Accuracy and Prognostic Impact of Nodal Status on Preoperative Imaging for Management of Pancreatic Neuroendocrine Tumors: A Multi-Institutional Study.

BACKGROUND: We sought to define the accuracy of preoperative imaging to detect lymph node metastasis (LNM) among patients with pancreatic neuroendocrine tumors (pNETs), as well as characterize the impact of preoperative imaging nodal status on survival. METHODS: Patients who underwent curative-intent resection for pNETs between 2000 and 2020 were identified from eight centers. Sensitivity and specificity of computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET)-CT, and OctreoScan for LNM were evaluated. The impact of preoperative lymph node status on lymphadenectomy (LND), as well as overall and recurrence-free survival was defined. RESULTS: Among 852 patients, 235 (27.6%) individuals had LNM on final histologic examination (hN1). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 12.4%, 98.1%, 71.8%, and 74.4% for CT, 6.3%, 100%, 100%, and 80.1% for MRI, 9.5%, 100%, 100%, and 58.7% for PET, 11.3%, 97.5%, 66.7%, and 70.8% for OctreoScan, respectively. Among patients with any combination of these imaging modalities, overall sensitivity, specificity, PPV, and NPV was 14.9%, 97.9%, 72.9%, and 75.1%, respectively. Preoperative N1 on imaging (iN1) was associated with a higher number of LND (iN1 13 vs. iN0 9, p = 0.003) and a higher frequency of final hN1 versus preoperative iN0 (iN1 72.9% vs. iN0 24.9%, p < 0.001). Preoperative iN1 was associated with a higher risk of recurrence versus preoperative iN0 (median recurrence-free survival, iN1→hN1 47.5 vs. iN0→hN1 92.7 months, p = 0.05). CONCLUSIONS: Only 4% of patients with LNM on final pathologic examine had preoperative imaging that was suspicious for LNM. Traditional imaging modalities had low sensitivity to determine nodal status among patients with pNETs.

Association of Neighborhood Disadvantage with Short- and Long-Term Outcomes After Pancreatectomy for Pancreatic Ductal Adenocarcinoma.

BACKGROUND: While lower socioeconomic status has been shown to correlate with worse outcomes in cancer care, data correlating neighborhood-level metrics with outcomes are scarce. We aim to explore the association between neighborhood disadvantage and both short- and long-term postoperative outcomes in patients undergoing pancreatectomy for pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: We retrospectively analyzed 243 patients who underwent resection for PDAC at a single institution between 1 January 2010 and 15 September 2021. To measure neighborhood disadvantage, the cohort was divided into tertiles by Area Deprivation Index (ADI). Short-term outcomes of interest were minor complications, major complications, unplanned readmission within 30 days, prolonged hospitalization, and delayed gastric emptying (DGE). The long-term outcome of interest was overall survival. Logistic regression was used to test short-term outcomes; Cox proportional hazards models and Kaplan-Meier method were used for long-term outcomes. RESULTS: The median ADI of the cohort was 49 (IQR 32-64.5). On adjusted analysis, the high-ADI group demonstrated greater odds of suffering a major complication (odds ratio [OR], 2.78; 95% confidence interval [CI], 1.26-6.40; p = 0.01) and of an unplanned readmission (OR, 3.09; 95% CI, 1.16-9.28; p = 0.03) compared with the low-ADI group. There were no significant differences between groups in the odds of minor complications, prolonged hospitalization, or DGE (all p > 0.05). High ADI did not confer an increased hazard of death (p = 0.63). CONCLUSIONS: We found that worse neighborhood disadvantage is associated with a higher risk of major complication and unplanned readmission after pancreatectomy for PDAC.

Low Prognostic Nutritional Index Is Common and Associated with Poor Outcomes following Curative-Intent Resection for Gastro-Entero-Pancreatic Neuroendocrine Tumors.

INTRODUCTION: To investigate the impact of prognostic nutritional index (PNI) on short- and long-term outcomes of patients who underwent curative-intent resection for gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). METHODS: Patients with GET-NETs who underwent curative-intent resection were identified from a multi-center database. The prognostic impact of clinicopathological factors including PNI on post-operative outcomes were evaluated. A novel nomogram was developed and externally validated. RESULTS: A total of 2,099 patients with GEP-NETs were included in the training cohort; 255 patients were in the external validation cohort. Median PNI (n = 973) was 47.4 (IQR 43.1-52.4). At the time of presentation, 1,299 (61.9%) patients presented with some type of clinical symptom. Low-PNI (≤42.2) was associated with gastrointestinal symptoms, as well as nodal metastasis and distant metastasis (all p < 0.05). Patients with a low PNI had a higher incidence of severe (≥Clavien-Dindo grade IIIa: low PNI 24.9% vs. high PNI 15.4%, p = 0.001) and multiple (≥3 types of complications: low PNI 14.5% vs. high PNI 9.2%, p = 0.024) complications, as well as a worse overall survival (OS)(5-year OS, low PNI 73.7% vs. high PNI 88.5%, p < 0.001), and RFS (5-year RFS, low PNI 68.5% vs. high PNI 79.8%, p = 0.008) versus patients with high PNI (>42.2). A nomogram based on PNI, tumor grade and metastatic disease demonstrated excellent discrimination and calibration to predict OS in both the training (C-index 0.748) and two external validation (C-index 0.827, 0.745) cohorts. CONCLUSIONS: Low PNI was common and associated with worse short- and long-term outcomes among patients with GEP-NETs.

Incidence and Prognostic Implications of Lymphovascular Invasion in Node-Negative Pancreatic Neuroendocrine Tumors: Results From the US Neuroendocrine Study Group.

BACKGROUND: Despite the well-known prognostic role of lymph node metastasis (LNM) in pNETs, less is known about the importance of lymphovascular invasion (LVI) among patients with these tumors. METHODS: Patients undergoing pancreatectomy for pNET between 2002 and 2020 were identified in the US Neuroendocrine Tumor Study Group database. Cox regression analysis was utilized to identify the impact of LVI on recurrence-free survival (RFS) among patients with node-negative pNET. RESULTS: Among 853 patients who underwent resection for pNET, 214 patients (25.1%) had LNM, while 116 (13.6%) and 523 individuals (61.3%) were LVI + N0 and LVI - N0, respectively. The overall incidence of LVI among patients with N0 pNET was 18.1%; the incidence of LVI increased with increasing tumor size and Ki-67 levels (size < 2 cm and Ki-67 < 3%: 5.5%; size < 2 cm and Ki-67 ≥ 3%: 17.2%; size ≥ 2 cm and Ki-67 < 3%: 22.2%; size ≥ 2 cm and Ki-67 ≥ 3%: 43.1%, p < 0.001). Five-year RFS was highest among patients with LVI - N0 disease followed by individuals with LVI + N0 and N+ pNETs (92.8% vs. 61.6% vs. 58.3%, p < 0.001). On multivariable analysis, the presence of LVI on pathology remained independently associated with almost 2.5 times higher hazards of recurrence (HR 2.47, 05% CI 1.44-4.24) among individuals with N0 pNETs. CONCLUSION: The incidence of LVI varied according to tumor size and Ki-67. LVI was associated with a higher likelihood of recurrence among individuals who underwent formal pancreatic resection for N0 pNETs. LVI is an important prognostic indicator among patients with node-negative pNETs.

Preoperative Glycosylated Hemoglobin A1C Impacts Long-Term Outcomes Following Curative-Intent Resection of Nonfunctional Gastroenteropancreatic Neuroendocrine Tumors.

BACKGROUND: To investigate the impact of preoperative glycosylated hemoglobin A1C (HbA1c) among patients following curative-intent resection of nonfunctional gastroentropancreatic neuroendocrine tumors (GEP-NETs). METHODS: Patients who underwent curative-intent resection for GEP-NETs from 2000 to 2020 were identified from the US Neuroendocrine Tumor Study Group (US-NETSG). Preoperative blood HbA1c levels were defined as high HbA1c (≥ 6.5%) versus low HbA1c group (< 6.5%). Impact of HbA1c level on postoperative short-term and long-term overall (OS) were investigated. RESULTS: A total of 130 patients with HbA1c < 6.5% and 60 patients with HbA1c ≥ 6.5% were included. Patients with HbA1c ≥ 6.5% had higher proportion of comorbidities, such as hypertension, obesity, anemia, and lower preoperative albumin levels versus patients with HbA1c < 6.5% (all p < 0.05). In addition, high level of preoperative HbA1c was associated with increased incidence of wound and infectious complications, as well as decreased long-term OS (median OS: high Hb1Ac 89.8 months vs. low Hb1Ac not reached, HR 3.487, p = 0.004) among patients with nonfunctional GEP-NETs, as well as among the subset of pancreatic NET patients (median OS: high Hb1Ac 74.3 months vs. low Hb1Ac not reached, p = 0.004), and patients with normal fasting blood glucose (< 140 mg/dL) (median OS: high Hb1Ac 75.4 months vs. low Hb1Ac not reached, p = 0.001). CONCLUSIONS: Hb1Ac might have value as a screening tool to identify high-risk patients following surgical resection of nonfunctional GEP-NETs for consideration of more strict postoperative surveillance and treatment of elevated Hb1Ac level.

Understanding futility in pancreaticoduodenectomy: Insights from a national cohort.

BACKGROUND AND OBJECTIVES: Pancreaticoduodenectomy (PD), the only surgical option for right-sided pancreatic ductal adenocarcinoma (PDAC), carries significant morbidity. Not all patients may be deriving a survival benefit from this operation. We sought to identify the rate of futile PD and its associated factors in a large national cohort. METHODS: We performed a retrospective analysis using the National Cancer Database (2004-2020), including all patients who underwent PD for non-metastatic PDAC. The primary outcome was operative futility, which was defined as death within 12 months of diagnosis despite PD. Multivariable regression was used to identify factors associated with futility. We performed a subgroup analysis on patients who received neoadjuvant systemic therapy. RESULTS: Data from 66 326 patients were analyzed, and 16 772 (25.3%) underwent PD that met criteria for futility. Macroscopically positive margins (odds ratio [OR]: 2.87; 95% confidence interval [CI]: 2.36-3.48), poor tumor differentiation (OR: 2.44; 95% CI: 2.25-2.65), and N2 nodal stage (OR: 2.09; 95% CI: 1.98-2.20) were associated with the greatest odds of futility. Meanwhile, receipt of any systemic therapy (OR: 0.33; 95% CI: 0.31-0.34), receipt of any radiation (OR: 0.60; 95% CI: 0.57-0.63), and receipt of neoadjuvant systemic therapy (OR: 0.62; 95% CI: 0.57-0.66) were associated with the lowest odds of futility. In the neoadjuvant subgroup, a longer diagnosis-to-surgery interval was associated with lower odds of futility. CONCLUSION: PD was futile in about one quarter of patients. Futility was associated with higher age and worse tumor biology. Receipt of neoadjuvant therapy resulted in fewer futile operations.

Association Between Biliary Pathogens, Surgical Site Infection, and Pancreatic Fistula: Results of a Randomized Trial of Perioperative Antibiotic Prophylaxis in Patients Undergoing Pancreatoduodenectomy.

OBJECTIVE: To establish the association between bactibilia and postoperative complications when stratified by perioperative antibiotic prophylaxis. BACKGROUND: Patients undergoing pancreatoduodenectomy experience high rates of surgical site infection (SSI) and clinically relevant postoperative pancreatic fistula (CR-POPF). Contaminated bile is known to be associated with SSI, but the role of antibiotic prophylaxis in mitigation of infectious risks is ill-defined. METHODS: Intraoperative bile cultures (IOBCs) were collected as an adjunct to a randomized phase 3 clinical trial comparing piperacillin-tazobactam with cefoxitin as perioperative prophylaxis in patients undergoing pancreatoduodenectomy. After compilation of IOBC data, associations between culture results, SSI, and CR-POPF were assessed using logistic regression stratified by the presence of a preoperative biliary stent. RESULTS: Of 778 participants in the clinical trial, IOBC were available for 247 participants. Overall, 68 (27.5%) grew no organisms, 37 (15.0%) grew 1 organism, and 142 (57.5%) were polymicrobial. Organisms resistant to cefoxitin but not piperacillin-tazobactam were present in 95 patients (45.2%). The presence of cefoxitin-resistant organisms, 92.6% of which contained either Enterobacter spp. or Enterococcus spp., was associated with the development of SSI in participants treated with cefoxitin [53.5% vs 25.0%; odds ratio (OR)=3.44, 95% CI: 1.50-7.91; P =0.004] but not those treated with piperacillin-tazobactam (13.5% vs 27.0%; OR=0.42, 95% CI: 0.14-1.29; P =0.128). Similarly, cefoxitin-resistant organisms were associated with CR-POPF in participants treated with cefoxitin (24.1% vs 5.8%; OR=3.45, 95% CI: 1.22-9.74; P =0.017) but not those treated with piperacillin-tazobactam (5.4% vs 4.8%; OR=0.92, 95% CI: 0.30-2.80; P =0.888). CONCLUSIONS: Previously observed reductions in SSI and CR-POPF in patients that received piperacillin-tazobactam antibiotic prophylaxis are potentially mediated by biliary pathogens that are cefoxitin resistant, specifically Enterobacter spp. and Enterococcus spp.

Calcifications and Cystic Morphology on Preoperative Imaging Predict Survival After Resection of Pancreatic Neuroendocrine Tumors.

BACKGROUND: Radiographic calcifications and cystic morphology are associated with higher and lower tumor grade, respectively, in pancreatic neuroendocrine tumors (PNETs). Whether calcifications and/or cystic morphology could be used preoperatively to predict post-resection survival in patients with PNETs remains elusive. METHODS: Patients undergoing curative-intent resection of well-differentiated PNETs from 2000 to 2017 at eight academic institutions participating in the US Neuroendocrine Tumor Study Group were identified. Preoperative cross-sectional imaging reports were reviewed to identify the presence of calcifications and of a cystic component occupying >50% of the total tumor area. Clinicopathologic characteristics and recurrence-free survival (RFS) were compared. RESULTS: Of 981 patients studied, 18% had calcifications and 17% had cystic tumors. Tumors with calcifications were more commonly associated with Ki-67 ≥3% (47% vs. 33%; p = 0.029), lymph node metastasis (36% vs. 24%; p = 0.011), and distant metastasis (13% vs. 4%; p < 0.001). In contrast, cystic tumors were less commonly associated with lymph node metastasis (12% vs. 30%; p < 0.001). Five-year RFS after resection was most favorable for cystic tumors without calcifications (91%), intermediate for solid tumors without calcifications (77%), and least favorable for any calcified PNET (solid 69%, cystic 67%; p = 0.043). Calcifications remained an independent predictor of RFS on multivariable analysis (p = 0.043) controlling for nodal (p < 0.001) and distant metastasis (p = 0.001). CONCLUSIONS: Easily detectable radiographic features, such as calcifications and cystic morphology, can be used preoperatively to stratify prognosis in patients with PNETs and possibly inform the decision to operate or not, as well as guide the extent of resection and potential use of neoadjuvant therapy.

Impact of adjuvant therapy on outcomes after curative-intent resection for distal cholangiocarcinoma.

BACKGROUND: The benefit of adjuvant therapy (AT) after curative resection of distal cholangiocarcinoma (DCC) remains unclear. The objective of the current study was to investigate the impact of AT on long-term survival of patients who underwent curative-intent resection for DCC. METHODS: Patients who underwent curative-intent resection for DCC between 2000 and 2020 were identified from a multi-institutional database. The primary outcomes included overall (OS) and recurrence-free survival (RFS). RESULTS: Among 245 patients, 150 (61.2%) patients received AT (chemotherapy alone: n = 43; chemo- and radiotherapy: n = 107) after surgical resection, whereas 95 (38.8%) patients underwent surgery only. Patients who received AT were younger, and more likely to have an advanced tumor with the presence of perineural invasion (PNI), lymph node metastasis (LNM), lymph-vascular invasion, and higher T categories (all p < 0.05). Overall, there was no difference in OS (median, surgery + AT 25.5 vs. surgery alone 24.5 months, p = 0.27) or RFS (median, surgery + AT 15.8 vs. surgery alone 18.9 months, p = 0.24) among patients who did versus did not receive AT. In contrast, AT was associated with improved long-term survival among patients with PNI (median OS, surgery + AT 25.9 vs. surgery alone 17.8 months, p = 0.03; median RFS, surgery + AT 15.9 vs. surgery alone 11.9 months, p = 0.04) and LNM (median, surgery + AT 20.0 vs. surgery alone 17.8 months, p = 0.03), but not among patients with no PNI or LNM (all p > 0.1). CONCLUSIONS: AT was commonly utilized among patients with DCC. Patients with more advanced disease, including the presence of PNI or LNM, benefited the most from AT with improved long-term outcomes among this subset of patients.

Piperacillin-Tazobactam Compared With Cefoxitin as Antimicrobial Prophylaxis for Pancreatoduodenectomy: A Randomized Clinical Trial.

Importance: Despite improvements in perioperative mortality, the incidence of postoperative surgical site infection (SSI) remains high after pancreatoduodenectomy. The effect of broad-spectrum antimicrobial surgical prophylaxis in reducing SSI is poorly understood. Objective: To define the effect of broad-spectrum perioperative antimicrobial prophylaxis on postoperative SSI incidence compared with standard care antibiotics. Design, Setting, and Participants: Pragmatic, open-label, multicenter, randomized phase 3 clinical trial at 26 hospitals across the US and Canada. Participants were enrolled between November 2017 and August 2021, with follow-up through December 2021. Adults undergoing open pancreatoduodenectomy for any indication were eligible. Individuals were excluded if they had allergies to study medications, active infections, chronic steroid use, significant kidney dysfunction, or were pregnant or breastfeeding. Participants were block randomized in a 1:1 ratio and stratified by the presence of a preoperative biliary stent. Participants, investigators, and statisticians analyzing trial data were unblinded to treatment assignment. Intervention: The intervention group received piperacillin-tazobactam (3.375 or 4 g intravenously) as perioperative antimicrobial prophylaxis, while the control group received cefoxitin (2 g intravenously; standard care). Main Outcomes and Measures: The primary outcome was development of postoperative SSI within 30 days. Secondary end points included 30-day mortality, development of clinically relevant postoperative pancreatic fistula, and sepsis. All data were collected as part of the American College of Surgeons National Surgical Quality Improvement Program. Results: The trial was terminated at an interim analysis on the basis of a predefined stopping rule. Of 778 participants (378 in the piperacillin-tazobactam group [median age, 66.8 y; 233 {61.6%} men] and 400 in the cefoxitin group [median age, 68.0 y; 223 {55.8%} men]), the percentage with SSI at 30 days was lower in the perioperative piperacillin-tazobactam vs cefoxitin group (19.8% vs 32.8%; absolute difference, -13.0% [95% CI, -19.1% to -6.9%]; P < .001). Participants treated with piperacillin-tazobactam, vs cefoxitin, had lower rates of postoperative sepsis (4.2% vs 7.5%; difference, -3.3% [95% CI, -6.6% to 0.0%]; P = .02) and clinically relevant postoperative pancreatic fistula (12.7% vs 19.0%; difference, -6.3% [95% CI, -11.4% to -1.2%]; P = .03). Mortality rates at 30 days were 1.3% (5/378) among participants treated with piperacillin-tazobactam and 2.5% (10/400) among those receiving cefoxitin (difference, -1.2% [95% CI, -3.1% to 0.7%]; P = .32). Conclusions and Relevance: In participants undergoing open pancreatoduodenectomy, use of piperacillin-tazobactam as perioperative prophylaxis reduced postoperative SSI, pancreatic fistula, and multiple downstream sequelae of SSI. The findings support the use of piperacillin-tazobactam as standard care for open pancreatoduodenectomy. Trial Registration: ClinicalTrials.gov Identifier: NCT03269994.

Development and Validation of a Modified Eighth AJCC Staging System for Primary Pancreatic Neuroendocrine Tumors.

OBJECTIVE: To improve the prognostic accuracy of the eighth edition of AJCC staging system for pNETs with establishment and validation of a new staging system. BACKGROUND: Validation of the updated eighth AJCC staging system for pNETs has been limited and controversial. METHODS: Data from the SEER registry (1975-2016) (n = 3303) and a multi-institutional database (2000-2016) (n = 825) was used as development and validation cohorts, respectively. A mTNM was proposed by maintaining the eighth AJCC T and M definitions, and the recently proposed N status as N0 (no LNM), N1 (1-3 LNM), and N2 (≥4 LNM), but adopting a new stage classification. RESULTS: The eighth TNM staging system failed to stratify patients with stage I versus IIA, stage IIB versus IIIA, and overall stage I versus II relative to long-term OS in both database. There was a monotonic decrement in survival based on the proposed mTNM staging classification among patients derived from both the SEER (5-year OS, stage I 87.0% vs stage II 80.3% vs stage III 72.9% vs stage IV 57.2%, all P < 0.001), and multi-institutional (5-year OS, stage I 97.6% vs stage II 82.7% vs stage III 78.4% vs stage IV 50.0%, all P < 0.05) datasets. On multivariable analysis, mTNM staging remained strongly associated with prognosis, as the hazard of death incrementally increased with each stage among patients in the 2 cohorts. CONCLUSION: A mTNM pNETs clinical staging system using N0, N1, N2 nodal categories was better at stratifying patients relative to long-term OS than the eighth AJCC staging.

Does the Volume-Outcome Association in Pancreas Cancer Surgery Justify Regionalization of Care? A Review of Current Controversies.

INTRODUCTION: Increasing hospital or surgeon volume is associated with improved outcomes among patients with pancreatic cancer. Promotion of regionalized care is based on this volume-outcome association. However, other research has exposed nuances and complexities inherent to this association that should be considered when promoting regionalized care models. We herein provide a critical review of the literature on the volume-outcome association and a discussion of areas of ongoing controversy. METHODS: A PubMed literature search was conducted for the years 1995-2020. Peer reviewed original research studies were selected for critical review based on study design, potential to draw meaningful conclusions from the data, and discussion of current knowledge gaps. RESULTS: Based on the cumulative published literature, hospital/surgeon volume and patient mortality are inversely related. However, it remains unclear whether volume is a proxy for other more causative variables inherent in high-volume centers. Interpretation of the volume-outcome association is made more difficult to interpret due to the large variation in the definition of high volume, difficulty in isolating the individual impact of surgeon versus hospital volume, challenges in quantifying health system processes related to volume, and the fact that some low-volume centers consistently achieve excellent clinical results. Implementation of true regionalized care models has been rare, likely reflecting both health system and patient level challenges. CONCLUSION: The volume-outcome association has been consistently demonstrated to be important to the care of patients with pancreas cancer. The underlying mechanism of this association to explain the overall benefit is likely multifactorial. Better understanding of what drives the volume-outcome association may increase access to optimized care for a broader range of hospital systems and patients.

Incidence of Second Primary Melanoma in Cutaneous Melanoma Survivors.

BACKGROUND: Cutaneous melanoma survivors are at increased risk of a second primary melanoma. Valid estimates facilitate counseling on recommended surveillance after a melanoma diagnosis. However, most estimates of 5- and 10-year incidences of second melanomas are from older cohorts and/or single institutions. This study aimed to determine the 5- and 10-year incidences of second primary cutaneous melanomas in survivors of cutaneous melanoma. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify cases of non-metastatic, first cutaneous melanoma diagnosed between 1998 and 2012 (follow-up through December 2017). Eligible survivors were 18 years old or older who underwent surgery as a treatment component. Kaplan-Meier survival analysis was used to estimate 5- and 10-year incidences of a second melanoma, excluding new diagnoses within 3 months after the initial diagnosis. Patients were censored at second melanoma diagnosis, death, or 10-years, whichever was first. Multivariable Cox regression analysis was used to identify factors associated with a second cutaneous melanoma diagnosis. RESULTS: The study cohort comprised 152,811 patients. The incidence of second primary melanoma was 3.9% at 5 years (95% confidence interval [CI], 3.8-4.0%) and 6.7% at 10 years (95% CI, 6.6-6.9%). Older age, male sex, and regional disease were associated with increased risk of a second primary melanoma diagnosis. CONCLUSION: Melanoma survivors are at risk of a second primary melanoma, making routine skin surveillance part of recommended follow-up evaluation. A higher incidence of second melanoma with older age and regional disease at presentation is possibly explained by increased health care use providing more diagnostic opportunities, whereas male sex may represent an inherent risk factor.

Very Early Recurrence After Curative-Intent Surgery for Gastric Adenocarcinoma.

BACKGROUND: Recurrence after curative-intent surgery can occur in more than 50% of gastric cancer (GC) patients. We sought to identify predictors of very early recurrence (VER) among GC patients who underwent curative-intent surgery. METHODS: A multi-institutional database of GC patients undergoing curative-intent surgery between 2000 and 2020 at 8 major institutions was queried. VER was defined as local or distant tumor recurrence within 6 months from surgery. Univariable Cox proportional hazard models were used to evaluate the predictive value of clinical-pathological features on VER. A regularized Cox regression model was employed to build a predictive model of VER and recurrence within 12 months. The discriminant ability of the Cox regularized models was evaluated by reporting a ROC curve together with the calibration plot, considering 200 runs. RESULTS: Among 1133 patients, 65 (16.0%) patients experienced a VER. Preoperative symptoms (HR 1.198), comorbidities (HR 1.289), tumor grade (HR 1.043), LNR (HR 4.339) and T stage (HR 1.639) were associated with an increased likelihood of VER. Model performance was very good at predicting VER at 6 months (AUC of 0.722) and 12 months (AUC 0.733). Two nomograms to predict 6-month and 12-month VER were built based on the predictive model. A higher nomogram score was associated with worse prognosis. There was good prediction between observed and estimated VER with minimal evidence of overfitting and good performance on internal bootstrapping validation. CONCLUSION: One in 6 patients experienced VER following curative-intent surgery for GC. Nomograms to predict risk of VER performed well on internal validation, and stratified patients into distinct prognostic groups relative to 6- and 12-months recurrence.

Rethinking Routine Intensive Care After Cytoreductive Surgery With Heated Intraperitoneal Chemotherapy: The Fiscal Argument.

BACKGROUND: Patients undergoing cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) are frequently admitted to the intensive care unit (ICU) for mitigation of potential complications, although ICU length of stay (LOS) is a significant driver of cost. This study asked whether a fiscal argument could be made for the selective avoidance of ICU admission after CRS/HIPEC. METHODS: Prospective data for select low-risk patients (e.g., lower peritoneal cancer index [PCI]) admitted to the intermediate care unit (IMC) instead of the ICU after CRS/HIPEC were matched with a historic cohort routinely admitted to the ICU. Cohort comparisons and the impact of the intervention on cost were assessed. RESULTS: The study matched 81 CRS/HIPEC procedures to form a cohort of 49 pre- and 15 post-intervention procedures for patients with similar disease burdens (mean PCI, 8 ± 6.7 vs. 7 ± 5.1). The pre-intervention patients stayed a median of 1 day longer in the ICU (1 day [IQR, 1-1 day] vs. 0 days [IQR, 0-0 days]) and had a longer LOS (8 days [IQR, 7-11 days] vs. 6 days [IQR, 5.5-9 days]). Complications and complication severity did not differ statistically. The median total hospital cost was lower after intervention ($30,845 [IQR, $30,181-$37,725] vs. $41,477 [IQR, $33,303-$51,838]), driven by decreased indirect fixed cost ($8984 [IQR, $8643-$11,286] vs. $14,314 [IQR, $12,206-$18,266]). In a weighted multiple variable linear regression analysis, the intervention was associated with a savings of $2208.68 per patient. CONCLUSIONS: Selective admission to the IMC after CRS/HIPEC was associated with $2208.68 in savings per patient without added risk. In this era of cost-conscious practice of medicine, these data highlight an opportunity to decrease cost by more than 5% for patients undergoing CRS/HIPEC.

Development of a Prognostic Nomogram and Nomogram Software Application Tool to Predict Overall Survival and Disease-Free Survival After Curative-Intent Gastrectomy for Gastric Cancer.

BACKGROUND: We sought to derive and validate a prediction model of survival and recurrence among Western patients undergoing resection of gastric cancer. METHODS: Patients who underwent curative-intent surgery for gastric cancer at seven US institutions and a major Italian center from 2000 to 2020 were included. Variables included in the multivariable Cox models were identified using an automated model selection procedure based on an algorithm. Best models were selected using the Bayesian information criterion (BIC). The performance of the models was internally cross-validated via the bootstrap resampling procedure. Discrimination was evaluated using the Harrell's Concordance Index and accuracy was evaluated using calibration plots. Nomograms were made available as online tools. RESULTS: Overall, 895 patients met inclusion criteria. Age (hazard ratio [HR] 1.47, 95% confidence interval [CI] 1.17-1.84), presence of preoperative comorbidities (HR 1.66, 95% CI 1.14-2.41), lymph node ratio (LNR; HR 1.72, 95% CI 1.42-2.01), and lymphovascular invasion (HR 1.81, 95% CI 1.33-2.45) were associated with overall survival (OS; all p < 0.01), whereas tumor location (HR 1.93, 95% CI 1.23-3.02), T category (Tis-T1 vs. T3: HR 0.31, 95% CI 0.14-0.66), LNR (HR 1.82, 95% CI 1.45-2.28), and lymphovascular invasion (HR 1.49; 95% CI 1.01-2.22) were associated with disease-free survival (DFS; all p < 0.05) The models demonstrated good discrimination on internal validation relative to OS (C-index 0.70) and DFS (C-index 0.74). CONCLUSIONS: A web-based nomograms to predict OS and DFS among gastric cancer patients following resection demonstrated good accuracy and discrimination and good performance on internal validation.

Peripheral nerve blocks with liposomal bupivacaine are associated with increased opioid use compared to thoracic epidural in patients with an epigastric incision.

BACKGROUND: Thoracic epidurals are commonly recommended in enhanced recovery protocols, though they may cause hypotension and urinary retention. Peripheral nerve blocks using liposomal bupivacaine are a potential alternative, though they have not been extensively studied in major cancer operations with an epigastric incision. METHODS: We conducted a retrospective review of prospectively collected data following the transition from thoracic epidural to liposomal peripheral nerve blocks in patients undergoing major oncologic surgery. Patients receiving peripheral nerve blocks were compared to those receiving thoracic epidural. Outcome variables included postoperative opioid use (milligram morphine equivalents [MME]), severe pain, and postoperative complications. RESULTS: Forty-seven of 102 patients studied (46%) received peripheral nerve blocks. Opioid use was higher in the peripheral nerve block group during the 0-24 h (116 vs. 94 MME, p = 0.04) and 24-48 h postoperative period (94 vs. 23 MME, p < 0.01). There was no significant difference in severe pain, hypotension, urinary retention, or ileus. Peripheral nerve blocks were associated with earlier ambulation (1 vs. 2 days, p = 0.04), though other milestones were similar. CONCLUSIONS: Liposomal peripheral nerve blocks were associated with increased opioid use compared to thoracic epidural. On the basis of our results, thoracic epidural might be preferred in surgical oncology patients with an epigastric incision.

Surgical treatment of gastric adenocarcinoma: Are we achieving textbook oncologic outcomes for our patients?

BACKGROUND AND OBJECTIVES: Composite measures are increasingly used to assess quality of care in surgical oncology. We sought to define the incidence of "textbook oncologic outcome" (TOO) following resection of gastric adenocarcinoma among a large, international cohort of patients. METHODS: Gastric adenocarcinoma patients undergoing resection between 2000 and 2020 were identified from an international database. TOO was defined as margin-negative resection, examination of ≥16 lymph nodes, no prolonged length-of-stay (LOS), no 30-day mortality, and stage-appropriate receipt of chemotherapy. RESULTS: Among a total of 910 patients, 321 patients (35.3%) achieved a postoperative TOO. While failure to evaluate ≥16 lymph nodes (n = 591, 65.0%) and receipt of chemotherapy (n = 651, 71.5%) had the greatest negative impact on the ability to obtain a TOO, no 30-day mortality (n = 880, 96.7%), margin-negative resection (n = 831, 91.3%), and no extended LOS (n = 706, 77.6%) were more commonly achieved. No postoperative complications (OR: 0.44; 95% CI: 0.31-0.63) and T1a/T1b-stage disease (OR: 2.87; 95% CI: 1.59-5.18) were independently associated with achieving a TOO (p < 0.05). The odds of achieving a TOO improved over time (p-trend < 0.05), which was largely attributable to improved odds of evaluating ≥16 lymph nodes (2010-2014 vs. 2000-2004: OR, 5.21; 95% CI: 3.22-8.45). CONCLUSIONS: Only about one in three patients achieved a TOO following resection of gastric adenocarcinoma. Odds of TOO increased over time, largely due to improved lymph node evaluation.

Surgical outcomes of gastro-entero-pancreatic neuroendocrine tumors G3 versus neuroendocrine carcinoma.

BACKGROUND: To define surgical outcomes of patients with high-grade gastro-entero-pancreatic neuroendocrine neoplasm grade G3 (GEP-NEN G3). METHODS: Patients who underwent surgical resection between 2000 and 2016 were identified. The overall survival (OS) and recurrence-free survival (RFS) of patients with gastro-entero-pancreatic neuroendocrine tumors grade G3 (GEP-NET G3) versus neuroendocrine carcinoma (NEC) were evaluated. RESULTS: Fifty-one out of 2182 (2.3%) patients who underwent surgical resection were diagnosed as GEP-NEN G3. The pancreas was the most common primary site (n = 3772.5%). A majority of patients had lymph node metastasis (n = 3262.7%); one in three (n = 1631.4%) had distant metastasis. The median OS and RFS of the entire cohort were 56.4 and 34.5 months, respectively. Perineural invasion was a strong prognostic factor associate with OS after surgical resection. Patients with NEC had a worse survival outcome versus patients with NET G3 (median OS: 33.1 months vs. not attained, p = 0.088). In contrast, among patients who underwent curative-intent resection, patients with NEC had comparable RFS versus patients with NET G3 (median RFS: 35.6 vs. 33.9 months, p = 0.774). CONCLUSIONS: Surgical resection provided acceptable short- and long-outcomes for well-selected patients with resectable GEP-NEN G3. NEC was associated with a worse OS versus NET G3.

Using machine learning to preoperatively stratify prognosis among patients with gallbladder cancer: a multi-institutional analysis.

BACKGROUND: Gallbladder cancer (GBC) is an aggressive malignancy associated with a high risk of recurrence and mortality. We used a machine-based learning approach to stratify patients into distinct prognostic groups using preperative variables. METHODS: Patients undergoing curative-intent resection of GBC were identified using a multi-institutional database. A classification and regression tree (CART) was used to stratify patients relative to overall survival (OS) based on preoperative clinical factors. RESULTS: CART analysis identified tumor size, biliary drainage, carbohydrate antigen 19-9 (CA19-9) levels, and neutrophil-lymphocyte ratio (NLR) as the factors most strongly associated with OS. Machine learning cohorted patients into four prognostic groups: Group 1 (n = 109): NLR ≤1.5, CA19-9 ≤20, no drainage, tumor size <5.0 cm; Group 2 (n = 88): NLR >1.5, CA19-9 ≤20, no drainage, tumor size <5.0 cm; Group 3 (n = 46): CA19-9 >20, no drainage, tumor size <5.0 cm; Group 4 (n = 77): tumor size <5.0 cm with drainage OR tumor size ≥5.0 cm. Median OS decreased incrementally with CART group designation (59.5, 27.6, 20.6, and 12.1 months; p < 0.0001). CONCLUSIONS: A machine-based model was able to stratify GBC patients into four distinct prognostic groups based only on preoperative characteristics. Characterizing patient prognosis with machine learning tools may help physicians provide more patient-centered care.