Kaare J. Weber

Immune Stimulatory Receptor CD40 Is Required for T-Cell Suppression and T Regulatory Cell Activation Mediated by Myeloid-Derived Suppressor Cells in Cancer

Immune tolerance to tumors is often associated with accumulation of myeloid-derived suppressor cells (MDSC) and an increase in the number of T-regulatory cells (Treg). In tumor-bearing mice, MDSCs can themselves facilitate the generation of tumor-specific Tregs. In this study, we demonstrate that expression of the immune stimulatory receptor CD40 on MDSCs is required to induce T-cell tolerance and Treg accumulation. In an immune reconstitution model, adoptive transfer of Gr-1+CD115+ monocytic MDSCs derived from CD40-deficient mice failed to recapitulate the ability of wild-type MDSCs to induce tolerance and Treg development in vivo. Agonistic anti-CD40 antibodies phenocopied the effect of CD40 deficiency and also improved the therapeutic efficacy of IL-12 and 4-1BB immunotherapy in the treatment of advanced tumors. Our findings suggest that CD40 is essential not only for MDSC-mediated immune suppression but also for tumor-specific Treg expansion. Blockade of CD40-CD40L interaction between MDSC and Treg may provide a new strategy to ablate tumoral immune suppression and thereby heighten responses to immunotherapy.

Regulation of Dendritic Cell Function by NK Cells: Mechanisms Underlying the Synergism in the Combination Therapy of IL-12 and 4-1BB Activation

The interactions between NK cells and dendritic cells (DCs) have been previously demonstrated in vitro. In this report, the in vivo cross-regulation between NK cells and DCs was studied in tumor-bearing mice treated with adenoviral vector expressing IL-12 and agonistic anti-4-1BB Abs. NK cells are essential for both tumor rejection and CTL development in the combination therapy (IL-12 plus anti-4-1BB). The numbers and functional activities of both NK cells and DCs in tumor-infiltrating leukocytes were synergistically increased in the IL-12 plus anti-4-1BB-treated mice compared with treatment with either reagent alone. NK depletion in vivo resulted in a significant decrease in the number of DCs in tumor-infiltrating leukocytes, strongly suggesting that NK cells are involved in the activation and expansion of DCs. The mechanism by which IL-12-activated NK cells regulate DC functions is, in part, mediated through the secretion of IFN-γ that leads to the up-regulation of 4-1BB by DCs. Furthermore, 4-1BB activation in conjunction with IL-12 gene delivery increased tumor infiltration of green fluorescence protein-labeled DCs and enhanced their MHC class II expression. The activation of DCs by NK cells and the subsequent development of antitumoral CTL responses facilitated by 4-1BB-activated DCs may account for the synergistic effects observed in the combination therapy in comparison to adenoviral vector expressing IL-12 or anti-4-1BB treatment alone.

Current Recommendations on Diagnosis and Management of Right-Sided Diverticulitis

We present the case of a 52-year-old female with recurrent symptomatic ascending colon diverticulitis who ultimately underwent elective laparoscopic right hemicolectomy. The following is a case report and literature review pertaining to right colonic diverticular disease.

Laparoscopic Cortical-Sparing Adrenalectomy for Bilateral Pheochromocytoma

A 32-year-old female with asthma was hospitalized for pneumonia in 2/06. She underwent a CT scan of the chest which revealed an incidental finding of bilateral adrenal masses. On further questioning, she admitted to palpitations and flushing. She was normotensive. Biochemical workup was significant for elevated urinary norepinephrine and normetanephrines, and plasma catecholamine level. MIBG scan showed positive uptake in the left adrenal gland consistent with pheochromocytoma. T2 weighted MRI showed bilateral adrenal masses, left greater than right. After adequate alpha blockade with phenoxybenzamine, the patient underwent a laparoscopic left adrenalectomy. Pathology revealed a 3.5 cm pheochromocytoma. The patient then underwent a right cortical-sparing adrenalectomy to avoid complete adrenal insufficiency and Addisonian crisis. The choice of operation was made realizing the potential for increased bleeding, which was further complicated by the patient’s Jehovah’s Witness beliefs, which prohibit transfusion of any blood products. At surgery, a small, well-circumscribed mass of the inferior right adrenal gland was found, and excised in its entirety. A postoperative ACTH-stimulation test showed appropriate cortisol response. Pathology revealed a 1.5 cm pheochromocytoma, and the patient recovered uneventfully. Cortical-sparing adrenalectomy has been reported with success rates of 65–100% in avoiding exogenous steroid dependence.1,2 Bilateral pheochromocytoma remains the most common indication. Risks for both recurrence and malignancy require lifelong follow-up in these patients.

Completely intracorporeal retraction of the gallbladder for laparoendoscopic single site (LESS) surgery.

Laparoendoscopic single site surgery (LESS) cholecystectomy requires a creative solution to retract the gallbladder. Transabdominal suture retraction is a commonly used technique to achieve adequate exposure of the critical structures within Calots triangle. To avoid the multiple punctures of the gallbladder and abdominal wall required by such suture retraction, we developed a novel internal retractor specifically for use during LESS cholecystectomy. This retractor consists of a laparoscopic bulldog clamp fitted with a small metal hook, and was successfully used in a recent case of LESS cholecystectomy.

Laparoscopic single site adrenalectomy using a conventional laparoscope and instrumentation.

These authors conclude that laparoscopic single site adrenalectomy can be performed without articulating instruments or a flexible laparoscope.

A novel laparoscopic ventral herniorrhaphy training system.

Surgical simulation offers a safe opportunity to develop the skills required for the operating room. Box trainers are an excellent low-cost training option but there are limited options for teaching laparoscopic ventral hernia repair. We developed a realistic and cost-effective box system for laparoscopic ventral herniorrhaphy that will enhance training experience before entering the operating theater.

Polyester composite versus PTFE in laparoscopic ventral hernia repair.

This study demonstrated no significant association between polyester composite and PTFE mesh and postoperative complications.