Faculty Bibliography

Attempts to enhance patients' immune responses to malignancies have been largely unsuccessful. We now describe an immune-escape mechanism mediated by the inhibitory receptor Ig-like transcript 3 (ILT3) that may be responsible for such failures. Using a humanized SCID mouse model, we demonstrate that soluble and membrane ILT3 induce CD8(+) T suppressor cells and prevent rejection of allogeneic tumor transplants. Furthermore, we found that patients with melanoma, and carcinomas of the colon, rectum, and pancreas produce the soluble ILT3 protein, which induces the differentiation of CD8(+) T suppressor cells and impairs T cell responses in MLC. These responses are restored by anti-ILT3 mAb or by depletion of soluble ILT3 from the serum. Immunohistochemical staining of biopsies from the tumors and metastatic lymph nodes suggests that CD68(+) tumor-associated macrophages represent the major source of soluble ILT3. Alternative splicing, resulting in the loss of the ILT3 transmembrane domain, may contribute to the release of ILT3 in the circulation. These data suggest that ILT3 depletion or blockade is crucial to the success of immunotherapy in cancer. In contrast, the inhibitory activity of soluble ILT3 on T cell alloreactivity in vitro and in vivo suggests the potential usefulness of rILT3 for immunosuppressive treatment of allograft recipients or patients with autoimmune diseases.

The Raf/MEK/ERK (MAPK) signal transduction is an important mediator of a number of cellular fates including growth, proliferation, and survival. The BRAF gene is activated by oncogenic RAS, leading to cooperative effects in cells responding to growth factor signals. Our study was performed to elucidate a possible role of BRAF in the development of IPMN (Intraductal Papillary Mucinous Neoplasm) and IPMC (Intraductal Papillary Mucinous Carcinoma) of the pancreas. Mutations of BRAF and KRAS were evaluated in 36 IPMN/IPMC samples and two mucinous cystadenomas by direct genomic sequencing. Exons 1 for KRAS, and 5, 11, and 15 for BRAF were examined. Totally we identified 17 (47%) KRAS mutations in exon 1, codon 12 and one missense mutation (2.7%) within exon 15 of BRAF. The mutations appear to be somatic since the same alterations were not detected in the corresponding normal tissues. Our data provide evidence that oncogenic properties of BRAF contribute to the tumorigenesis of IPMN/IPMC, but at a lower frequency than KRAS.

INTRODUCTION/BACKGROUND:Patients undergoing partial pancreatectomy are at risk for developing surgically induced diabetes. Patients with lesions in the neck and body of the pancreas are at increased risk because traditional resectional approaches (pancreaticoduodenectomy or distal pancreatectomy) must be extended to remove the tumor with adequate margins. Increasingly, we have been performing pancreatic parenchyma-sparing resections (central pancreatectomy with pancreaticogastrostomy) in an effort to reduce the risk of postpancreatectomy endocrine insufficiency. METHODS:The operative records of patients who underwent pancreatectomy at our institution from 1999 to 2005 were reviewed. We identified 26 patients who underwent central pancreatectomy with pancreaticogastrostomy reconstruction for cystic lesions (n = 23), neuroendocrine tumors (n = 2), and Frantz's tumor (n = 1). Charts were reviewed for patient demographics, volume of resection, complications, and evaluation of postoperative glycemic control. RESULTS:The mean follow-up was 33 months (range 3-72 months). The average volume of pancreas resected was 49.6 +/- 38.6 cm(3), and the mean diameter of the lesions was 2.6 +/- 1.5 cm. Nine complications occurred in eight patients (overall morbidity 31%), and the average length of stay was 6.9 +/- 2.7 days. Pancreatic leaks (n = 2; 7.7%) were successfully managed nonoperatively. There was no operative mortality, and there has been no tumor recurrence. None of the patients were diabetic preoperatively. Postoperatively, two (7.7%) developed endocrine insufficiency with a mean postoperative hemoglobin A1c (HbA1c) value of 7.65%. Neither patient has required exogenous insulin. HbA1c in the remaining patients was 5.9% +/- 0.5%. CONCLUSIONS:Pancreatic parenchyma-sparing surgery for lesions in the midportion of the gland can be performed with acceptable morbidity. Postoperative glycemic control after pancreatic parenchyma-sparing surgery compares favorably with that reported for patients with traditional resections.

PURPOSE/OBJECTIVE:Recent studies have reported high frequencies of somatic mutations in the phosphoinositide-3-kinase catalytic-alpha (PIK3CA) gene in various human solid tumors. More than 75% of those somatic mutations are clustered in the helical (exon 9) and kinase domains (exon 20). The three hot-spot mutations, E542K, E545K, and H1047R, have been proven to elevate the lipid kinase activity of PIK3CA and activate the Akt signaling pathway. The mutational status of PIK3CA in intraductal papillary mucinous neoplasm/carcinoma (IPMN/IPMC) has not been evaluated previously. EXPERIMENTAL DESIGN/METHODS:To evaluate a possible role for PIK3CA in the tumorigenesis of IPMN and IPMC, exons 1, 4, 5, 6, 7, 9, 12, 18, and 20 were analyzed in 36 IPMN/IPMC and two mucinous cystadenoma specimens by direct genomic DNA sequencing. RESULTS:We identified four missense mutations in the nine screened exons of PIK3CA from 36 IPMN/IPMC specimens (11%). One of the four mutations, H1047R, has been previously reported as a hot-spot mutation. The remaining three mutations, T324I, W551G, and S1015F, were novel and somatic. CONCLUSION/CONCLUSIONS:This is the first report of PIK3CA mutation in pancreatic cancer. Our data provide evidence that the oncogenic properties of PIK3CA contribute to the tumorigenesis of IPMN/IPMC.

BACKGROUND:Thyroid surgery is performed using general anesthesia by the majority of surgeons in current practice. This study was conducted to analyze the utility and safety of local anesthesia for thyroid surgery. STUDY DESIGN/METHODS:Prospective data were collected for 1,025 consecutive patients undergoing thyroidectomy using monitored local anesthesia during a 16-year period by a single surgeon at a tertiary referral center. Patient features, operative data, length of stay, and complications are reported with multivariate analysis for factors associated with outcomes. RESULTS:A total of 1,025 patients underwent local thyroidectomy procedures; 34 required conversion to general anesthesia (3.3%). Total thyroidectomy (n = 589), lobectomy (n = 391), or subtotal and partial resections (n = 45) were performed for benign (n = 402), suspicious (n = 154), or malignant (n = 463) conditions. Local anesthesia was successful for thyroidectomy with concomitant parathyroidectomy (n = 142) or lymphadenectomy (n = 27), extensive goiter (n = 102), and reoperative neck procedures (n = 59). The majority of patients (90%) were considered low to intermediate risk (American Society of Anesthesiologists score </= 2), but 10% were considered high-risk (American Society of Anesthesiologists score >/= 3). With accumulating experience, local anesthesia was applied more broadly to high-risk (p < 0.001), older (p = 0.04), or obese patients (p = 0.04), and likewise used in more extensive goiter resections (p = 0.05) and bilateral procedures (p < 0.001). Patients experienced temporary (n = 20) and permanent (n = 10) recurrent laryngeal nerve injuries, hematoma (n = 5), permanent hypocalcemia (n = 1), emergent tracheostomy (n = 1), wound infection (n = 1), and myocardial infarction (n = 1). Outpatient procedures (96%) substantially increased with maturation of the local anesthesia program (p < 0.001). Length of stay > 24 hours was associated with patient comorbidity (p < 0.001, relative risk 3.25). CONCLUSIONS:Thyroidectomy using local anesthesia appears safe and applicable to a wide range of patients, including those who pose a general anesthetic risk or require more complex procedures, when performed by an experienced surgeon.

This article reviews the relevant literature and reports on The Columbia University Medical Center experience with chemoradiation for pancreatic cancer.

Although sestamibi scanning has been shown to have greater sensitivity and specificity than other preoperative localization techniques for parathyroid adenoma, it is unclear whether preoperative scanning improves outcomes for parathyroid surgery. Data from 528 consecutive patients who underwent neck exploration for primary hyperparathyroidism by one surgeon were collected prospectively over a 5-yr period. Patients were classified by preoperative scanning status (no scan, positive scan, and negative scan), and outcomes were compared in terms of operative time, length of hospital stay, and cure rate. Patients who had undergone a previous parathyroid operation and patients who received alternate preoperative localization techniques (ultrasound, magnetic resonance imaging, and computed tomography) were excluded from the study. All scans were ordered by the referring physician-the surgeon made no recommendations for preoperative scanning. All groups were similar in terms of gender, age, anesthesia class, body habitus, and complication rate. There was no significant difference in cure rate between patients who had preoperative scanning (97.5%) vs. those who did not (99.3%); however, there was a significant difference in cure rate between the negative-scan group (92.7%) and the positive and no-scan groups (99.3%, P < 0.01). In patients without concomitant thyroid surgery, there was no significant difference in operative time between the no scan (42.4 +/- 14.9 min) vs. the all-scan group (40.2 +/- 15.2 min); however, there was a significant difference between the negative scan group (44.5 +/- 21.9 min) and the positive scan group (38.5 +/- 12.6 min, P < 0.01). There was no significant difference in length of hospital stay among the three groups. These results suggest that, although preoperative sestamibi scanning does not alter the outcome of parathyroid surgery, it does identify those patients who are less likely to be cured.

BACKGROUND:Our laboratory and others have previously demonstrated that tumors grow larger and are more easily established following laparotomy than after CO(2) pneumoperitoneum. The etiology of increased tumor growth after surgery is unknown. We hypothesized that, following laparotomy, a serum soluble factor(s) is generated that causes tumors to proliferate more rapidly. The purpose of the current study was to determine if in vitro tumor cells proliferate faster when incubated with serum from laparotomized mice than cells incubated with sera from mice who have undergone CO(2) pneumoperitoneum or anesthesia alone. METHODS:In the first experiment, female Balb/C mice (n = 84) were randomly divided into the following three groups: (a) control (AC), (b) CO(2) insufflation (INS), and (c) laparotomy (OPEN). The AC mice underwent no procedure. The INS group underwent CO(2) pneumoperitoneum at 4-6 mmHg for 20 min. The OPEN group had a midline incision from xiphoid to pubis. The serum of seven mice from each group were collected on postoperative days (POD) 1, 2, 4, and 7 via a cardiac puncture. The sera at each time point for each group were pooled. Twenty thousand C-26 colon cancer cells were incubated separately in growth media containing 10% mouse serum from each group (seven determinations/group) at each time point. In the second experiment, female Balb/C (n = 30) mice were divided into AC and OPEN groups. On POD4, sera were collected and pooled. Three separate studies were performed for the second experiment. In the first study, tumor cells were incubated with 10% AC sera or varying concentrations of OPEN mice sera (4-10%). In the second study, aliquots of sera from the OPEN group mice were then heated at 100 degrees C for 1 or 5 min. Tumors were then incubated separately in media with 10% AC, OPEN, or heated OPEN group sera. In the third study, aliquots of sera from the OPEN group mice were dialyzed against PBS through a 3.5-kD or an 8-kD dialysis membrane tubing for 24 h. Tumors were then incubated separately in media with 10% AC, OPEN, or dialyzed OPEN group sera. For both experiments, tumor proliferation was determined and compared between groups after 72 h of incubation. RESULTS:Tumor cells incubated with POD2 and POD4 sera from OPEN group mice proliferated twice as fast as those incubated with sera from either AC or INS group mice. The difference in proliferation was maximal on POD4 and started to decline by POD7. Proliferative activity from the OPEN group sera decreased significantly when heated for 1 min and was completely ablated after 5 min of heating. Proliferative activity from the OPEN group sera was completely ablated after dialysis. CONCLUSIONS:We conclude that there is a serum-soluble factor(s) present postoperatively that stimulates tumors to grow significantly faster after laparotomy. The mitogenic effect of laparotomized mice sera is dilutable. It is uncertain whether the factor is heat labile, since heating most likely destroys other necessary proteins in the sera. The size of the factor is undeterminable using the dialysis method. Further efforts to identify these factors are currently underway.