Textbook outcome as a composite measure of quality in hepaticopancreatic surgery.

BACKGROUND: Textbook outcome (TO) is a valuable metric to assess postoperative outcomes. The aim of this study was to assess TO in patients undergoing hepatopancreatic surgery. METHODS: This was a retrospective cohort NSQIP study from 2015 to 2018. TOs are defined as no complication or mortality and length of stay within the 75th percentile. RESULTS: This study included 44 235 patients. Of those patients, 61% underwent pancreatic surgery (PS) and 39% hepatic surgery (HS). The most common surgical procedure was pancreaticoduodenectomy (16 464), followed by partial hepatectomy (11 817), distal pancreatectomy (8292), hemihepatectomy (4247), hepatic trisegmentectomy (1366) and total pancreatectomy (706). TO was more common for HS than PS, 47% versus 40%, p < .001. TO was more common for younger (0-65, OR: 1.60; CI: 1.30-1.96, p < .001), female (OR: 1.23; CI: 1.17-1.29, p < .001), white (OR: 1.10; CI: 1.01-1.19, p = .022), and lower ASA class (OR: 2.11; CI: 1.54-2.90, p < .001) patients. For patients undergoing HS TO was more common after partial lobectomy than trisegmentectomy and lobectomy (OR: 1.36; CI: 1.18-1.57, p < .001). For those undergoing PS, there was a lower likelihood of TO for those who are obese/morbidly obese compared to normal-weight patients (OR: 0.73; CI: 0.67-0.79, p < .001). Unlike HS, TO for patients undergoing PS was not associated with the type of surgical procedure. CONCLUSIONS: TO is a composite that can be applied to a national data set to analyze outcome quality. In HS, more complex surgical procedures are associated with a decreased likelihood of TO. In PS, TO are similar regardless of the procedure but less common in obese or morbidly obese patients.

Minimally invasive distal pancreatectomy for adenocarcinoma of the pancreas.

INTRODUCTION: Minimally invasive (MI) surgery has been widely adopted to treat left-sided pancreatic cancer. However, outcomes are not clearly defined. MATERIALS: Retrospective cohort study utilizing NCDB and NSQIP data. RESULTS: Patients undergoing distal pancreatectomy for pancreatic adenocarcinoma from 2004 to 2016 were included (n = 7347). Utilizing NSQIP (n = 2406), patients were divided into two groups: intention-to-treat (ITT) MI (including MI converted to open, n = 929) and open (n = 1477). Patients undergoing open pancreatectomy were more likely to have longer length of stay (6 vs. 5 days, p=<0.001). On multivariate analysis, open procedures were not associated with mortality (OR 1.24; CI 0.51-3.30, p = 0.64), serious complications (OR 1.03; CI 0.90-1.37, p = 0.79), and any complications (OR 1.07; CI 0.86-1.32, p = 0.56). NCDB patients (n = 4941) were also divided into two groups, ITT MI (n = 1,769, 36%) and open group (n = 3,172, 64%). The median survival was lower in open procedure patients, 23 vs. 27.1 months (p < 0.001). This finding was maintained on multivariable analysis (HR 1.16; CI 1.03-1.32, p = 0.017). CONCLUSION: Based on these data, MI distal pancreatectomy could be considered a standard of care for pancreatic cancer when technically feasible. Although morbidity and mortality were similar, the laparoscopic approach had a shorter length of stay and could hasten recovery.

Improved Overall Survival of Patients with Pancreatic Cancer through Multiagent Chemotherapy and Increased Rates of Surgical Resection.

BACKGROUND: Seminal trials have demonstrated improved survival in pancreatic adenocarcinoma with novel multiagent chemotherapy regimens. To understand the clinical ramifications of this paradigm shift, we reviewed our institutional experience. METHODS: This retrospective cohort study utilized a prospective database at a single institution to study all patients diagnosed with and treated for pancreatic adenocarcinoma between 2000 and 2020. RESULTS: 1,572 patients were included of which 36% were diagnosed before (Era 1) and 64% after (Era 2) 2011. Survival improved in Era 2 (Median survival 10 vs 8 months, HR .79; P < .001). The survival advantage for Era 2 was primarily seen in patients with high-risk disease (12 vs10 months, HR .71; P < .001). A similar trend was noted for patients undergoing surgical resection (26 vs 21 months, HR .80; P = .081) and with imminently resectable tumors (19 vs 15 months, HR .88; P = .4); however, this was not statistically significant. There was no survival advantage for patients with stage IV disease (4 vs 4 months). Patients in Era 2 were more likely to undergo surgery (OR 2.78; CI 2.00-3.92, P < .001). This increase was driven primarily by increased surgical resection for those with high-risk disease (42 vs 20%, OR 3.74; P < .001). DISCUSSION/CONCLUSIONS: This single institutional study showed improved survival after the shift to novel chemotherapy regimens. This was driven by improved survival for patients with high-risk disease and may be due to more effective eradication of microscopic metastatic disease with adjuvant chemotherapy and increased resection rates.

Pathologic Tumor Regression is Associated With Improved Survival in Pancreatic Cancer.

OBJECTIVES: The advent of effective chemotherapy regimens has increased the use of neoadjuvant multiagent chemotherapy in pancreatic cancer. However, the effect of tumor downstaging with neoadjuvant treatment on survival is unclear. METHODS: Retrospective study included all resected patients with pancreatic adenocarcinoma who underwent neoadjuvant chemotherapy with FOLFIRINOX or gemcitabine/Abraxane. Downstaging was quantified using (1) difference between presenting AJCC clinical and final pathologic stage and (2) College of American Pathologists (CAP) Tumor Regression Grading Schema. RESULTS: Eighty-seven patients met inclusion criteria. FOLFIRINOX was the most common regimen, 63.2% vs 21.8%. Change in regimen occurred in 15% of patients. Downstaging based on a difference in AJCC stage group occurred in only 4.6%. In contrast, 45.2% were classified as downstaged by the CAP Tumor Regression of 0-2. Downstaging was similar for FOLFIRINOX gemcitabine/Abraxane (64.7 vs 53.6, P = .12) using the CAP criteria. On univariate analysis, treatment regimen (gemcitabine/Abraxane vs FOLFIRINOX, median survival 27 vs 29 mo; HR 1.57, P = .2) had similar survival. Downstaging by the AJCC stage was not associated with improved survival (HR 1.51, P = .4). However, there was a survival benefit for those downstaged by the CAP Tumor Regression Grading Schema, the median survival of 41 mo vs 25 mo; HR 3.05, P = .009. Improved survival 3.32 (1.35-8.16), P = .009) was maintained on multivariate analysis. CONCLUSION: Survival is significantly improved in those downstaged, as assessed by the CAP Tumor Regression Schema. Downstaging is an important prognostic variable that can help with joint decision making for clinicians and patients.

Preoperative downstaging of pancreatic cancer is associated with improved survival after multi-agent chemotherapy, but not after radiation.

BACKGROUND: Downstaging has been associated with improved survival for many cancers. However, the implications of downstaging are unclear for pancreatic cancer in an era of effective neoadjuvant systemic chemotherapy. METHODS: NCDB retrospective cohort study of resected pancreatic carcinoma treated with neoadjuvant therapy. RESULTS: The study included 73,985 patients: 66,589 with no neoadjuvant therapy, 2,102 neoadjuvant radiation therapy (N-RT), 3,195 neoadjuvant multiagent chemotherapy (N-MAC) and 2.099 with both neoadjuvant radiation and multiagent chemotherapy. There was increased use of N-MAC over the period of this study. Patients selected for treatment with N-MAC had longer survival from surgery on univariate (23.1 vs. 18.7 months, p = < 0.01) and multivariate analyses HR 0.81 (0.76-0.87, p < 0.001) compared to those selected with N-RT. Downstaging was similar in N-RT and N-MAC groups (25.1 vs. 24.1%, p = 0.43). Downstaging following N-MAC was associated with a survival benefit, HR 0.85 (0.74-0.98). However, downstaging following N-RT was not associated with a survival advantage, HR 1.12 (0.99-0.99). CONCLUSION: Clinicians have rapidly adopted N-MAC for treatment of pancreatic cancer. Although the rates of downstaging are similar between treatment groups, response translates into increased survival only with N-MAC and not with N-RT.

Contemporary Treatment Paradigms are Associated with Improved Survival in Pancreatic Cancer.

INTRODUCTION: Over the last decade, a paradigm shift has been made in treating pancreatic cancer. Starting in 2011, several trials demonstrated a survival advantage for multiagent chemotherapy (MAC). However, the implication for survival at the population level remains unclear. METHODS: A retrospective study of the National Cancer Database from 2006 to 2019 was conducted. Patients treated from 2006 to 2010 were classified as "Era 1", and those treated from 2011 to 2019 as "Era 2." RESULTS: A total of 316,393 patients with pancreatic adenocarcinoma were identified, with 87,742 treated in Era 1 and 228,651 in Era 2. Survival increased from Era 1 to Era 2 in all patients and sub-analyses; surgical (18.7 vs 24.6 months, HR .85, 95% CI 0.82-.88, P < .001), imminently resectable (Stage IA and IB, 12.2 vs 14.8 months, HR .90, 95% CI 0.86-.95, P < .001), high-risk (Stage IIA, IIB, and III, 9.6 vs 11.6 months, HR .82, 95% CI 0.79-.85, P < .001), and Stage IV (3.5 vs 3.9 months, HR .86, 95% CI 0.84-.89, P < .001). Survival was decreased for those who were African American (P = .031), on Medicaid (P < .001), or in the lowest quartile of annual income (P < .001). Surgery rates decreased from 20.5% in Era 1 to 19.8% in Era 2 (P < .001). DISCUSSION: Adoption of MAC regimens at a population level correlates with improved pancreatic cancer survival. Unfortunately, socioeconomic factors are associated with an unequal benefit from new treatment regimens, and underuse of surgery for resectable neoplasms persists.

Pancreatic Cancer with Vascular Involvement: Adherence to Current Standard-of-Care Associated with Improved Survival.

METHODS: This study is a retrospective cohort study of National Cancer Data Base (NCDB) data for pancreatic cancer with vascular involvement. RESULTS: A total of 23 903 patients with vascular involvement were included and divided into 3 groups; no treatment (40.6%), medical treatment (36.6%), and resection (22.8%). Of the patients undergoing resection, 31.3% received neoadjuvant multiagent chemotherapy (N-MAC). The remainder were treated with postoperative adjuvant treatment (33.8%), surgery alone (24.9%), preoperative radiotherapy (8.3%), or single-agent preoperative chemotherapy (1.7%). Median survival for N-MAC was superior (28.42 months) when compared to neoadjuvant radiotherapy (20.73 months), neoadjuvant single-agent chemotherapy (20.8 months), postoperative adjuvant therapy (17.87 months), and surgery alone (10.12 months). N-MAC was associated with improved survival compared to postoperative multiagent chemotherapy (P-MAC) (28.4 vs 16.95, HR 1.82; CI 1.64-2.02, P < .0010) (Figure 1). The addition of radiation therapy to N-MAC did not improve survival (27.4 vs 29.8, HR .93; CI .83-1.05, P = .3). Clinical downstaging occurred in 40% of patients treated with N-MAC, and downstaging was associated with improved survival (HR .74; CI .64-.85, P < .001). N-MAC patients were more likely to undergo an R0 resection than P-MAC (74% v. 48, P < .001). CONCLUSIONS: Most resected pancreatic cancer patients in this study with vascular involvement receive either postoperative or no adjuvant therapy. N-MAC increases downstaging, R0 resection rates, and survival.

Revisiting the Pancreatic Fistula Risk Score: Clinical Nomogram Accurately Assesses Risk.

OBJECTIVES: Surgeons have created numerous iterations of the pancreatic fistula risk score (FRS) to predict risk for clinically relevant postoperative pancreatic fistula (CR-POPF). The multitude of often conflicting models makes it difficult for surgeons to apply data in clinical practice. METHODS: We conducted a retrospective cohort study utilizing National Surgical Quality Improvement Program data from 2015 to 2018. The study included patients undergoing pancreaticoduodenectomy. Missing data were resolved with multiple imputations. RESULTS: The study included 5975 patients; 1018 (17%) had a CR-POPF. On multivariate analysis, male sex (odds ratio (OR) 1.60 CI: 1.29-1.98 P < .001), obesity (OR 1.65 CI: 1.31-2.08 P < .001), and soft gland texture (OR 3.21 CI: 2.45-4.23 P < .001) were all associated with increased odds of a CR-POPF. Variables not associated with CR-POPF included diabetes, preoperative bilirubin, preoperative albumin, and American Society of Anesthesiologists (ASA) classification. On multivariate analysis, duct diameter >6 mm (OR .52 CI: .34-.77 P = .001), pancreatic adenocarcinoma pathology (OR .67 CI: .53-.84 P < .001), and neoadjuvant treatment (OR .71 CI: .51-.98 P = .042) were all associated with decreased odds of a CR-POPF. We constructed a clinically relevant nomogram from this model known as the Portland FRS. Model characteristics were superior to previously published FRS models. The area under the curve (AUC) for the Portland FRS was .72 (CI: .704-.737). In comparison, AUCs for the Alternative and Seoul FRS were .70 and .64, respectively. CONCLUSION: Utilizing readily available clinical data, the Portland FRS can accurately predict the risk for pancreatic fistula. The nomogram may assist surgeons in patient counseling and perioperative management.

The Cost of Frailty in Complex Gastrointestinal Surgery.

BACKGROUND: Frailty is a syndrome characterized by decreased physiologic reserve related with aging; it has been associated with increased costs of health care. Factors driving its economic impact remain poorly understood. We examine the association between frailty, complications, and costs in complex gastrointestinal surgery. METHODS: Retrospective review of a prospective database encompassing elective complex gastrointestinal operations from 2017 to 2018 at a tertiary care hospital. Patients were categorized into non-frail (NF): MFI 0, pre-frail (PF): MFI 1-2, and frail (FR): MFI >2 based on the 5-Factor Modified Frailty Index. Linear regression models were applied. RESULTS: 612 patients were included; 268 (44%) were NF, 325 (53%) were PF, and 19 (3%) were FR. The FR group had a longer length of stay (7.26 days) compared to NF (5.05 days) or PF (5.67 days) (p = 0.031). The average total cost of care for all patients was $19,413.06 (CI 18,297.13-20,528.98). The cost for NF was $17,648.54 (CI 15,969.18-19,327.9), PF $20,435.70 (CI 18,911.01-21,960.4, p = .016), and FR patients was $26,809.36 (CI 20,511.9-33,106.81). A complication was observed in 91 patients (14.9%); of these, 76 (12.4%) were serious complications, as defined by NSQIP. There was no difference in incidence of complications (NF 14.93%, PF 14.46%, FR 21.05%, p = .734). On average, a complication added $12,656.67 regardless of frailty category. DISCUSSION: Frail patients are more costly and have a longer length of stay than their more robust counterparts. Complications were the major driver of costs after complex gastrointestinal surgery regardless of frailty status.

Multiscale anisotropy analysis of second-harmonic generation collagen imaging of human pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with a minority (< 10%) of patients surviving five years past diagnosis. This could be improved with the development of new imaging modalities for early differentiation of benign and cancerous fibrosis. This study intends to explore the application of a two-photon microscopy technique known as second harmonic generation to PDAC using the 2D Wavelet Transform Modulus Maxima (WTMM) Anisotropy method to quantify collagen organization in fibrotic pancreatic tissue. Forty slides from PDAC patients were obtained and eight images were captured per each tissue category on each slide. Brownian surface motion and white noise images were generated for calibration and testing of a new variable binning approach to the 2D WTMM Anisotropy method. The variable binning method had greater resistance to wavelet scaling effects and white noise images were found to have the lowest anisotropy factor. Cancer and fibrosis had greater anisotropy factors (Fa) at small wavelet scales than normal and normal adjacent tissue. At a larger scale of 21 µm this relationship changed with normal tissue having a higher Fa than all other tissue groups. White noise is the best representative image for isotropy and the 2D WTMM anisotropy method is sensitive to changes induced in collagen by PDAC.

Predicting loss of independence after high-risk gastrointestinal abdominal surgery: Frailty vs. NSQIP risk calculator.

BACKGROUND: Loss of independence (LOI) is a significant concern for patients undergoing high-risk abdominal surgery. Although the risk for morbidity and mortality has been well studied, there is a dearth of data on risk for LOI. METHODS: This study utilized NSQIP data from 2015 to 2018 in a retrospective cohort study of patients undergoing high-risk gastrointestinal surgery (e.g. gastric, colorectal, liver, and pancreatic). RESULTS: The study included 229,573 patients who were preoperatively functionally independent. Of those, 5.3% experienced LOI. The median age for LOI patients was 74 (CI: 67-81), and 56% were female. The most common race was white (n = 9585), followed by African-American (n = 1223) and other (n = 369). The most common GI procedure was colorectal (65%), followed by the pancreas (23%), liver (8.2%), and gastric (3%). On univariate analysis, age, sex, BMI, race, frailty, and pancreatectomy were associated with LOI. On multivariate analysis age (≥85, OR 18.3 CI:16.9-19.9 p < 0.001), female sex (OR 1.24CI: 1.19-1.29 p < 0.001), BMI <18.5 (OR 1.66 CI:1.48-1.86 p < 0.001), BMI >40 (OR 1.43 CI:1.31-1.56 p < 0.001), African American race (OR 1.20 CI:1.12-1.28 p < 0.001), smoking (OR 1.21 CI:1.14-1.28 p < 0.001), frailty (MFI-5 > 2, OR 4.47 CI:2.63-7.31 p < 0.001), and pancreatectomy (OR 1.86 CI:1.74-1.98 p < 0.001) continued to be associated with LOI. To better define a predictive model, the NSQIP risk calculator was compared to the modified frailty index-5. AUC was 0.80 (CI: 0.797-0.805) and 0.76 (0.760-0.769), respectively. CONCLUSION: LOI occurs in over five percent of patients undergoing high-risk abdominal surgery. LOI occurs more commonly after pancreatectomy or for those who are frail, underweight, or morbidly obese. Both frailty and the NSQIP risk calculator models similarly predicted LOI.

Improvement in Surgical Quality Following Pancreaticoduodenectomy With Increasing Case Volume in a Rural Hospital.

BACKGROUND: The literature is replete with studies that define the nexus of quantity and quality in complex surgical operations. These observations have heralded a call for centralization of care to high-volume centers. The purpose of this study was to chronicle improvements in quality associated with pancreaticoduodenectomy (PD) as a rural hospital matures from a low- to very high-volume center. METHODS: A retrospective review of a prospective pancreatic surgery database was undertaken from July 2007 to June 2020. Annual periods were characterized as low (≤12/year), high (13-29/year), and very high volume (≥30/year). Data for the following quality benchmarks were aggregated and compared: length of stay (LOS), 30-day readmissions, 30-day mortality, and 1- and 3-year survival. A subgroup analysis was undertaken in those patients undergoing PD for adenocarcinoma detailing margin status and number of lymph nodes harvested. Outcomes were compared using the Fisher's exact and Student's t-test. RESULTS: 375 PD were completed over the 13-year period; 62.1% were undertaken for ductal adenocarcinoma. There was a significant decrease in LOS and 30-day readmissions as the institution matured toward very high volume. There were no significant differences in 30-day mortality, 1- and 3-year survival, or margin negativity rates associated with volume. Extent of lymph node harvest significantly improved as institutional experience increased. DISCUSSION: Our pancreatic surgery program matured rapidly from low to very high volume with institutional commitment and dedicated resources. As the institution matured, operational efficiencies and surgical quality improved. Not unexpectedly, biology trumped volume as reflected in 1- and 3-year survival rates.

Traveling to Receive Treatment for Extremity Soft Tissue Sarcomas: Is it worth the drive?

BACKGROUND: Regionalization of sarcoma care may improve outcomes. Concerns exist regarding the burdens of travel and its effects on care. We evaluate the presence of a "distance bias". METHODS: Retrospective cohort study of patients with extremity soft tissue sarcoma (stage I-III) within the NCDB. Travel distance (TD) and hospital volume (VOL) were categorized into quartiles. Alternating statistical models were used for analysis. RESULTS: 1,035 hospitals contributed 11,979 cases. Median and maximum VOL were 5 and 45 cases/year. VOL quartiles were "low-volume" (LV) (892 hospitals, < 3 cases/yr.), "intermediate low-volume" (ILV) (89, 3-5 cases/yr.), "intermediate high-volume" (IHV) (39, 6-12 cases/yr.), and "high-volume" (HV) (15, > 12 cases/yr.). TD quartiles: "short-travel" (ST) (< 8 mi), "intermediate-short travel" (IST) (8-17), "intermediate long-travel" (ILT) (18-49), and "long-travel" (LT) (> 50). VOL but not TD is associated with improved survival [HR 0.65 (CI 0.52-0.83)] and rate of R0 resection [1.87 (CI 1.4-2.5)] but has no effect on amputation rates. Matched analyses demonstrate similar results. CONCLUSIONS: Hospital volume but not distance traveled to treatment facility is associated with improved survival and R0 resections for extremity soft tissue sarcomas. Despite the inconveniences of travel, patients may benefit from treatment at high volume centers.

Upfront resection versus neoadjuvant therapy for T1/T2 pancreatic cancer.

BACKGROUND: The role of neoadjuvant therapy remains controversial for resectable pancreatic neoplasms. We evaluated treatment outcomes for T1/T2 tumors. METHODS: Retrospective study of patients with T1/T2 (Stage I-II) pancreatic cancer within the NCDB. Treatment-sequence variables were used for classification: "surgery + chemotherapy" (S+C), "chemotherapy + surgery" (C+S), "surgery only" (SO), and "chemotherapy only" (CO). RESULTS: 13 412 patients were included; the majority had T2 tumors. 8 490 received upfront surgery; 4 922 preoperative chemotherapy. In the surgery branch, 5 684 received surgery and chemotherapy (S+C); 2 806 did not receive chemotherapy (SO). Of those intended to receive preoperative chemotherapy, 3 804 received only chemotherapy (CO); 1 118 proceeded to surgery (C+S). Median survival for S+C and C+S groups was similar (25.9 vs 26.2) [HR 0.92, p= 0.41]. Compared to the CO group, the SO group had improved median survival (13.5 vs. 10.8) [HR 0.63, p<0.001]. Branched analyses demonstrated improved median and 5-year (20.8% vs 12.7%) survival for patients receiving upfront resection [HR 0.77, p<0.001]. CONCLUSION: Patients with T1/T2 pancreatic cancer have similar survival irrespective of the timing of chemotherapy and surgery, if they receive both. Upfront resection ensures surgery is delivered, increasing the possibility of long-term survival.

When Is It Safe to Proceed With Pancreaticoduodenectomy Without Biliary Decompression?

BACKGROUND: An absolute bilirubin level where preoperative biliary decompression (PBD) is indicated before pancreaticoduodenectomy has been elusive. Our goal was to identify a total bilirubin level whereby biliary decompression provides clear benefit, despite associated expenses and potential complications. MATERIALS AND METHODS: We reviewed a prospectively collected database of patients undergoing pancreaticoduodenectomy at the Vidant Medical Center between 2007 and 2016. Patients were arbitrarily subdivided into 3 groups based on presenting bilirubin level (≤10 mg/dL, 10.1-14.9 mg/dL, and ≥15 mg/dL) to determine the presence of overall complications, severe complications (Clavien-Dindo classification ≥3), prolonged length of stay (>1 SD), readmissions, or mortality. RESULTS: Common bile duct stenting independently predicted a higher incidence of complications in patients presenting with bilirubin ≤10 mg/dL (P = .03) vs. those patients going directly to surgery. No differences were observed for patients with bilirubin between 10.1 mg/dL and 14.9 mg/dL. Biliary decompression in patients with bilirubin ≥15 mg/dL independently predicted fewer overall (73.8% vs. 100%, P = .0082) and less severe complications (14.3% vs. 44.5%, P = .03) and lower readmission rates (15.8% vs. 55.6%, P = .03) vs. those going directly to surgery. Patients not undergoing biliary decompression underwent pancreaticoduodenectomy sooner than those decompressed (4.7 days vs. 17.2 days, P = .01). DISCUSSION: All patients presenting with bilirubin ≥15 mg/dL should undergo PBD, while those with bilirubin ≤10 mg/dL should forego stent placement to avoid stent-related complications. The decision to stent between 10.1 and 14.9 mg/dL should be made on a case-by-case basis keeping in mind timeliness to definitive cancer treatment.

GSK-3: An important kinase in colon and pancreatic cancers.

In this review, the role of glycogen synthase kinase 3 (GSK-3) in pancreatic and colon cancers will be explored. GSK-3 plays a fundamental role in many metabolic processes, primarily as the final enzyme in glycogen synthesis. Active ß-catenin represents the final step for the transcription of Wnt target genes. Both GSK-3 and ß-catenin are key in the neoplastic transformation and tumorigenesis of human cells. Despite the advances in diagnosis and treatment of pancreatic malignancies, survival remains dismal. Continued poor outcomes are attributable to tumor cell resistance and high frequency of metastatic disease. Survival for patients diagnosed with colon cancer is often excellent, and many patients achieve long term remission. However, the incidence of colon cancers continues to increase, especially among the young. The future use of targeted therapy in pancreatic and colo-rectal cancer utilizing GSK-3 may be promising, pending a more thorough understanding of potential downstream effects. This article is part of a Special Issue entitled: GSK-3 and related kinases in cancer, neurological and other disorders edited by James McCubrey, Agnieszka Gizak and Dariusz Rakus.

Better Defining the Role of Total Neoadjuvant Radiation: Changing Paradigms in Locally Advanced Pancreatic Cancer.

BACKGROUND: This study was designed to better define the role of radiation (Neo-Rad) in addition to neoadjuvant multiagent chemotherapy (NAT) for the treatment of locally advanced pancreatic cancer. METHODS: Retrospective cohort study using the NCDB. Individuals with AJCC clinical T3/T4 pancreatic carcinoma who underwent resection and multiagent chemotherapy were included. Kaplan-Meier, logistic-regression, and Cox proportional-hazard models were used for analysis. RESULTS: A total of 2703 patients were included; 2039 had T3 and 664 had T4 tumors, and 1092 (40.4%) received Neo-Rad. Median follow-up was 22.5 months. During the study period, there was increased use of NAT and a decline in the use of Neo-Rad. Addition of Neo-Rad did not affect 30-day (2.51% vs. 3.24%, p = 0.272) or 90-day mortality (5.23% vs. 6.38%, p = 0.216). Neo-Rad was not associated with improved overall survival on univariable (25.95 vs. 24.7 months, p = 0.202), or multivariable analyses (hazard ratio [HR] 0.94; 95% confidence interval [CI] 0.85-1.05). Time from diagnosis to definitive surgery was increased by Neo-Rad (204 vs. 115 days, p < 0.001). Neo-Rad was associated with increased pathologic downstaging in T3 (32.8% vs. 14.4%) (odds ratio [OR] 2.90; 95% CI 2.30-3.66) and T4 tumors (88.9% vs. 77.8%) (OR 2.29; 95% CI 1.44-3.67); complete pathologic response (5.3% vs. 1.6%) (OR 2.89; 95% CI 1.73-4.83), and increased R0 resection rates (85.7% vs. 76.8%) (OR 1.79; 95% CI 1.44-2.23). CONCLUSIONS: The use of neoadjuvant therapy is increasing for the treatment of locally advanced pancreatic cancer. The addition of radiation to neoadjuvant chemotherapy is associated with improved antineoplastic effectiveness (downstaging, complete pathologic response), surgical resection (R0 rates), but has no effect on overall survival.