Faculty Bibliography

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.

PURPOSE/OBJECTIVE:Our laboratory has previously shown that tumors are more easily established and grow larger after laparotomy vs. laparoscopy. The purpose of this study was to better characterize these differences in tumor growth by assessing tumor cell proliferation via the proliferating cell nuclear antigen assay, which has been shown to be a reliable marker of cellular proliferation. METHODS:Female C3H/He mice (N = 40) were inoculated intradermally in the dorsal skin with 10(6) cultured mouse mammary carcinoma cells <1 hour before interventions. Anesthesia control mice underwent no procedure. Laparotomy group mice had a midline incision from xiphoid to pubis that was closed after 20 minutes. Insufflation group mice underwent CO2 pneumoperitoneum (4-6 mmHg) for 20 minutes. On postoperative Day 6, tumors were excised from one-third of the mice in each group, and from the remaining mice on postoperative Day 12. Sections were made and stained immunohistochemically for proliferating cell nuclear antigen, and the proliferative index of each tumor was determined by taking the average of proliferating cell nuclear antigen-positive cells in five high-power fields (x450), counted in a blinded fashion with the aid of an optical grid. RESULTS:On postoperative Day 6, the mean proliferative index for the laparotomy group was significantly higher than those for both the insufflation (P < 0.04) and the control (P < 0.001) groups. Of note, the proliferative index of the insufflation group was significantly higher than that of the control (P < 0.01) group. Similarly, on postoperative Day 12, the mean proliferative index for the laparotomy group was significantly higher than for both the insufflation (P < 0.05) and the control (P < 0.005) groups. The proliferative index in the insufflation group was also significantly higher than that of the control (P < 0.04) group. CONCLUSIONS:We have demonstrated that there is a significantly higher rate of tumor cell proliferation with the mouse mammary carcinoma cell tumor line after laparotomy than after pneumoperitoneum or anesthesia alone at two postoperative times. Additionally, insufflation alone increases postoperative tumor cell proliferation but to a lesser extent than laparotomy. The mechanism underlying these findings is unclear.

BACKGROUND:Previous work has demonstrated that cell-mediated immune function in rats is better preserved after laparoscopic than open surgery. We have also shown that tumors are more easily established in mice and grow larger after sham laparotomy than after pneumoperitoneum. The purpose of this study is to determine if the functional status of the cell-mediated immune system influences postoperative tumor growth. METHODS:Immunocompetent (study 1) and T-cell deficient athymic (study 2) mice were injected with mouse mammary carcinoma cells in the dorsal skin. Mice then underwent either no procedure, midline laparotomy, or carbon dioxide pneumoperitoneum. Tumor masses on postoperative day 12 were compared. RESULTS:In immunocompetent mice, laparotomy group tumors were nearly twice as large as laparoscopy group tumors (p < 0.02), which were 1.5 times as large as control group tumors (NS). In the athymic model, however, differences between the sham laparotomy and pneumoperitoneum groups were lost (p > 0.5). Tumors grew much larger in the athymic control mice than in the immunocompetent control mice (p < 0.01). CONCLUSION/CONCLUSIONS:We conclude that T-cell function plays a significant role in host containment of mouse mammary carcinoma and in the mechanism of differences in tumor growth observed after laparotomy and pneumoperitoneum.

BACKGROUND:Many cellular elements responsible for wound healing are affected by laparotomy. The aim of this study was to evaluate the effects of laparotomy and CO2 pneumoperitoneum on wound healing. METHODS:Male Sprague Dawley rats were randomly assigned to one of three experimental groups. Anesthesia control rats underwent no procedure. Pneumoperitoneum group rats were insufflated with CO2 gas. Laparotomy group rats underwent a 7-cm midline laparotomy incision. The interventions were 30 min long. For the incisional study (n = 30), a 4-cm dorsal full-thickness skin incision was made on each rat and then closed with staples. On postoperative days 7 and 14, an equal number of rats were sacrificed from each group, and wound tensile strength measurements were performed. For the excisional study (n = 45), each group of 15 rats underwent a 2-cm diameter circular dorsal full-thickness skin excision. Blinded measurements of wound area were performed every other day until wounds closed. RESULTS:Wound tensile strength values were not significantly different among experimental groups at either time point. The study had a power of 80% to find a 30% difference at POD 7 and a power of 80% to find a 23% difference at POD 14 to a confidence level of p < 0.05. Wound contraction data from the excisional model were analyzed with the Generalized Estimation Equations statistical approach. When we modeled the treatment group as a covariate, no statistical difference was found between groups, demonstrating equal slopes across time. CONCLUSIONS:From the results of these studies, we conclude that wound healing in this model is not significantly diminished following laparotomy or peritoneal insufflation, as compared to anesthesia control.