Ergun Kocak

Combination Therapy with Anti–CTL Antigen-4 and Anti-4-1BB Antibodies Enhances Cancer Immunity and Reduces Autoimmunity

The majority of cancer antigens identified thus far have limited expression in normal tissues. It has been suggested that autoimmune disease is a necessary price for cancer immunity. This notion is supported by a recent clinical trial involving an anti-CTL antigen-4 (CTLA-4) antibody that showed significant clinical responses but severe autoimmune diseases in melanoma patients. To selectively modulate cancer immunity and autoimmunity, we used anti-CTLA-4 and anti-4-1BB antibodies to treat mice with a preexisting cancer, MC38. The combination of the two antibodies led to CD8 T-cell-mediated rejection of large established MC38 tumors and long-lasting immunity to the same tumor cells, although the same regimen was not effective for B16 melanoma. More importantly, whereas individual antibodies induced inflammation and autoimmune manifestations, combination therapy increased cancer immunity while reducing autoimmunity. The reduction of autoimmune effects correlates with an increased function of regulatory T cells. Our results suggest a novel approach to simultaneously enhance cancer immunity and reduce autoimmunity.

Combined use of preoperative 18F FDG-PET imaging and intraoperative gamma probe detection for accurate assessment of tumor recurrence in patients with colorectal cancer

BackgroundThe purpose of this study was to combine intraoperative gamma probe (GP) detection with preoperative fluorine 18-fluoro-2-deoxy-glucose positron emission tomography (18F FDG-PET) imaging in order to improve detection of tumor recurrence in colorectal cancer (CRC) patients.MethodsTwenty-one patients (12 females, 9 males) with a mean age of 54 years (range 31–78) were enrolled. Patients were suspected to have recurrent CRC by elevated CEA (n = 11), suspicious CT findings (n = 1), and clinically suspicious findings (n = 9). Preoperative FDG-PET scan and intraoperative GP study were performed in all patients. Mean time interval between preoperative FDG-PET scan and surgery was 16 days (range 1–41 days) in 19 patients. For intraoperative GP studies, 19 patients were injected with a dose of 10–15 mCi 18F FDG at approximately 30 minutes before the planned surgery time. In two patients, the intraoperative GP study was performed immediately after preoperative FDG-PET scan.ResultsPreoperative FDG-PET and intraoperative GP detected 48 and 45 lesions, respectively. A total of 50 presumed site of recurrent disease from 20 patients were resected. Thirty-seven of 50 presumed sites of recurrent disease were histological-proven tumor positive and 13 of 50 presumed sites of recurrent disease were histological-proven tumor negative. When correlated with final histopathology, the number of true positive lesions and false positive lesions by preoperative FDG-PET and intraoperative GP were 31/9 and 35/8, respectively. Both preoperative FDG-PET and intraoperative GP were true positive in 29 lesions. Intraoperative GP detected additional small lesions in the omentum and pelvis which were not seen on preoperative FDG-PET scan. FDG-PET scan demonstrated additional liver metastases which were not detected by intraoperative GP. Preoperative FDG-PET detected distant metastasis in the lung in one patient. The estimated radiation dose received by a surgeon during a single 18F FDG GP surgery was below the occupational limit.ConclusionThe combined use of preoperative FDG-PET and intraoperative GP is potentially helpful to the surgeon as a roadmap for accurately locating and determining the extent of tumor recurrence in patients with CRC. While intraoperative GP appears to be more sensitive in detecting the extent of abdominal and pelvic recurrence, preoperative FDG-PET appears to be more sensitive in detecting liver metastases. FDG-PET is also a valuable method in detecting distant metastases.

Massive and destructive T cell response to homeostatic cue in CD24-deficient lymphopenic hosts

In response to a lymphopenic cue, T lymphocytes undergo a slow-paced homeostatic proliferation in an attempt to restore T cell cellularity. The molecular interaction that maintains the pace of homeostatic proliferation is unknown. In this study, we report that in lymphopenic CD24-deficient mice, T cells launch a massive proliferation that results in the rapid death of the recipient mice. The dividing T cells have phenotypes similar to those activated by cognate antigens. The rapid homeostatic proliferation is caused by a lack of CD24 on dendritic cells (DCs). Interestingly, although CD24 expression in T cells is required for optimal homeostatic proliferation in the wild-type (WT) host, mice lacking CD24 on all cell types still mount higher homeostatic proliferation than the WT mice. Thus, a lack of CD24 in the non–T host cells bypassed the requirement for T cell expression of CD24 in homeostatic proliferation in the WT host. Our data demonstrate that CD24 expressed on the DCs limits T cell response to homeostatic cue and prevents fatal damage associated with uncontrolled homeostatic proliferation.

B7-deficient autoreactive T cells are highly susceptible to suppression by CD4(+)CD25(+) regulatory T cells.

CD4+CD25+ regulatory T cells (Tregs) suppress immunity to infections and tumors as well as autoimmunity and graft-vs-host disease. Since Tregs constitutively express CTLA-4 and activated T cells express B7-1 and B7-2, it has been suggested that the interaction between CTLA-4 on Tregs and B7-1/2 on the effector T cells may be required for immune suppression. In this study, we report that autopathogenic T cells from B7-deficient mice cause multiorgan inflammation when adoptively transferred into syngeneic RAG-1-deficient hosts. More importantly, this inflammation is suppressed by adoptive transfer of purified wild-type (WT) CD4+CD25+ T cells. WT Tregs also inhibited lymphoproliferation and acquisition of activation markers by the B7-deficient T cells. An in vitro suppressor assay revealed that WT and B7-deficient T cells are equally susceptible to WT Treg regulation. These results demonstrate that B7-deficient T cells are highly susceptible to immune suppression by WT Tregs and refute the hypothesis that B7-CTLA-4 interaction between effector T cells and Tregs plays an essential role in Treg function.

A review of devices used in the monitoring of microvascular free tissue transfers.

The use of microvascular anastomoses to allow transfer of viable tissue is a fundamental technique of reconstructive surgery, and is used to treat a broad spectrum of clinical problems. The primary threat to this type of reconstructive surgery is anastomotic vascular thrombosis, which can lead to complete loss of tissue with potentially devastating consequences. Monitoring of tissue perfusion postoperatively is critical, since early recognition of vascular compromise and prompt surgical intervention is correlated with the ability for tissue salvage. Traditionally, physical examination was the primary means of monitoring, but possesses several limitations. Medical devices introduced for the purposes of flap monitoring address many of these deficiencies, and have greatly enhanced this critical aspect of the reconstructive surgery process.

Biologic matrices in oncologic breast reconstruction after mastectomy

As the demand for post-mastectomy breast reconstruction has continued to rise, options for the implantable soft-tissue replacement products which enhance the aesthetic and reconstructive outcome of these procedures has grown as well. While the most common product used in an alloplastic breast reconstruction is an acellular dermal matrix derived from human sources, many other options are currently available, each offering their own unique properties and benefits. This review presents a concise description of each of the biologic matrices currently available and discusses their use in the context of one-stage and two-stage breast reconstructions.

Optimizing the closed suction surgical drainage system.

Background: Closed suction drains are indicated in a wide array of postoperative settings, with many distinct drainage systems available to the surgeon. The purpose of this study was to compare the suction gradients achieved using 2 different sizes of suction reservoirs and 2 different techniques for generating negative pressure. Materials and Methods: Drainage reservoirs of 100 and 400 ml were chosen to evaluate their ability to achieve suction. Suction was established in both sizes of drains by pressing the sides of the reservoir together or by pushing the bottom of the reservoir toward the top. Negative pressures were recorded with the reservoir empty, and after every 10-ml addition of saline. Averages were graphed to illustrate the applied suction over a range of drain volumes. Results: The 100-ml drainage system reached a peak suction of −117.6 mmHg, while the 400-ml drainage system reached only a peak suction of −71.4 mmHg. Both of the maximum suction readings were achieved using the full-squeeze technique. The bottom-pushed-in technique did not result in any sustained measurable levels of suction using either of the reservoir volumes. Conclusions: Smaller drain reservoirs are more successful in generating a high initial suction than larger reservoirs, especially when the volume of fluid in the drain is relatively low. In all sizes of drains, compressing the sides of the reservoir is a far better technique for establishing negative pressure than pressing the bottom of the drain up toward the top.

Stiff‐Person Syndrome: A Rare Presentation for Breast Cancer

To the Editor: In very rare cases, breast cancer may present as an autoimmune-mediated, paraneoplastic, neurologic syndrome (1). Various specific syndromes have been reported, including cerebellar degeneration, opsoclonus-myoclonus syndrome, and stiff-person syndrome (SPS) (2,3). We herein report an atypical presentation of breast cancer in the form of a deteriorating neurologic syndrome and discuss the ramifications of diagnosing and treating such disorders. Our patient is a 71-year-old woman who initially presented with a 2-week history of left lower extremity pain and severe muscle spasms that progressed to involve the entire left lower extremity and the proximal right lower extremity. Physical examination revealed marked weakness, rigidity, stiffness, and extensor spasm of both lower extremities. Electromyography (EMG) showed continuous motor activity with motor unit potentials (MUPs) of normal amplitude and duration firing at a frequency of 15 to 20 Hz. A paraneoplastic laboratory panel of the serum was positive for antiamphiphysin antibodies only. Initial medical therapy included high-dose intravenous steroids, intravenous immune globulin (IVIG), and multiple rounds of plasmapheresis, but yielded only slight clinical improvement. Further evaluation with mammography revealed abnormal calcifications in the left breast with a normal-appearing right breast. Physical examination revealed a diffusely firm right breast with no palpable mass of the left breast. Surgical biopsies showed invasive ductal carcinoma in the right breast and only fibrocystic changes with mild ductal epithelial hyperplasia and benign microcalcifications in the left breast. Subsequent modified radical mastectomy on the right side revealed multifocal carcinoma involving the entire breast with accompanying ductal carcinoma in situ (DCIS) and extensive lymphatic invasion. Adjuvant therapy included Adriamycin, cyclophosphamide, and radiation to the chest wall and axilla. The patient’s symptoms significantly improved within 4 to 6 months after surgical resection and adjuvant treatment of the cancerous tissues, corroborating the paraneoplastic nature of her clinical syndrome. At the 2-year follow-up, the patient is without evidence of recurrence of her cancer, with minimal residual weakness and stiffness of her bilateral lower extremities. She does have some persistent spasticity which is controlled with intrathecal baclofen and phenol blocks. In an attempt to further investigate the paraneoplastic nature of the patient’s clinical symptoms, the right breast tissue was subjected to immunohistochemical staining with antiamphiphysin antibodies (BD Biosciences, catalog no. 610714). Our protocol has been previously published (4,5). The photomicrographs confirm the presence of amphiphysin in the malignant cells (Fig. 1). Our patient, combined with five previously reported cases, demonstrates the relationship of amphiphysin, SPS, and breast cancer (6–8). Five of these six patients were found to have significant clinical improvement in their neurologic symptoms after resection and adjuvant treatment of their cancerous tissues. Interestingly, our patient differs from these previous reports by demonstrating mainly lower extremity involvement with sparing of the upper limbs. We herein report an unusual presentation of breast cancer in the form of a rare neurologic syndrome. The detection of amphiphysin from cancerous breast tissue using immunohistochemical techniques is, to our knowledge,

Patient Attitudes Toward Resident Participation in Cosmetic vs Reconstructive Outpatient Consultations

OBJECTIVES The goal of residency programs is to provide trainees with exposure to all aspects of their chosen field so that they exit the program ready to be independent practitioners. However, it is common in some plastic surgery residency training programs to exclude residents from participation in consultations with patients who are seeking cosmetic surgery. The purpose of this study was to determine whether cosmetic surgery patients had a different view about resident involvement than reconstructive surgery patients and to evaluate what factors might be linked to patient attitudes on this topic. METHODS PARTICIPANTS All new patients older than 18 years presenting to either academic or nonacademic locations were asked to complete the voluntary survey at their initial consultation. SETTING The study was conducted at both the Ohio State University (academic) and Advanced Aesthetic and Laser Surgery (private practice) in Columbus, Ohio. DESIGN The survey asked patients to identify their surgical concern as either cosmetic or reconstructive and to indicate the location on their body where they were having surgery. Additionally, a series of statements regarding resident involvement was presented with a 5-point Likert-type rating system to assess each patients attitudes about a range of factors, such as resident sex and seniority. RESULTS In total, 119 patients participated in the study by completing the survey. Of this population, 59.7% (n = 71) were classified as reconstructive surgery patients and 40.3% (n = 48) were classified as cosmetic surgery patients. Based on responses, it was determined that reconstructive surgery patients were more approving of resident involvement in their care than cosmetic surgery patients were. When other factors were analyzed, the patients seeking breast surgery were found to be more apprehensive about resident participation than non-breast surgery patients were. CONCLUSION Although there were some differences in the way resident participation was perceived by cosmetic and reconstructive surgery patient populations, neither group strongly believed that resident participation decreased the quality of patient care. Based on these findings, plastic surgery training programs should begin to allow residents to become more involved in the care of cosmetic surgery patients.

Image Guidance during Abdominal Exploration for Recurrent Colorectal Cancer

BackgroundReal-time intraoperative image guidance has been successfully applied to malignancies of the head, neck and central nervous system. Few attempts have been made to apply this technology to gastrointestinal cancers. Our purpose was to determine if a computer-assisted navigation system could be accurately used at the time of abdominal exploration.MethodsFourteen patients with resectable recurrent colorectal cancer underwent computer tomography (CT) imaging of the abdomen and pelvis. The CT images were uploaded to a StealthStation (Medtronic, Inc., Minneapolis, MN), a device that tracks the motion of a handheld probe in the operating field and displays its position, in real time, on the uploaded images. Various anatomic points were utilized to match, or register, the patient to the images in the navigation system. After four or more anatomic points were registered, the accuracy of the registration process was computed by the navigation system and reported as the global error.ResultsA total of 23 different anatomic structures were used for registration. The median number of points used for registration per patient was 6.5 (range 5–9). The anatomic sites most commonly used were the anterior superior iliac spines, aortic bifurcation, sacral promontory, symphysis pubis, and iliac artery bifurcation. The median global error was 10.0 mm (range 6.7 mm–27.0 mm).ConclusionComputer-assisted navigation systems can be used to accurately deliver image guidance at the time of abdominal exploration. Future work will be directed at determining the value of this technology in the localization and resection of tumors.