melanoma Patients

Circulating tumor cells (CTCs) are of recognized importance for diagnosis and prognosis of cancer patients. With melanoma, most studies do not show any clear relationship between CTC levels and stage of disease. Here, CTCs were enriched (∼400X) from blood of melanoma patients using a simple centrifugation device (OncoQuick), and 4 melanocyte target RNAs (TYR, MLANA, MITF, and MIF) were quantified using QPCR. Approximately one-third of melanoma patients had elevated MIF and MLANA transcripts (p<0.0001 and p<0.001, respectively) compared with healthy controls. In contrast, healthy controls had uniformly higher levels of TYR and MITF than melanoma patients (p<0.0001). There was a marked shift of leukocytes into the CTC-enriched fractions (a 430% increase in RNA recovery, p<0.001), and no relationship between CTC levels and stage of disease was found. CTCs were captured on microfabricated filters and cultured. Captured melanoma CTCs were large cells, and consisted of 2 subpopulations, based on immunoreactivity. One subpopulation (∼50%) stained for both pan-cytokeratin (KRT) markers and the common leukocyte marker CD-45, whereas the second subpopulation stained for only KRT. Since similar cells are described in many cancers, we also examined blood from colorectal and pancreatic cancer patients. We observed analogous results, with most captured CTCs staining for both CD-45/KRT markers (and for the monocyte differentiation marker CD-14). Our results suggest that immature melanocyte-related cells (expressing TYR and MITF RNA) may circulate in healthy controls, although they are not readily detectable without considerable enrichment. Further, as early-stage melanomas develop, immature melanocyte migration into the blood is somehow curtailed, whereas a significant proportion of patients develop elevated CTC levels (based on MIF and MLANA RNAs). The nature of the captured CTCs is consistent with literature describing leukocyte/macrophage-tumor cell fusion hybrids, and their role in metastatic progression.

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.

SV40 Tag-specific cytotoxic T lymphocytes generated from the peripheral blood of malignant pleural mesothelioma patients

Abstract. Malignant pleural mesothelioma (MPM) is an aggressive cancer, with survival of less than one year following diagnosis and treatment with current protocols. Recent studies have demonstrated the presence of the simian virus 40 (SV40)-like, large tumor antigen (Tag) in nearly 60% of MPMs. SV40 Tag is a viral-encoded tumor-specific antigen, and thus a potential target for the induction of anti-tumor immunity and the development of therapeutic vaccines. We describe here evidence for the existence of SV40 Tag-specific immune responses in patients with MPM whose tumors express Tag. Humoral immunity was demonstrated by the detection of IgG titers against Tag in serum samples from 1/3 of patients examined. CTLs were generated from the peripheral blood of an HLA-A2+ MPM patient with a synthetic peptide representing an HLA-A2 binding epitope in SV40 Tag. The CTLs demonstrated epitope fine specificity, in that other peptides from SV40 Tag and a peptide from influenza virus were not recognized in the context of HLA-A2. Moreover, the CTLs were capable of recognizing mesothelioma tumor cells that expressed SV40 Tag, in an MHC class I restricted manner.

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)