Faculty Bibliography

OBJECTIVE:There is much accumulated evidence that EGFR, HER2, and their downstream signaling pathway members such as KRAS, BRAF, and PIK3CA are strongly implicated in cancer development and progression. Recently, mutations in the kinase domains of EGFR and HER2, associated with increased sensitivity to tyrosine kinase inhibitors, have been described. METHODS:To evaluate the mutational status of these genes in intraductal papillary mucinous neoplasm (IPMN)/intraductal papillary mucinous carcinoma (IPMC), EGFR and HER2 were analyzed in 36 IPMN/IPMC, and the results were correlated to the mutational status of the KRAS, BRAF, and PIK3CA genes in the samples. RESULTS:Together, we identified 1 silent mutation of HER2, 17 (43%) KRAS mutations, 1 (2.7%) BRAF mutation, and 4 (11%) mutations of PIK3CA in the IPMN/IPMC samples. CONCLUSIONS:The EGFR and ERBB2 (HER2) mutations are very infrequent in IPMN/IPMC, suggesting the limited possibility of targeting mutated ERBB2 and EGFR for therapy for these lesions. The KRAS, BRAF, and PIK3CA, however, could represent interesting targets for future therapies in these lesions.

BACKGROUND:We evaluated the feasibility and efficacy of neoadjuvant chemotherapy and radiation for patients with locally unresectable pancreatic cancer. MATERIALS AND METHODS/METHODS:From October 2000 to August 2006, 245 patients with pancreatic adenocarcinoma underwent surgical exploration at our institution. Of these, 78 patients (32%) had undergone neoadjuvant therapy for initially unresectable disease, whereas the remaining patients (serving as the control group) were explored at presentation (n=167). All neoadjuvant patients received gemcitabine-based chemotherapy, often in conjunction with docetaxal and capecitabine in a regimen called GTX (81%). Seventy-five percent of neoadjuvant patients also received preoperative abdominal radiation (5,040 rad). RESULTS:Neoadjuvant patients were younger than control-group patients (60.8 vs 66.2 years, respectively, p<0.002). Seventy-six percent of neoadjuvant patients were resected as compared to 83% of control patients (NS). Concomitant vascular resection was required in 76% of neoadjuvant patients but only 20% of NS (p<0.01). Complications were more frequent in the neoadjuvant group (44.1 vs 30.9%, p<0.05), and mortality was higher (10.2 vs 2.9%, p<0.03). Among the neoadjuvant patients, all but one of the deaths were in patients that underwent arterial reconstruction. Mortality for patients undergoing a standard pancreatectomy without vascular resection was 0.8% in this series. Of patients resected, negative margins were achieved in 84.7% of neoadjuvant patients and 72.7% of NS. Within the cohort of neoadjuvant patients, radiation significantly increased the complication rate (13.3 vs 54.6%, p<0.006), but did not affect median survival (512 vs 729 days, NS). Median survival for patients who received neoadjuvant therapy (503 days) was longer than NS that were found to be unresectable at surgery (192 days, p<0.001) and equivalent to NS that were resected (498 days). CONCLUSIONS:Resection rate, margin status, and median survivals were equivalent when neoadjuvant patients were compared to patients considered resectable by traditional criteria, demonstrating equal efficacy. Surgical resection with venous reconstruction following neoadjuvant therapy for patients with locally advanced pancreatic cancer can be performed with acceptable morbidity and mortality. This approach extended the boundaries of surgical resection and greatly increased median survival for the "inoperable" patient with advanced pancreatic cancer.

BACKGROUND:Bilateral neck exploration has been the standard approach for patients with primary hyperparathyroidism. Improved localization studies and the availability of intraoperative parathyroid hormone monitoring have challenged the necessity of four-gland exploration. In this series we report a single surgeon's experience with bilateral neck exploration for primary hyperparathyroidism in an effort to establish benchmark outcomes from which to evaluate minimally invasive protocols. METHODS:The charts of 1112 consecutive patients who underwent neck exploration for primary hyperparathyroidism by a single surgeon over a 17-year period were reviewed. All patients underwent bilateral neck exploration under either general (n = 264) or local (n = 848) anesthesia. RESULTS:The overall cure rate was 97.4% with a complication rate of 3.4%. Morbidity included recurrent laryngeal nerve injury (0.2%), postoperative bleeding (0.8%), and transient hypocalcemia (1.8%). There was no mortality. Overall mean operating time was 52.5 +/- 30.2 minutes. A single gland was removed in 78.4% of patients, and 22.3% of patients underwent concomitant thyroidectomy. The cure rate was lower for patients undergoing reexploration (89.2% vs. 97.9%, p < 0.05). Choice of anesthetic approach did not affect the cure or complication rate. The overall conversion rate from local to general anesthesia was 1.5%. Patients undergoing general anesthesia were operated on earlier in the series and were less likely to be managed on an ambulatory basis (local 87.5% vs. general 38.4%, p < 0.05). During the last 5 years of the series, more than 90% of patients underwent exploration under local anesthesia. CONCLUSION/CONCLUSIONS:This large modern series of neck explorations for primary hyperparathyroidism confirms the safety, feasibility, and efficacy of the bilateral approach. It further demonstrates that individual surgeons can achieve outcomes equivalent to those with four-gland explorations under local anesthesia.

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.