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Autophagy or self-eating is an evolutionarily conserved process whereby cells, in response to stress conditions, use lysosomal-mediated degradation of long-­lived proteins and retired organelles to regenerate energy. It protects cells from harsh conditions and prolongs cell survival. Cancer therapeutics induce a variety of stresses in tumor cells including nutritional starvation, DNA damage, ER stress, and ROS generation. Not surprisingly, the great majority of cancer therapeutics also induce autophagy. As such, autophagy becomes an inseparable part of cancer therapy and its modulation, and thus deserve attention. In this review, we discuss the current prostate cancer therapies, the cell biology and detection method of autophagy, the relationship of autophagy to apoptosis and necroptosis, and autophagy modulation in experimental prostate cancer therapies. Finally, we provide a comprehensive summary of the autophagy characteristics (induction and function) of experimental and clinically tested prostate cancer treatments, as well as current clinical trials involving autophagy modulators.

Retinoids are a class of molecules structurally related to vitamin A that have potent antiproliferative and differentiating effects on a variety of normal and neoplastic tissues. All-trans-retinoic acid (ATRA) has become a first-line chemotherapeutic agent in the treatment of certain leukemias; however, the effect of ATRA on pancreatic tumors is unknown. The purpose of this study was to determine the effect of ATRA on the growth characteristics of both exocrine and endocrine human pancreatic cancer cell lines. The in vitro growth of four cell lines was examined after treatment with a wide dose range of ATRA. The growth of all tumor cell lines was inhibited by ATRA in a dose-dependent fashion beginning at 0.1 microgram M. The in vivo growth of functioning human pancreatic carcinoid (BON) xenografts in Balb/c athymic mice was determined by treatment with several doses of ATRA over 1 month. The growth of BON tumors was inhibited in a dose-dependent fashion. These results suggest that ATRA exerts direct antiproliferative effects on both exocrine and endocrine human pancreatic cancers and may be useful in the chemotherapy of these tumors.

The purpose of the study was to produce human monoclonal antibodies (hMcAb) against human colon cancer for use in radioimmunoimaging. Human-mouse heterohybridomas were developed by fusing SHM-D33 mouse-human hybrid heteromyeloma cells with human lymphocytes from colon cancer tumor-draining lymph nodes. The hybridomas capable of secreting human monoclonal antibodies were screened by using human colon cancer cell lines and pathological biopsies with ELISA and immunohistochemical methods. hMcAb clone H11 was selected for a large-scale antibody production, which was purified from mouse ascites. Biodistribution study demonstrated that specific uptake of 125I-hMcAb H11 by human colon cancer xenografts was significantly higher than by normal tissues. Radioimmunoimaging of human colon cancer xenografts exhibited distinct tumor visualization during the period of 72-96 hr after intraperitoneal injection of 125I-hMcAb H11. The development of human monoclonal antibodies such as hMcAb H11 may be useful for radioimmunodetection and therapy of colon cancer.

We sought to characterize the extent of extremity soft tissue tumor (ESTT) resections among surgical specialties, hypothesizing that substantial variation exists in the number of ESTT resections performed by specialty.We queried the UHC-AAMC database for data from 85 institutions for years 2007-2009. We abstracted data on total number of musculoskeletal (MSK) procedures, number of subcutaneous (SQ), deep, and malignant ESTT resections, and anatomic site of resection. Data were available for 4,682 practitioners including the following specialties: general surgery (GS, N = 2,195), plastic surgery (PS, N = 792), surgical oncology (SO, N = 533), general orthopedics (GO, N = 1,079), and orthopedic oncology (OO, N = 83).The mean number of all MSK procedures performed per year was 19.0 ± 2.3 GS, 179.6 ± 3.0 PS, 32.4 ± 6.2 SO, 798.6 ± 115.4 GO, and 482.9 ± 6.5 OO (P = 0.001). SQ ESTT resections per year were similar among specialties (1.7 ± 0.3 GS, 2.7 ± 0.3 PS, 2.4 ± 0.4 SO, 1.7 ± 0.5 GO, 4.7 ± 0.2 OO), while deep and malignant resections were more likely performed by OO (combined deep and malignant: 0.9 ± 0.1 GS, 2.0 ± 0.4 PS, 9.9 ± 0.6 SO, 5.8 ± 0.3 GO, and 63.6 ± 8.1 OO, P = 0.001). Adjusting for number of physicians in the database, of the total deep and malignant ESTT resections, 9.4% were performed by GS, 7.7% by PS, 26.0% by SO, 30.8% by GO, and 26.0% by OO.Nearly 50% of deep and malignant ESTT resections are performed by non-oncology-designated surgeons. Approximately 17% are performed by practitioners who complete an average of one to two of these procedures per year. These findings may have significant implications for quality of care in soft tissue tumor surgery.

10 Background: Among individuals with advanced cancer (AC), frequent hospitalization is often at odds with patient preference and is increasingly viewed as a hallmark of poor quality care. Hospitalization contributes substantially to costs and regional spending variation in this population, but patterns and reasons are poorly described in the literature. Methods: California Cancer Registry data linked with hospital claims were used to quantify hospitalization in the year after diagnosis among individuals with AC [colorectal, pancreatic, prostate, breast, non-small cell lung cancer (NSCLC)] between 2009-2012 (n = 25, 032). Multi-state models and multilevel log-linear Poisson regression were used to model re-hospitalizations as a function of individual and hospital characteristics, accounting for the competing risk of mortality. Results: Among individuals with AC, 71% were hospitalized, 16% had at least 3 hospitalizations, and 64% of hospitalizations originated in the emergency department. Re-hospitalization rates were significantly higher for black, non-Hispanic (IRR 1.3; 95% CI: 1.1-1.4); Hispanic (IRR 1.1; 95% CI: 1.0-1.2); or Asian/Pacific Islander (IRR 1.1; 95% CI: 1.0-1.2) race/ethnicity vs. white, non-Hispanic; for public (IRR 1.4; 95% CI: 1.3-1.5) or no insurance (IRR 1.2; 95% CI: 1.0-1.5) vs. private; for lower SES quintiles (IRRs 1.1-1.3) vs. the highest; for 1 and 2 or more (IRR 1.1-1.6) comorbidities versus none, and for pancreatic cancer (IRR 2.1; 95% CI 1.9-2.2) and NSCLC (IRR 1.7; 95% CI 1.5-1.9) vs. colorectal cancer. Re-hospitalization rates were significantly lower after discharge from a hospital reporting an outpatient palliative care program (IRR 0.90; 95% CI 0.84-0.96). Conclusions: Individuals with AC experience a heavy burden of hospitalizations, many of which originate in the ED. Discharge from a hospital reporting an outpatient palliative care program appears to protect against re-hospitalization. Efforts to reduce hospitalization and provide care congruent with patient preferences might focus on improving access to outpatient palliative care, particularly among subgroups at greater risk, including racial/ethnic minority groups, those with lower SES, comorbidities and pancreatic or NSCLC.

Hepatocyte growth is regulated by various growth factors, including epidermal growth factor (EGF) and insulin. Recently, several additional peptide hormones have been shown to stimulate growth of hepatocyte only in the presence of EGF or insulin and are thus termed secondary mitogens. Gastrin regulates growth of normal and neoplastic gastrointestinal tissues, but the effect on growth of hepatocyte is unknown. We examined the effect of gastrin on growth of a normal mouse hepatocyte (NMH) line established in our laboratory. Effect of gastrin-17 (G-17) (10−8 to 10−6 M) on growth of NMH cells was examined in either the presence or absence of EGF in the culture medium. Growth of NMH cells was evaluated by incorporation of either bromodeoxyuridine (BrdU) or 3H-thymidine and by counting cells. Presence of a cell-surface receptor for G-17 was determined by Scatchard analysis using 125I-G-17. In the presence of EGF, gastrin stimulated growth of NMH cells; in the absence of EGF, gastrin did not affect growth. The stimulatory effect of gastrin on NMH cells was blocked by JMV 320, a CCK-B type receptor antagonist. NMH cells possess a single, high affinity binding site for gastrin (Kd = 1.2 nM); EGF increased the gastrin binding capacity compared to non-treated cells (3.5 ± 0.4 vs. 2.2 ± 0.6 fmol/106 cells). G-17 stimulated growth of NMH cells through a single high affinity receptor for G-17 which pharmcologically appears to be the CCK-B type only in the presence of EGF and thus can be considered a secondary mitogen. © 1995 Wiley-Liss, Inc.

Breast sentinel node biopsy (SNB) is a well-established procedure that has supplanted traditional axillary dissection for most clinically node-negative breast cancer patients. Techniques to identify the draining lymph nodes include colored dyes and radioactive compounds. The Sentimag system uses a non-radioactive magnetic tracer and a handheld magnetic probe to identify sentinel nodes (SNs). The Sentimag Intraoperative Comparison (SentimagIC) study compares the magnetic technique with the standard combination of radioisotope and isosulfan blue dye. Methods: SiennaXP is a nano device composed of coated iron oxide nanoparticles designed to optimize lymphatic uptake and SN retention. The Sentimag breast SNB technique involves injection of 2cc of SiennaXP fluid into Sappey's subareolar plexus followed by 5 minutes of breast massage and an additional 15 minutes of time to optimize drainage prior to beginning the procedure. The Sentimag hand held probe is then used to identify a magnetic 'hotspot' through the skin of the axilla. The usual transverse axillary incision is made and the magnetometer is used to identify the SNs. The SentimagIC study involves utilizing the Sentimag technique in combination with the 'standard' techniques of isosulfan blue dye and 99technetium sulfur colloid. All blue, radioactive and magnetic SNs are removed and identified as stained blue (from isosulfan blue dye) or black/brown (from SiennaXP) or not, and both radioactive and magnetic counts are taken ex vivo on each node. Currently there are 6 active sites with a total of 60 patients enrolled. Trial design: This is a pivotal, prospective, open label, multicenter, paired comparison of the magnetic technique with the standard of care for lymph node localization in patients with breast cancer. Primary endpoints: The lymph node detection rate with SentiMag / SiennaXP and the detection rate with the standard of care; and the safety of Sentimag / SiennaXP as indicated by adverse events. Eligibility: Diagnosis of primary breast cancer or pure ductal carcinoma in situ (DCIS); Scheduled for sentinel lymph node biopsy; Clinical negative node status (i.e. T0-3, N0, M0). Statistical methods: The primary hypothesis is that the magnetic technique is non-inferior to the standard technique. Based on an expected detection rate of 95% for both techniques and a non-inferiority margin of 5%, 140 subjects will be required to show non-inferiority with 85% power. Discussion: SNB for breast cancer is a robust procedure, able to identify the draining lymph nodes of the breast in essentially all patients. Many techniques have been used including radioactive tracers (utilized on most cases) and colored dyes. SentiMag utilizes a unique nano device that can identify the same draining nodes but without the radioactivity used in most procedures. Radioactive dyes must be handled carefully to minimize radiation exposure to healthcare providers and the patient from the manufacturing process, delivery to facility, injection under a nuclear physician license, and the surgical procedure. This novel technique may supplant radioactive tracers allowing SNs to be removed without the patient/healthcare providers being exposed to radiation or the scheduling inconvenience of pre-procedure injection. Citation Format: Beitsch PD, Hunt KK, Bold RJ, Gittleman MA, Blair SL, Alvarado MD, Harmer QJ. Magnetic nano-device for identification of the breast sentinel nodes – A novel method. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-02-03.

There are conflicting data regarding improvements in postoperative outcomes with perioperative epidural analgesia. We sought to examine the effect of perioperative epidural analgesia vs. intravenous narcotic analgesia on perioperative outcomes including pain control, morbidity, and mortality in patients undergoing gastric and pancreatic resections. We evaluated 169 patients from 2007 to 2011 who underwent open gastric and pancreatic resections for malignancy at a university medical center. Emergency, traumatic, pediatric, enucleations, and disseminated cancer cases were excluded. Clinicopathologic data were reviewed among epidural (E) and non-epidural (NE) patients for their association with perioperative endpoints. One hundred twenty patients (71 %) received an epidural and 49 (29 %) did not. There were no significant differences (P > 0.05) in mean pain scores at each of the four days (days 0–3) among the E (3.2 ± 2.7, 3.2 ± 2.3, 2.3 ± 1.9, and 2.1 ± 1.9, respectively) and NE patients (3.7 ± 2.7, 3.4 ± 1.9, 2.9 ± 2.1, and 2.4 ± 1.9, respectively). Within each of the E and NE patient groups, there were significant differences (P

Surgical resection of isolated pulmonary metastatic melanoma improves overall survival in a highly select group of patients. However, the devil is in the details. By that, I mean that a critical examination of how these “selected” patients are identified needs to be made to ensure a benefit from the surgical intervention while sparing those patients with poor outcomes the complications of a thoracic operation. Peterson et al 1 reported a series of more than 1700 patients with pulmonary metastasis from cutaneous melanoma; less than 20% underwent resection of the metastatic disease to the lung. From this and other studies, those patients most likely to benefit harbor solitary lesions; furthermore, incomplete resection offers minimal improvement in survival. Chua et al 2 recently reported a single-institution series of 292 consecutive patients; the median survival for patients undergoing resection of a solitary melanoma metastasis was 35 months, decreasing to 21 months for 2 or 3 melanoma metastases and 10 months for more than 3 distinct lesions, 2 which is not different from the median survival of 8 months for those patients who did not undergo resection of pulmonary metastatic melanoma. 1 Therefore, the preoperative selection of patients is essential to identify those patients most likely to benefit from thoracic surgery and to spare an unnecessary and potentially morbid operation for those who will not benefit. In the current series 3 reported from the group at the John Wayne Cancer Institute in Santa Monica, California,reportedinthisissueofArchives,26%ofpatientstaken to the operating room for a thoracic resection of pulmonary melanoma metastases have more lesions than anticipated based on preoperative imaging using contrastenhancedcomputedtomography.Theseadditionallesions were small (median size of 5 mm) and located in a different lobe than the index lesion in one-third of patients. Although Kidner et al 3 recommend caution when considering a thoracoscopic approach (because the additional lesions were identified by palpation or visual inspection), their data are really a plea for better preoperative imaging for more accurate patient selection. As additional unsuspected lesions are identified during the exploratory phase of the operation, the benefits of resection start to decrease. Although resection of all palpable or noticeable melanomas may seem a surgical success, biologywilltriumphattheendoftheday.Wemuststrive to move from “selected” patients for surgical procedures to “accurately and individually selected” patients. Until then, a surgeon’s hands may be the best tool to facilitate surgical planning.

Two receptors for cholecystokinin (CCK) have been isolated which also bind gastrin: CCK-A type and CCK-B type, both are coupled to phospholipase C (PLC) activation. However, identification of the "true" gastrin receptor remains controversial. We determined which CCK receptor mediated the trophic effect of gastrin on human colon cancer cells (LoVo). LoVo cells lack mRNA for either CCK receptor by Northern hybridization. Gastrin stimulated cyclic AMP production, not PLC activity, in LoVo cells. The trophic effect was not blocked by receptor antagonists for CCK-A (L364,718) or CCK-B (L365,260). The gastrin receptor pharmacology on LoVo cells and the lack of appropriate transcripts suggest that gastrin stimulated growth of these cells by a receptor other than CCK-A or CCK-B type and there likely exists another receptor for gastrin.

Cultured LLC-WRC256 (Walker rat carcinoma) cells were exposed to different doses of high energy shock waves (HESW). The immediate viabilities were 98% in the control cells, and 74%, 53% and 18% following 400, 800, and 1500 HESW treatment, respectively. Surviving cells in the 400 and 800-treated HESW demonstrated delayed upward growth rate curves, and the 1500 HESW-treated a downward curve. Agar clonogenic etficiencies for surviving cells were 36% (control), 20% (400 HESW), 15% (800 HESW) and 3% (1500 HESW). LLC-WRC256 tumours in Wistar rats were treated once every other day with 1500 HESW on a total of three occasions. Tumours treated with HESW grew more slowly (4.9 cm3) than those in the control (13.5 cm3). HESW fragmented cells and destroyed cell membranes and intracellular organelles. A histological examination of tumours treated with HESW demonstrated local haemorrhage with necrosis in the HESW focus area. Damage to the surrounding skin and soft tissue was slight and transient. These findings suggest that the growth of tumour cells can be suppressed in vitro and in vivo by treatment with HESW.

Hemorrhage from the presacral venous plexus is a potentially life-threatening complication of pelvic operations. The morbidity and mortality that stems from severe hemorrhage has led to the development of various hemostatic techniques. Although suture ligature, packing, and placement of tacks can be very effective, they can often be unsuccessful. When these conventional hemostatic techniques fail, alternative approaches are required. We describe the successful use of an expandable breast implant sizer and outline the practical, theoretical, and financial advantages of applying this technique when more conservative approaches have failed.

Post-mastectomy radiation therapy (PMRT) is indicated for local-regionally advanced breast cancer (LABC). We hypothesized that candidates for PMRT from non-urban areas would receive lower rates of RT than urban patients and would have poorer overall survival (OS) and disease-specific survival (DSS). We used the Surveillance, Epidemiology, and End Results database to identify patients diagnosed with LABC and treated with mastectomy in Sacramento and its surrounding 13 counties between 2000 and 2006. All patients were eligible to receive RT according to established guidelines, with tumors >5 cm size, ≥ 4 metastatic lymph nodes, or both. According to a United States Department of Agriculture scale, we designated counties as urban or non-urban and used multivariate logistic regression and Cox proportional hazards models to predict the use of RT, overall survival (OS), and disease-specific survival (DSS). Density of radiation oncologists in non-urban and urban counties was determined using the American Medical Association database in relation to census-derived populations of the respective counties. Entry criteria were met by 1,507 patients. Most (56.5%) were from urban counties; only 61% received RT. There was no radiation oncologist listed for 8/10 non-urban counties and 2/4 urban counties. Each radiation oncologist served 88,804 people in non-urban counties and 68,624 residents in urban counties. On multivariate analysis, non-urban patients (OR 0.56, CI 0.44-0.72) and increasing age were the only factors predicting a decreased likelihood of receiving RT (OR 0.97, CI 0.96-0.98). Patients not receiving PMRT experienced poorer OS (HR 1.77, CI 1.39-2.25; P < 0.001) and DSS (HR 1.62, CI 1.23-2.15; P = 0.001); however, non-urban status did not predict OS or DSS. Non-urban residents with LABC are less likely to receive indicated PMRT. This discrepancy may be due to limited RT access in non-urban areas. The lack of poorer OS and DSS due to this disparity requires further study.

Prognostic factors specific to medullary carcinoma of the breast (MCB) are unknown. Our objective was to identify patient and tumor factors predictive of overall survival (OS) in a large cohort of MCB patients. The Surveillance, Epidemiology, and End Results database was used to identify patients with MCB diagnosed from 1988 to 2004. Patient, tumor, and treatment factors were compared by univariate analysis via the Kaplan–Meier method and survival differences detected using the log-rank test. A multivariate Cox proportional hazards model controlled for patient age, race, type of surgery, radiotherapy, tumor size, number of lymph node metastases (LNM), lymph node yield (LNY), estrogen receptor (ER) and progesterone receptor (PR) status, and extent of disease. On univariate analysis of 3,348 patients, factors influencing OS included age, race, tumor size, ER status, type of surgery, radiotherapy, LNM, LNY, and extent of disease (P < 0.001). On multivariate analysis, advancing age (P < 0.001), black race (P < 0.001), regional metastases (P < 0.001), distant metastases (P < 0.001), increasing tumor size (P < 0.001), ER positivity (P = 0.003), and increasing LNM (P < 0.001) were associated with decreased OS. An OS benefit was seen in PR-positive patients (P = 0.002) and in those with increasing LNY (P < 0.001). Even among node-negative patients, increasing LNY was associated with improved OS (P < 0.001). Tumor size, LNM, regional and distant metastases, PR status, age, and race are important prognostic factors in MCB. ER positivity was associated with decreased OS, which may reflect inaccuracy in diagnosing MCB or a significant biologic variant. The improved OS seen with increasing LNY in node-negative patients suggests MCB may be currently understaged.

To estimate individual risk of 30-day surgical morbidity and mortality after surgical intervention for patients with disseminated malignancy (DMa).Patients with DMa frequently require surgical consultation for palliative operations. Although these patients are at high risk for surgical morbidity and mortality, limited data exist allowing individual risk stratification.Using the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) from 2005 to 2007, we identified 7447 patients with DMa. Each of the 53 preoperative ACS NSQIP variables was analyzed to assess risk of morbidity and mortality. Logistic regression models were developed using stepwise model selection and generalized additive models. Covariates were evaluated for nonlinearity and interactions among variables. We constructed nomograms utilizing clinically and statistically significant covariates to predict 30-day risk of morbidity and mortality.Overall 30-day unadjusted morbidity and mortality rates were 28.3% and 8.9%, respectively. Mortality rates reached 18.4% for vascular procedures and 27.9% for emergent operations. Increasing age, impaired functional status, Do-Not-Resuscitate status, impaired respiratory function, ascites, hypoalbuminema, elevated creatinine, and abnormal WBC were all significant predictors (P0.0001) of increased morbidity and mortality on multivariate analysis. Nomograms to predict individual 30-day risk of complications and death based on preoperative factors were developed and validated by bootstrapping. Concordance indices were 0.704 and 0.861 for morbidity and mortality, respectively.Surgical intervention among patients with DMa is associated with substantial morbidity and mortality. We have constructed nomograms to predict individual risk of 30-day morbidity and mortality. These have significant implications for surgical decision-making in this group of patients.

Background Although well-differentiated liposarcoma (WD Lipo) is a low grade neoplasm with a negligible risk of metastatic disease, it can be locally aggressive. We hypothesized that survival for WD Lipo varies significantly based on tumor location. Methods We identified 1266 patients with WD Lipo in the Surveillance, Epidemiology, and End Results database from 1988–2004. After excluding patients diagnosed by autopsy only, those lacking histologic confirmation, those lacking data on tumor location, and those with metastatic disease or unknown staging information, we arrived at a final study cohort of 1130 patients. Clinical, pathologic, and treatment variables were analyzed for their association with overall survival (OS) and disease-specific survival (DSS) using Kaplan-Meier analysis and Cox proportional hazards multivariate models. Results Mean age was 61 y (±14.6), 72.2% were white, and 60.4% were male. Eighty-one percent of patients were treated with surgical therapy alone, 4.6% were treated with radiotherapy (RT) alone, and 12.9% were treated with both surgery and RT. Extremity location was most common (41.6%), followed by trunk (29%), retroperitoneal/intra-abdominal (RIA, 21.6%), thorax (4.2%), and head/neck (3.6%). With a median follow-up of 45 mo, median OS was 115 mo (95% confidence interval [CI] 92–138 mo) for RIA tumors compared to not reached for other tumor locations ( P = 0.002). On multivariate analysis, increasing age and RIA location both predicted worse OS and DSS while tumor size, race, sex, receipt of RT, and Surveillance, Epidemiology, and End Results (SEER) stage did not. Tumor size became a significant predictor of worse DSS, but not OS, only when site, SEER stage, and extent of resection were removed from the multivariate model. Non-RIA locations, including extremity, experienced statistically similar OS, but 5-y DSS for trunk location was intermediate [92.3%, (95% CI 88.5%–96.1%) compared with 98.0% (95% CI, 96.2%–99.8%) for extremity and 86.6 (95% CI 81.1%–92.1%) for RIA, P Conclusions Among patients with WD Lipo, RIA location is associated with significantly worse outcomes independent of tumor size. Future studies should focus on the anatomic and biologic reasons for these differences.

Open distal pancreatectomy (ODP) outcomes have largely relied on single-institution data from high-volume, tertiary centers. To provide contemporary, national benchmarks of ODP outcomes, we examined the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database. Using the ACS-NSQIP database (2005–2007), we identified 868 cases of ODP. Operative time, intraoperative transfusion, and length-of-stay (LOS) data were compiled. Univariate and multivariate analyses were performed adjusting for age, body mass index, diagnosis, creatinine, albumin, hematocrit, and American Society of Anesthesiologists (ASA) classification for likelihood of any postoperative complication and severe complication (composite endpoint: organ space surgical site infection, reoperation, or death). Thirty-day overall complication, severe complication, and mortality rates were 27.2%, 11.6%, and 1%, respectively. Mean operative time was 206 min (±86), 18.1% patients required intraoperative red blood cell transfusion (median 2 units), and median LOS was 6 days. Predictors of any complication or severe complication were renal insufficiency, hypoalbuminemia, and worsening ASA classification. Malignant diagnosis was not associated with poorer outcomes. ODP remains the gold standard for lesions of the pancreatic body or tail. The current analysis reflects nationwide data that may serve as current benchmarks for both open and laparoscopic techniques.

Outcomes of surgical resident training are under scrutiny with the changing milieu of surgical education. Few have investigated the effect of surgical resident involvement (SRI) on operative parameters. Examining 7 common general surgery procedures, we evaluated the effect of SRI on perioperative morbidity and mortality and operative time (OpT).The American College of Surgeons National Surgical Quality Improvement Program database (2005 to 2007) was used to identify 7 cases of nonemergent operations. Cases with simultaneous procedures were excluded. Logistic regression was performed across all procedures and within each procedure incorporating SRI, OpT, and risk-stratifying American College of Surgery National Surgical Quality Improvement Program morbidity and mortality probability scores, which incorporate multiple prognostic individual patient factors. Procedure-specific, SRI-stratified OpTs were compared using Wilcoxon rank-sum tests.A total of 71.3% of the 37,907 cases had SRI. Absolute 30-day morbidity for all cases with SRI and without SRI were 3.0% and 1.0%, respectively (p0.001); absolute 30-day mortality for all cases with SRI and without SRI were 0.1% and 0.08%, respectively (p0.001). After multivariate analysis by specific procedure, SRI was not associated with increased morbidity but was associated with decreased mortality during open right colectomy (odds ratio 0.32; p = 0.01). Across all procedures, SRI was associated with increased morbidity (odds ratio 1.14; p = 0.048) but decreased mortality (odds ratio 0.42; p0.001). Mean OpT for all procedures was consistently lower for cases without SRI.SRI has a measurable impact on both 30-day morbidity and mortality and OpT. These data have implications to the impact associated with surgical graduate medical education. Further studies to identify causes of patient morbidity and prevention strategies in surgical teaching environments are warranted.

Increases in intracellular Ca2+ ([Ca2+]i) levels mediated by bombesin (BBS) are believed to be important signals leading to stimulation of DNA synthesis and an increase in cellular proliferative rate. Since the role of BBS on growth of normal or malignant cells in the GI tract is still unclear, we examined whether BBS affects in vitro growth of human colon cancer cells (COLO 320, HCT116 and LoVo). We also examined the effect of BBS on intracellular Ca2+ levels to determine if the growth-regulatory effect of BBS is mediated through increases in [Ca2+]i. Levels of [Ca2+]i in response to BBS were measured by single cell fluorescence after loading with fura-2. BBS stimulated the mobilization of [Ca2+]i in COLO 320, LoVo, and HCT116 cells in a dose-dependent fashion, but did not affect in vitro growth. These findings suggest that the BBS-mediated increase in [Ca2+]i does not always correlate with the growth-regulatory effect of BBS.

Health care disparities have been documented in rural populations. The authors hypothesized that breast cancer patients in urban counties would have higher rates of postmastectomy breast reconstruction relative to patients in surrounding near-metro and rural counties.The authors used the Surveillance, Epidemiology, and End Results database to identify patients diagnosed with breast cancer and treated with mastectomy in the greater Sacramento area between 2000 and 2006. Counties were categorized as urban, near-metro, or rural. Univariate models evaluated the relationship of rural, near-metro, or urban location with use of breast reconstruction by means of the chi-square test. Multivariate logistic regression models controlling for patient, tumor, and treatment-related factors predicted use of breast reconstruction. The likelihood of undergoing breast reconstruction was reported as odds ratios with 95 percent confidence intervals; significance was set at p≤0.05.Complete information was available for 3552 breast cancer patients treated with mastectomy. Of these, 718 (20.2 percent) underwent breast reconstruction. On univariate analysis, differences in the rates of breast reconstruction were noted among urban, near-metro, and rural areas (p0.001). On multivariate analysis, patients from rural (odds ratio, 0.51; 95 percent confidence interval, 0.28 to 0.93; p0.03) and near-metro (odds ratio, 0.73; 95 percent confidence interval, 0.59 to 0.89; p=0.002) areas had a decreased likelihood of undergoing breast reconstruction relative to patients from urban areas.Patients from near-metro and rural areas are less likely to undergo breast reconstruction following mastectomy for breast cancer than their urban counterparts. Differences in use of breast reconstruction detected at a population level should guide future interventions to increase rates of breast reconstruction at the local level.

The practice of aggressive contiguous organ resection (COR) of retroperitoneal sarcoma (RPS) is controversial. We examined rates of 30-day morbidity and mortality following resection of RPS utilizing data from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database.From 2005 to 2007, we identified 156 cases of primary malignant neoplasm of the retroperitoneum. Univariate and multivariate analyses were performed using all pre-operative ACS-NSQIP variables for likelihood of post-operative overall morbidity or severe morbidity (composite endpoint including organ space infection, septic shock, acute renal failure requiring dialysis, reoperation, and death). Insufficient events precluded multivariate analysis of mortality as an independent outcome.Overall 30-day morbidity, severe morbidity, and mortality were 26% (N = 40), 11.5% (N = 18), and 1.3% (N = 2), respectively. Fifty-eight patients (37%) underwent COR, most commonly kidney. American Society for Anesthesiologists classification predicted overall morbidity (OR 3.23, 95% CI 1.33-7.84), while increasing operative time predicted severe morbidity (OR 1.38 per hour, 95% CI 1.05-1.81). COR was not associated with increased 30-day overall morbidity (OR 1.38, 95% CI 0.49-3.89) or severe morbidity (OR 0.78, 95% CI 0.05-13.18).Rates of post-operative morbidity and mortality are acceptable following RPS resection, even in the setting of multi-visceral resection. COR should not be viewed as a contraindication to complete RPS resection.

The PI3K/Akt signaling pathway is constitutively activated in some pancreatic cancers; when activated, it inhibits chemotherapy-mediated apoptosis. We examined whether Akt activity correlates with apoptotic resistance to chemotherapy in pancreatic cancer.A panel of human pancreatic cancer cells was evaluated for basal Akt activity as well as response to three chemotherapies. Chemotherapy-induced cell death was evaluated following either up- or down-regulation of Akt activity. Evaluation of phosphorylation of p21Cip/Waf1, a downstream target of Akt, was also evaluated.There was a broad distribution among pancreatic cancer cell lines by Akt activity, as well as sensitivity to the three chemotherapeutic agents with no apparent correlation. Phosphorylation of p21Cip/Waf1, but not change in total levels, correlated with the chemosensitizing effect of Akt inhibition to paclitaxel.Basal Akt activity does not appear to be a useful predictor for selection of pancreatic cancers in targeting Akt to broadly induce chemosensitivity.

Background Bcl-2 is an essential regulator of programmed cell death (PCD). Overexpression of Bcl-2 is common in pancreatic cancer; the high levels have been shown to correlate with resistance to PCD. This resistance is mediated by binding of Bcl-2 via its BH-3 domain to diverse proteins, including the Bax/Bak family members, various protein kinases, and beclin 1, which are involved in regulation of autophagy (type II PCD). Small molecule inhibitors of BH-3-mediated binding of Bcl-2 have been recently developed, although no investigation has been conducted in pancreatic cancer, a malignancy characterized by extreme resistance to PCD. Methods The effect of the Bcl-2 binding inhibitor A-779024 on PCD was assessed by fluorescence activated cell sorting; the effect on Bcl-2 and other PCD-related proteins was analyzed by immunoblotting. Induction of autophagy was determined by fluorescence microscopy using a stably transfected GFP-LC3 construct to visualize autophagosome formation. Co-localization of Bcl-2 with binding partners regulating PCD was examined by immunoprecipitation and confocal immunofluorescent microscopy. Results A-779024 induced PCD in a dose- and time-dependent fashion. No change was seen in the protein levels of Bcl-2, Bax, Bcl-XL, or Mcl-1. Contrary to prediction, A-779024 was ineffective at inducing autophagy in these cells. Co-localization studies demonstrated that Bcl-2 was not bound to beclin 1 and, therefore, treatment with A-779024 could not induce release of beclin 1 and initiation of autophagy. Conclusions Disruption of Bcl-2 activity using the small molecule inhibitor A-779024 induces apoptotic but not autophagic PCD. This approach may be a novel therapy, either alone or in combination with other treatments such as chemotherapy or autophagy modulating agents in pancreatic cancer.

Background Histologic grade is considered the paramount prognostic factor in predicting survival for soft-tissue sarcomas (STS). Increasing data suggest that histologic type substantially impacts STS behavior. Study Design The Surveillance, Epidemiology, and End Results program was used to identify 17,364 cases of STS diagnosed between 1988 and 2004. Using death from STS as 1 of the outcomes variables, histologic types were grouped into 3 categories: favorable (survival ≥ 20% above the mean), neutral (survival within 20% of the mean), and unfavorable (survival ≥ 20% below the mean). The effect of histology on survival was analyzed stratified by tumor grade. Five-year survival was calculated using Kaplan-Meier analysis. Results Among 73 histologic types, malignant fibrous histiocytoma (24.1%); leiomyosarcoma, not otherwise specified (14.8%); sarcoma, not otherwise specified (12.8%); and myxoid liposarcoma (5.9%) were the most prevalent. Grade distribution was as follows: low, 12.6%; intermediate, 14.9%; high, 37.1%; and unknown, 35.4%. Risk of death from STS increased with increasing grade: 8.0% for low, 25.9% for intermediate, and 38.3% for high. Among low-grade tumors, risk of death from STS ranged from 4.3% for favorable types to 15.3% for unfavorable types. Among intermediate-grade tumors, risk of death from STS ranged from 6.0% for favorable types to 45.4% for unfavorable types. Among high-grade tumors, risk of death from STS ranged from 24.3% for favorable types to 58.9% for unfavorable types. Conclusions Within categories of STS grade, there are substantial differences in survival, depending on histologic type. Histologic type is an important predictor of biologic behavior in STS.

Apoptosis has long been recognized as a critical mechanism of programmed cell death that is preserved among all eukaryotes and is involved in a variety of disease processes. Malignant transformation of cells is associated with a constellation of pro-survival mutations rendering them resistant to apoptosis. Traditional cancer therapy evokes cell death by inducing apoptosis; however, the apoptotic resistance inherent in cancer cells has been a significant barrier to effective chemotherapy. More recently, other mechanisms of cell death have emerged as potential novel mechanisms for cancer therapies to induce cell death, either in addition to, or instead of, apoptosis-induced cytotoxic treatment. Autophagy is a process that occurs in all cells, but is induced in many types of cancer. Autophagy functions as both a cell survival and a cell death mechanism depending on the context and the stimuli, which are likely exploitable for cancer therapy. Anoikis is also a physiologic process in normal cells used to maintain homeostasis, in which cell death is induced in response to loss of extracellular membrane (ECM) attachment. Cancer cells are notoriously resistant to anoikis, enabling metastasis and new tumor growth beyond their original environment. Interestingly, autophagy may actually by a major contributor to anoikis resistance in cancer. As these two processes are elucidated in more detail, there is great potential for novel targets that affect cancer cell death, in addition to the current cytotoxic agents.

Introduction Bortezomib is a small-molecule proteasome inhibitor with single-agent activity in patients with non-small cell lung carcinoma (NSCLC) and synergy with gemcitabine in preclinical studies. The combination of gemcitabine and carboplatin is an accepted first-line treatment for advanced NSCLC. We conducted a phase I study of gemcitabine and carboplatin in combination with bortezomib. Methods Bortezomib was administered on days 1, 4, 8, and 11, after gemcitabine on days 1 and 8, and carboplatin on day 1 of a 21-day cycle. Three escalating dose levels were evaluated: bortezomib 1.0 mg/m 2 /gemcitabine 800 mg/m 2 , bortezomib 1.0 mg/m 2 /gemcitabine 1000 mg/m 2 , and bortezomib 1.3 mg/m 2 /gemcitabine 1000 mg/m 2 , in combination with carboplatin AUC 5.0. Results Twenty-six patients with advanced NSCLC were treated; 21 were chemotherapy-naive. The median age was 59 years (range, 34–74), and 23 patients were stage IV. The Karnofsky performance score was ≤80% in 10 and >80% in 16 patients. Dose-limiting toxicities were grade 3 thrombocytopenia with bleeding and febrile neutropenia accompanied by grade 4 thrombocytopenia and grade 3 hyponatremia. The maximum-tolerated dose was defined as bortezomib 1.0 mg/m 2 , gemcitabine 1000 mg/m 2 , and carboplatin AUC 5.0. The most common grade 3/4 toxicities were thrombocytopenia (rarely associated with bleeding), and neutropenia. Nine of 26 patients (35%) achieved partial response, and eight patients had stable disease. Conclusions The combination of bortezomib 1.0 mg/m 2 , gemcitabine 1000 mg/m 2 , and carboplatin AUC 5.0 demonstrated manageable toxicities and encouraging activity in NSCLC. This regimen was used in a phase II study.

BCL-2 is the prototypic anti-apoptotic protein involved in the regulation of apoptosis. Overexpression of BCL-2 is common in pancreatic cancer and confers resistance to the apoptotic effect of chemo- and radiotherapy. Although these cellular effects of BCL-2 are traditionally related to pathways involving the mitochondrial membrane, we sought to investigate whether BCL-2 is involved in other signaling pathways regulating cell survival and focused on AKT. We examined the effect of overexpression of BCL-2 in the MIA-PaCa-2 human pancreatic cancer cell line on the function and subcellular location of AKT. We observed that the stable subclones of MIA-PaCa-2 overexpressing BCL-2 demonstrated increased activity of AKT as well as IKK (a downstream target of AKT), increasing the transcriptional activity of NF-kappaB. Using immunoprecipitation techniques, we observed co-immunoprecipitation of AKT and BCL-2. Immunocytochemistry demonstrated co-localization of BCL-2 and AKT, which was abrogated by treatment with HA14-1, a small molecule inhibitor of BH-3-mediated protein interaction by BCL-2. Furthermore, treatment with HA14-1 decreased phosphorylation of AKT and increased sensitivity to the apoptotic effect of the chemotherapeutic agent, paclitaxel. These results demonstrate an additional mechanism of regulation of cell survival mediated by BCL-2, namely through AKT activation, in the MIA-PaCa-2 pancreatic cancer cell line. Therefore, directed inhibition of BCL-2 may alter diverse pathways controlling cell survival and overcome the apoptotic resistance that is the hallmark of pancreatic cancer.

Understanding how physicians acquire and adopt new technologies for cancer diagnosis and treatment is poorly understood, yet is critical to the dissemination of evidence-based practices. Sentinel lymph node biopsy (SLNB) has recently become a standard technique for axillary staging in early breast cancer and is an ideal platform for studying medical technology diffusion. We sought to describe the timing of SLNB adoption and patterns of surgeon interactions with the following educational sources: local university training program, surgical literature, national meetings/courses, national specialty centers, and other local surgeons. A cross-sectional survey that used semistructured interviews was used to assess timing of adoption, practice patterns, and learning sources for SLNB among surgical oncologists and general surgeons in a single metropolitan area. A total of 44 eligible surgeons were identified; 38 (86%) participated. All surgical oncologists (11 of 11) and most general surgeons (26 of 27) had implemented SLNB. Surgical oncologists were older (mean 51 vs. 48 years, P = .02) and had used SLNB longer (6.1 vs. 3.3 years, P = .01) than general surgeons. By use of social network diagrams, surgical oncologists and the university training program were shown to be key intermediaries between general surgeons and national specialty centers. Surgeons in group practice tended to use more learning sources than solo practitioners. Surgical oncologists and university-based surgeons play key educational roles in disseminating new cancer treatments and therefore have a professional responsibility to educate other community physicians to increase the use of the most current, evidence-based practices.

Sentinel lymph node biopsy (SLNB) has become a standard for axillary staging for early breast cancer patients. Prior studies suggest that SLNB may be more sensitive for the identification of lymph node disease than axillary lymph node dissection (ALND). We hypothesized that SLNB use increases the incidence of node-positivity in early breast cancer patients compared to ALND. Furthermore, survival improves due to more accurate staging (stage migration).Registry data from an NCI-designated cancer center was reviewed for breast cancer patients with T1 and T2 tumors for two 5-year periods: before (1993-1997) and after (2000-2004) SLNB implementation (1998). TNM staging was updated to conform to American Joint Committee on Cancer (AJCC) 2003 guidelines.There were no differences in tumor size or stage groupings between the two time periods (n = 316 and 577). There was a non-significant increase in the proportion of patients with lymph node involvement (32 vs. 27%; P = .16) after SLNB implementation; though a trend of increased incidence of single-node positive patients was observed (13 vs. 8%; P = .07). This was significant in patients with T1A/T1B tumors (10 vs. 3%; P = .04), though not seen in T1C or T2 tumors. Stage II survival improved in the later time period (P = .02).The increase in single-node positivity after SLNB implementation supports the theory that SLNB is more sensitive than ALND. Improvements in survival are likely due to the stage migration of patients who would have been node-negative by ALND (but were found to be node-positive by SLNB) in addition to improvements in adjuvant therapy.

Lung cancer is the most common cause of cancer-related death among men and women in the United States. Current trials are focusing on the integration of novel therapeutic agents into current non-small-cell lung cancer (NSCLC) treatment paradigms. Bortezomib, a small-molecule proteasome inhibitor, has single-agent activity in NSCLC and in combination with agents commonly used in NSCLC. This article will review the rationale and preclinical data supporting bortezomib combinations and the clinical trials with bortezomib alone and in combination in NSCLC to date.

Background Surgery can effectively palliate symptoms in patients with advanced malignancy and thereby maintain quality of life. However, the goal of surgical palliation should be balanced with the associated risks, and the decision to operate can be challenging for even the most experienced surgeon. Hypothesis There are significant deficiencies in training during residency and in continuing medical education in palliative surgical care leading to a lack of agreement for treatment recommendations. Design and Setting A survey of general surgeons involving 4 clinical vignettes of patients with advanced malignancies and varying degrees of symptoms. Respondents were asked to select the best treatment option for each patient from a list of 6 alternatives. Furthermore, respondents identified the clinical factors that most influenced the decision, as well as the major goal of the palliative intervention. Subjects Surgeons in a midsized urban setting and its surrounding region. Results Of 124 surveys sent out, 70 (56%) were completed. Significant deficiencies in education were identified; 59 (84%) of the respondents did not receive any education in palliative surgical care during residency and 28 (44%) lacked continuing medical education. A consensus treatment recommendation was not selected in 3 of the 4 clinical vignettes, but the respondents used similar clinical factors and goals of treatment for selection of the specific recommendation. Conclusions Palliative care is a major deficiency of postgraduate surgical training. A more focused effort in training surgeons in palliative care may allow for the more uniform and standard provision of palliative surgical care to patients with advanced cancer.

Background Immediate breast reconstruction is being increasingly used after mastectomy, although it may increase the incidence of wound complications. The indications for chemotherapy in breast cancer are expanding and wound complications following mastectomy may delay the initiation of adjuvant chemotherapy. Hypothesis Immediate breast reconstruction after mastectomy for breast cancer does not lead to an increased incidence of wound complications nor delay the initiation of systemic chemotherapy. Design and Setting Retrospective medical record review at a tertiary care center. Patients One hundred twenty-eight women treated with a mastectomy for breast cancer over an 8-year period (January 1, 1995, through December 31, 2002). Main Outcome Measures Surgical site complications (infectious and noninfectious) and time to initiation of postoperative chemotherapy. Results One hundred forty-eight mastectomy procedures in 128 women with breast cancer were evaluated. We analyzed 4 subgroups according to whether or not immediate breast reconstruction was part of the surgical procedure (76 or 72 procedures, respectively) and whether or not postoperative adjuvant chemotherapy was administered (81 or 47 patients, respectively). There was an increased incidence of wound complications in patients who underwent immediate breast reconstruction compared with those who did not (6/72 [8.3%] vs 17/76 [22.3%]; P = .02). However, these complications did not delay initiation of postoperative chemotherapy. Conclusions Although we observed an increased incidence of wound complications when immediate breast reconstruction was combined with mastectomy, there was no delay in the initiation of adjuvant therapy. Immediate breast reconstruction should remain an important treatment option after mastectomy even when postoperative chemotherapy is anticipated.

Background The optimal palliative method for patients with unresectable pancreatic cancer remains controversial. Methods A retrospective chart review evaluated patients who underwent exploration for presumed resectable pancreatic cancer. Cost-based analysis was performed using relative value units (RVUs) that included the initial surgical procedure and any additional procedure required to achieve satisfactory palliation. Results Of 96 patients (1993–2002), 6% had biliary bypass, 42% had duodenal bypass, 40% had double bypass, and 13% had no procedure with equivalent clinical outcomes. If biliary bypass was not initially performed, there was a significant incidence of biliary complications before definitive endoscopic stenting ( P = .01). If duodenal bypass was not initially performed, 11% developed duodenal obstruction ( P = .04). Total RVUs was highest for a double bypass and lowest for no initial surgical palliative procedure. Conclusions Although surgical bypass procedures at initial exploration provide durable palliation, these procedures are associated with greater costs.

HCCa remains an uncommon malignancy, though increasing use of more radical surgery has led to prolonged survival in those patients who undergo curative resection. The extent of these resections suggest that the best results are likely to be obtained in centers with the resources and experience to conduct these operations in a safe fashion. Until major advances in the systemic therapy of HCCa are made, however, the management should focus on optimal preoperative imaging and palliation of jaundice with improvement in quality of life.

Non-small-cell lung cancer (NSCLC) has a poor prognosis. Despite advances in therapy, survival has improved only slightly. The 26S proteasome regulates multiple cellular processes through degradation of ubiquitin-tagged proteins. The proteasome inhibitor, bortezomib (Velcade, formerly PS-341), has been shown to be an active anticancer agent both in vitro and in vivo in multiple tumor types. To determine the molecular and cellular effects of the proteasome inhibitor in NSCLC as well as to evaluate the effectiveness of sequential treatment with bortezomib and gemcitabine/carboplatin (G/C) chemotherapy both in vitro and in vivo. All experiments were performed in the A549 NSCLC cell line. MTT assays were used to evaluate cytotoxicity. Western blotting evaluated protein levels. Measures of apoptosis included FACS analysis, DAPI staining and caspase-3 cleavage. Long-term cell viability was determined using an anchorage-dependent clonogenic assay. Sequential studies were performed in vitro and in vivo. Bortezomib increased p21waf1/cip1, induced G2/M arrest, and triggered a small amount of apoptosis. The apoptotic effect of G/C chemotherapy was eliminated when bortezomib was administered prior to the chemotherapy; however, it was accentuated when the bortezomib was given simultaneously or after the chemotherapy. Bortezomib improves efficacy in combination with gemcitabine and carboplatin in NSCLC, but sequential effects are important and must be considered when developing therapeutic regimens.

We explore NIR autofluorescence and polarized light scattering imaging in combination with hyperspectral microscopy to detect and image various types of cancer . Fresh surgical human specimens are used and images are compared to histopathology

When activated, the serine/threonine kinase AKT mediates an antiapoptotic signal implicated in chemoresistance of various cancers. The mechanism(s) of AKT activation are unknown, though overexpression of HER-2/neu has been implicated in breast cancer. Therefore, we determined the incidence of activated AKT in human pancreatic cancer, whether HER-2/neu is involved in AKT activation, and if AKT activation is associated with biologic behaviour. HER-2/neu expression and AKT activation were examined in seven pancreatic cancer cell lines by Western blotting. The in vitro effect of HER-2/neu inhibition on AKT activation was similarly determined. Finally, 78 pancreatic cancer specimens were examined for AKT activation and HER-2/neu overexpression, and correlated with the clinical prognostic variable of histologic grade. HER-2/neu was overexpressed in two of seven cell lines; these two cell lines demonstrated the highest level of AKT activation. Inhibition of HER-2/neu reduced AKT activation in vitro. AKT was activated in 46 out of 78 (59%) of the pancreatic cancers; HER-2/neu overexpression correlated with AKT activation (P=0.015). Furthermore, AKT activation was correlated with higher histologic tumour grade (P=0.047). Thus, it is concluded that AKT is frequently activated in pancreatic cancer; this antiapoptotic signal may be mediated by HER-2/neu overexpression. AKT activation is associated with tumour grade, an important prognostic factor.

When activated, the nuclear factor (NF)-kappaB pathway is a potent cellular signal that inhibits apoptotic cell death. Pancreatic cancer is resistant to the apoptotic effect of chemotherapy, though it is unclear whether this is an inherent feature or a survival signal engaged in response to chemotherapy. We investigated whether pancreatic cancer cells activate the NF-kappaB pathway in response to chemotherapy and whether inhibition of this response altered the apoptotic efficacy of chemotherapy.We determined NF-kappaB activity after chemotherapy treatment of the MIA-PaCa-2 human pancreatic cancer cell line using both physical (electrophoretic mobility shift assay) and functional (luciferase) techniques. The effect of chemotherapy on transcription of the antiapoptotic gene BCL-2, a target of NF-kappaB, was determined. We examined the effect of inhibition of Akt, an upstream activator of NF-kappaB, on the molecular (NF-kappaB function and BCL-2 transcription) and cellular (apoptosis) effect of chemotherapy.Both the chemotherapeutic agents gemcitabine and paclitaxel activated NF-kappaB and stimulated BCL-2 gene promoter activity. The stimulation of BCL-2 promoter function was directly regulated by NF-kappaB. These cellular responses were blocked by inhibition of Akt. The apoptotic effect of gemcitabine and paclitaxel also was enhanced after Akt inhibition.Part of the apoptotic resistance of pancreatic cancer may be mediated by activation of the NF-kappaB survival pathway in response to chemotherapy. Inhibition of this response may be an important adjunct to increase the efficacy of chemotherapy.

Our report describes a 46-yr-old woman who presented with watery diarrhea in the presence of multiple endocrine neoplasia type I (MEN I) syndrome. Of various potential pancreatic endocrine hormones, only serum levels of pancreatic polypeptide were elevated. Radiologic imaging failed to identify a pancreatic tumor; her diarrhea was therefore managed with subcutaneous administration of somatostatin. Three years later she developed gallstone pancreatitis with the subsequent development of a pancreatic pseudocyst. At exploration for drainage of the pseudocyst, intraoperative ultrasound identified a 6-mm tumor in the distal pancreas that was resected. Final pathology documented a pancreatic endocrine tumor with immunohistochemical staining demonstrating the presence of pancreatic polypeptide. The present case illustrates the symptomatology that may be associated with pancreatic polypeptide-secreting endocrine tumors of the pancreas.

Recent studies have shown that the transcription factor, nuclear factor kappaB (NF-kappaB), regulates critical survival pathways in a variety of different cell types, including human pancreatic cancer cells. The activation of NF-kappaB is controlled by proteasome-mediated degradation of its endogenous polypeptide inhibitor, inhibitor of nuclear factor kappaBalpha. We investigated the effects of PS-341, a peptide boronate inhibitor of the proteasome in human pancreatic cancer cells in vitro and in vivo. Comparison of PS-341's effects on the growth of eight different human pancreatic cancer cell lines revealed marked heterogeneity in drug responsiveness, ranging from highly resistant (IC5010 microM; Panc-48, HS766T, and Mia-PaCa-2) to extremely sensitive (IC5040 nM; L3.6pl, Hpaf2, and BxPC3). However, these effects did not correlate with differential inhibition of NF-kappaB activation. Direct quantification of apoptosis revealed that PS-341's effects on cell growth largely correlated with sensitivity to programmed cell death. Evaluation of PS-341's effects on established orthotopic tumor xenografts demonstrated that biweekly intravenous administration of the maximum-tolerated dose of the drug (1 mg/kg) led to significant reductions in the volumes of L3.6pl tumors but not Mia-PaCa-2 tumors. Laser scanning cytometer-mediated quantification of drug-induced apoptosis in the xenografts confirmed that PS-341 induced DNA fragmentation and activation of caspase-3 in L3.6pl tumors but not in Mia-PaCa-2 tumors. However, histological examination of drug-treated tumors revealed extensive central necrosis and reductions in microvessel density and VEGF expression in both tumor types. Taken together, our results demonstrate that PS-341 inhibits the growth of human pancreatic tumors via direct effects on tumor cells and indirect effects on the tumor vasculature.

PURPOSE To determine the safety and utility of percutaneous transhepatic portography (PTP) with intravascular ultrasonography (IVUS) for preoperative evaluation of major spleno-mesenteric-portal venous invasion by tumors of the pancreas, porta hepatis, or liver. MATERIALS AND METHODS This is a 2-year prospective observational study including 15 consecutive patients (five men, 10 women; mean age, 63.3 y=10.2) with tumors of the pancreas ( n = 8), liver ( n = 3), or porta hepatis ( n = 4) who underwent PTP/IVUS after computed tomography indicated possible tumor invasion into a major portal radical. Transhepatic portal access was created under fluoroscopic guidance with an 8-F vascular sheath and IVUS was performed with an 8-F, 10-MHz system. When appropriate, operative exploration was performed (nine of 15) and findings were correlated with imaging data from PTP/IVUS. RESULTS PTP/IVUS was performed successfully in all patients and good visualization of the major portal radicals was achieved. There were no complications from PTP/IVUS, which was performed as an outpatient procedure in most ( n = 14) patients. PTP/IVUS provided precise anatomic data regarding the longitudinal and circumferential extent of major portal venous invasion by these tumors. There was excellent correlation between PTP/IVUS and operative findings. CONCLUSIONS PTP/IVUS can be performed safely in a preoperative outpatient setting and accurately defines the extent of major portal venous invasion by tumors of the pancreas, porta hepatis, and liver.

Hypothesis Preoperative and intraoperative localizing techniques are more cost-effective than a nondirected bilateral neck exploration in the initial treatment of primary hyperparathyroidism (HPT). Design A clinical outcome model was developed to simulate the surgical management of primary HPT. Clinical scenarios modeled included a nondirected bilateral neck exploration and surgery using the following localizing strategies: preoperative technetium Tc 99m sestamibi scanning, intraoperative "quick" intact parathyroid hormone assay, or intraoperative radioguidance. Average total charges based on intent to treat were estimated from our practice and from the literature. Main Outcome Measures Average total charges per patient (for the primary operation and for reexploration for persistent HPT, if needed), incidence of surgical failure (ie, persistent HPT), and risk of recurrent laryngeal nerve injury (cumulative risk of the primary procedure and a subsequent operation for persistent HPT). Results The use of any localizing strategy reduced total charges, risk of persistent HPT, and cumulative risk of recurrent laryngeal nerve injury compared with a nondirected bilateral neck exploration. The greatest cost savings and the lowest risk of recurrent laryngeal nerve injury were achieved when technetium Tc 99m sestamibi scanning was combined with intraoperative radioguidance. The lowest rate of persistent HPT was found when technetium Tc 99m sestamibi scanning was combined with an intraoperative parathyroid hormone assay. Conclusions Limited parathyroid surgery using any localizing strategy is cost-effective, safe, and efficacious in the management of primary HPT. The cost benefit was primarily achieved by reduced operative charges and immediate hospital discharge rather than a lower need for reexploration for persistent HPT.

Background: Pancreatic leak is a major source of morbidity associated with pancreatic surgery. We sought to identify disease and technique-dependent factors associated with morbidity and mortality after distal pancreatectomy. Methods: Retrospective review of patients who underwent distal pancreatectomy during a 5-year period. Clinical, technical, and pathologic data were correlated with operative morbidity or mortality. Results: Fifty-one patients underwent distal pancreatectomy for primary pancreatic disease, extrapancreatic malignancy, or trauma. Overall perioperative mortality and morbidity rates were 4% and 47%, respectively. Pancreatic leak was the most common complication, occurring in 26% of patients. Overall complications and pancreatic leaks occurred more often after distal pancreatectomy for trauma and in patients with a sutured pancreatic stump closure. Conclusions: Distal pancreatectomy can be performed with a low rate of mortality, though pancreatic leak is a common cause of morbidity. The urgency of the procedure and the method of pancreatic stump closure may influence postoperative morbidity.

The surgeon continues to play a key role in the initial local/regional management of breast cancer. Breast conserving therapy (BCT) utilizing segmental mastectomy has been developed as an alternative to total mastectomy to improve cosmetic and psychosocial outcomes while retaining oncologic benefits. Developments in the surgical treatment of breast cancer have changed the way breast cancer is diagnosed and treated, and will likely continue to evolve in the future. This review highlights aspects of breast cancer treatment in which the surgical approach has evolved or is evolving, and comments on how the surgeon may participate in breast cancer care in the future.