Cytokine-secreting herpes viral mutants effectively treat tumor in a murine metastatic colorectal liver model by oncolytic and T-cell-dependent mechanisms.

In this model of hepatic micrometastases, the antitumor efficacy and role of the T-cell and natural killer (NK) cell populations were studied for oncolytic herpes simplex virus type-1 (HSV-1) viral mutants containing the granulocyte-monocyte colony stimulating factor (GM-CSF (NV1034)) or interluken-12 (IL-12 (NV1042)) cytokine genes. These were compared to saline and control virus (NV1023) in vitro and in vivo. HSV-1 mutants were assessed for cytotoxicity, replication and cytokine expression in CT-26 cells. A syngeneic micrometastatic liver model was then established in naive and immune cell-depleted animals to assess the antitumor efficacy of these viruses. In vitro cytotoxicity and viral replication were similar for each virus, resulting in greater than 80 and 98% cytotoxicity at multiplicity of infection of 1 and 10, respectively. Peak viral titers were 25- to 50-fold higher than initial titer and were not significantly different between viruses. In vivo, all three viruses reduced metastases relative to control, but cytokine-secreting viruses did so with greater efficacy compared to NV1023. This effect was abrogated by T-cell depletion, but not NK-cell depletion. Single-agent therapy with oncolytic viral agents containing GM-CSF or IL-12 is effective in a murine model of liver metastases and likely involves direct viral oncolysis and actions of specific immune effector cells.

Evolution of the treatment of carotid occlusive disease: indications for carotid angioplasty and stenting versus carotid endarterectomy.

Carotid endarterectomy (CEA) was established as the gold standard for treatment of carotid occlusive disease by several landmark papers published in the 1990's. Several decades of experience with CEA, however, has revealed high-risk subsets of patients in whom CEA carries increased risk of adverse events. These patients have subsequently been the focus of several randomized trials and registry databases which evaluated and proved non-inferiority of carotid angioplasty and stenting (CAS) in recent years. CAS is now considered an appropriate and equivalent alternative to CEA in these high-risk patients, defined by the presence of severe cardiac, pulmonary, or renal disease or by the presence of local factors such as prior neck radiation, prior neck operations, contralateral carotid occlusion, or surgically inaccessible lesions. Although ongoing trials in normal-risk patients may ultimately expand the indications for CAS, there is currently insufficient evidence to recommend CAS in these patients over CEA. In addition, specific subsets of patients, such as octogenarians or those with anatomic complexity, may have increased incidence of adverse events with CAS and are best served by CEA.

Laparoscopic distal pancreatectomy for inflammatory pseudotumor of the pancreas.

An 82-year-old woman presented with abdominal pain, nausea, emesis, and weight loss of ~25 lb over 6 months. A CT scan and MRI of the abdomen revealed a mass in the tail of the pancreas that was suspicious for malignancy. The patient underwent successful laparoscopic distal pancreatectomy and was discharged home on the 4th postoperative day after an uneventful course. Pathology revealed an inflammatory pseudotumor of the pancreas (IPT). Pancreatic IPT is a rare entity, and this case represents the first report of laparoscopic resection of this lesion. The presentation, diagnosis, histologic features, and therapy of IPT of the pancreas are reviewed.

Neoadjuvant treatment of hepatic malignancy: an oncolytic herpes simplex virus expressing IL-12 effectively treats the parent tumor and protects against recurrence-after resection.

The objective of the study was to evaluate the utility of NV1042, a replication competent, oncolytic herpes simplex virus (HSV) containing the interleukin-12 (IL-12) gene, as primary treatment for hepatic tumors and to further assess its ability to reduce tumor recurrence following resection. Resection is the most effective therapy for hepatic malignancies, but is not possible in the majority of the patients. Furthermore, recurrence is common after resection, most often in the remnant liver and likely because of microscopic residual disease in the setting of postoperative host cellular immune dysfunction. We hypothesize that, unlike other gene transfer approaches, direct injection of liver tumors with replication competent, oncolytic HSV expressing IL-12 will not only provide effective control of the parent tumor, but will also elicit an immune response directed at residual tumor cells, thus decreasing the risk of cancer recurrence after resection. Solitary Morris hepatomas, established in Buffalo rat livers, were injected directly with 10(7) particles of NV1042, NV1023, an oncolytic HSV identical to NV1042 but without the IL-12 gene, or with saline. Following tumor injection, the parent tumors were resected and measured and the animals were challenged with an intraportal injection of 10(5) tumor cells, recreating the clinical scenario of residual microscopic cancer. In vitro cytotoxicity against Morris hepatoma cells was similar for both viruses at a multiplicity of infection of 1 (MOI, ratio of viral particles to target cells), with >90% tumor cell kill by day 6. NV1042 induced high-level expression of IL-12 in vitro, peaking after 4 days in culture. Furthermore, a single intratumoral injection of NV1042, but not NV1023, induced marked IL-12 and interferon-gamma (IFN-gamma) expression. Both viruses induced a significant local immune response as evidenced by an increase in the number of intratumoral CD4(+) and CD8(+) lymphocytes, although the peak of CD8(+) infiltration was later with NV1042 compared with NV1023. NV1042 and NV1023 reduced parent tumor volume by 74% (P<.003) and 52% (P<.03), respectively, compared to control animals. Treatment of established tumors with NV1042, but not with NV1023, significantly reduced the number of hepatic tumors after resection of the parent tumor and rechallenge (16.8+/-11 (median=4) vs. 65.9+/-15 (median=66) in control animals, P<.025). In conclusion, oncolytic HSV therapy combined with local immune stimulation with IL-12 offers effective control of parent hepatic tumors and also protects against microscopic residual disease after resection. The ease of use of this combined modality approach, which appears to be superior to either approach alone, suggests that it may have clinical relevance, both as primary treatment for patients with unresectable tumors and also as a neoadjuvant strategy for reducing recurrence after resection.

Laparoscopic appendectomy for Crohn's disease of the appendix presenting as acute appendicitis.

BACKGROUND: Crohn's disease confined to the appendix is rare but has been well described in the literature. It can mimic acute appendicitis clinically. After surgical treatment, recurrences of Crohn's disease are rare. We report the first case of treatment by laparoscopic appendectomy of Crohn's disease confined to the appendix. METHODS: A healthy 32-year old man presented with a week-long history of vague lower abdominal pain. Diagnostic work-up, which included CT, enteroclysis, and routine blood work, revealed a patent appendiceal lumen with an inflammatory mass in the right lower quadrant. RESULTS: Diagnostic laparoscopy revealed an inflamed appendix, and a laparoscopic appendectomy was performed, with frozen-section examination revealing Crohn's disease of the appendix. Two years after surgery, the patient has not had a recurrence of symptoms. CONCLUSIONS: Crohn's disease of the appendix can mimic acute appendicitis, although often with a more indolent course. The disease may be treated successfully by laparoscopic appendectomy, with good long-term results.