Comparison of early and late 68Ga-FAPI-46-PET in 33 patients with possible recurrence of pancreatic ductal adenocarcinomas.

Positron emission tomography with 68Gallium (68Ga) labeled inhibitors of fibroblast activation protein (68Ga-FAPI-PET) is a promising imaging technique for patients with recurrent pancreatic ductal adenocarcinomas (PDAC). To date, it is not clear if different acquisition timepoints for 68Ga-FAPI-PET may result in comparable imaging information and if repetitive 68Ga-FAPI-PET imaging may add diagnostic value to single timepoint acquisition for recurrent PDAC. Here we analyzed retrospectively early (20 min p.i.) and late (60 min p.i.) 68Ga-FAPI-PET imaging using FAPI-46 of 33 patients with possible recurrence of PDAC concerning detection rates and uptake over time of local recurrences, metastases, inflammatory lesions of the pancreas, cholestatic lesions of the liver and reactive tissue. 33 patients with histologically confirmed PDAC after complete or partial resection of the pancreas and possible recurrence were examined by 68Ga-FAPI-46-PET acquired 20- and 60-min post injection (p.i.) of the radiotracer. FAPI-positive lesions were classified as local recurrences, metastases, inflammatory lesions of the pancreas (ILP), cholestatic lesions of the liver and reactive tissue based on histology, PET- and CT-morphology and clinical information. Lesions were contoured, and standardized uptake values (SUVmax and SUVmean) and target-to-background ratios (TBR) were analyzed for both acquisition timepoints. In total, 152 FAPI-positive lesions (22 local relapses, 47 metastases, 26 inflammatory lesions of the pancreas, 28 reactive tissues, and 29 cholestatic lesions) were detected. Detection rates for the early and late acquisition of 68Ga-FAPI-46-PET were almost identical except cholestatic lesions, which showed a higher detection rate at early imaging. SUV parameters and TBRs of ILP significantly decreased over time. Cholestatic lesions showed a tendency towards decreasing uptake. All other types of lesions showed relatively stable uptake over time. Early and late acquisition of 68Ga-FAPI-PET results in comparable imaging information in patients with possible recurrence of PDAC. Two timepoint imaging offers additional diagnostic potential concerning differential diagnoses.

Persister cell phenotypes contribute to poor patient outcomes after neoadjuvant chemotherapy in PDAC.

Neoadjuvant chemotherapy can improve the survival of individuals with borderline and unresectable pancreatic ductal adenocarcinoma; however, heterogeneous responses to chemotherapy remain a significant clinical challenge. Here, we performed RNA sequencing (n = 97) and multiplexed immunofluorescence (n = 122) on chemo-naive and postchemotherapy (post-CTX) resected patient samples (chemoradiotherapy excluded) to define the impact of neoadjuvant chemotherapy. Transcriptome analysis combined with high-resolution mapping of whole-tissue sections identified GATA6 (classical), KRT17 (basal-like) and cytochrome P450 3A (CYP3A) coexpressing cells that were preferentially enriched in post-CTX resected samples. The persistence of GATA6hi and KRT17hi cells post-CTX was significantly associated with poor survival after mFOLFIRINOX (mFFX), but not gemcitabine (GEM), treatment. Analysis of organoid models derived from chemo-naive and post-CTX samples demonstrated that CYP3A expression is a predictor of chemotherapy response and that CYP3A-expressing drug detoxification pathways can metabolize the prodrug irinotecan, a constituent of mFFX. These findings identify CYP3A-expressing drug-tolerant cell phenotypes in residual disease that may ultimately inform adjuvant treatment selection.

Farnesoid X receptor activation inhibits pancreatic carcinogenesis.

Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily that controls bile acid (BA) homeostasis, has also been proposed as a tumor suppressor for breast and liver cancer. However, its role in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis remains controversial. We recently found that FXR attenuates acinar cell autophagy in chronic pancreatitis resulting in reduced autophagy and promotion of pancreatic carcinogenesis. Feeding Kras-p48-Cre (KC) mice with the BA chenodeoxycholic acid (CDCA), an FXR agonist, attenuated pancreatic intraepithelial neoplasia (PanIN) progression, reduced cell proliferation, neoplastic cells and autophagic activity, and increased acinar cells, elevated pro-inflammatory cytokines and chemokines, with a compensatory increase in the anti-inflammatory response. Surprisingly, FXR-deficient KC mice did not show any response to CDCA, suggesting that CDCA attenuates PanIN progression and decelerate tumorigenesis in KC mice through activating pancreatic FXR. FXR is activated in pancreatic cancer cell lines in response to CDCA in vitro. FXR levels were highly increased in adjuvant and neoadjuvant PDAC tissue compared to healthy pancreatic tissue, indicating that FXR is expressed and potentially activated in human PDAC. These results suggest that BA exposure activates inflammation and suppresses autophagy in KC mice, resulting in reduced PanIN lesion progression. These data suggest that activation of pancreatic FXR has a protective role by reducing the growth of pre-cancerous PDAC lesions in response to CDCA and possibly other FXR agonists.

Surgery for intraductal papillary mucinous neoplasms in young patients: High-risk population.

BACKGROUND: Intraductal papillary mucinous neoplasms of the pancreas are uncommon in young individuals. Management of these patients is challenging because the risk of malignancy and recurrence after surgery remains unclear. The aim of the present study was to assess the long-term risk for intraductal papillary mucinous neoplasm recurrence after surgery for intraductal papillary mucinous neoplasms in patients ≤50 years of age. METHODS: Perioperative and long-term follow-up data of patients who had undergone surgery for intraductal papillary mucinous neoplasms between 2004 and 2020 were extracted from a prospective unicentric database and retrospectively analyzed. RESULTS: Seventy-eight patients underwent surgical treatment for benign intraductal papillary mucinous neoplasms (low-grade n = 22 and intermediate-grade n = 21) and malignant intraductal papillary mucinous neoplasms (high-grade n = 16 and intraductal papillary mucinous neoplasm-associated carcinoma n = 19). Severe postoperative morbidity (Clavien-Dindo ≥III) was found in 14 patients (18%). The median length of hospital stay was 10 days. No perioperative mortality was observed. The median length of follow-up was 72 months. Recurrence of intraductal papillary mucinous neoplasm-associated carcinoma was found in 6 patients (19%) with malignant intraductal papillary mucinous neoplasm and 1 patient (3%) with benign intraductal papillary mucinous neoplasm. CONCLUSION: Surgery for intraductal papillary mucinous neoplasm is safe and can be performed with low morbidity and potentially no mortality in young patients. Given the high rate of malignancy (45%), these patients with intraductal papillary mucinous neoplasms represent a high-risk population, and prophylactic surgical treatment should be considered in these patients with long life expectancies. Regular clinical and radiologic follow-up examinations are important to rule out disease recurrence, which is high, especially in patients with intraductal papillary mucinous neoplasm-associated carcinoma.

Middle Segment-Preserving Pancreatectomy to Avoid Pancreatic Insufficiency: Individual Patient Data Analysis of All Published Cases from 2003-2021.

Middle segment-preserving pancreatectomy (MPP) can treat multilocular diseases in the pancreatic head and tail while avoiding impairments caused by total pancreatectomy (TP). We conducted a systematic literature review of MPP cases and collected individual patient data (IPD). MPP patients (N = 29) were analyzed and compared to a group of TP patients (N = 14) in terms of clinical baseline characteristics, intraoperative course, and postoperative outcomes. We also conducted a limited survival analysis following MPP. Pancreatic functionality was better preserved following MPP than TP, as new-onset diabetes and exocrine insufficiency each occurred in 29% of MPP patients compared to near-ubiquitous prevalence among TP patients. Nevertheless, POPF Grade B occurred in 54% of MPP patients, a complication avoidable with TP. Longer pancreatic remnants were a prognostic indicator for shorter and less eventful hospital stays with fewer complications, whereas complications of endocrine functionality were associated with older patients. Long-term survival prospects after MPP appeared strong (median up to 110 months), but survival was lower in cases with recurring malignancies and metastases (median < 40 months). This study demonstrates MPP is a feasible treatment alternative to TP for selected cases because it can avoid pancreoprivic impairments, but at the risk of perioperative morbidity.

Static and Dynamic 68Ga-FAPI PET/CT for the Detection of Malignant Transformation of Intraductal Papillary Mucinous Neoplasia of the Pancreas.

Pancreatic ductal adenocarcinoma (PDAC) may arise from intraductal papillary mucinous neoplasms (IPMN) with malignant transformation, but a significant portion of IPMN remains to show benign behavior. Therefore, it is important to differentiate between benign IPMN and IPMN lesions undergoing malignant transformation. However, nonoperative differentiation by ultrasound, CT, MRI, and carbohydrate antigen 19-9 (CA19-9) is still unsatisfactory. Here, we assessed the clinical feasibility of additional assessment of malignancy by PET using 68Ga-labeled fibroblast activation protein inhibitors (68Ga-FAPI PET) in 25 patients with MRI- or CT-proven cystic pancreatic lesions. Methods: Twenty-five patients with cystic pancreatic lesions who were followed up in the European Pancreas Center of Heidelberg University hospital and who were led to surgical resection or fine-needle aspiration due to suspicious clinical, laboratory chemistry, or radiologic findings were examined by static (all patients) and dynamic (20 patients) 68Ga-FAPI PET. Cystic pancreatic lesions were delineated and SUVmax and SUVmean were determined. Time-activity curves and dynamic parameters (time to peak, K 1, k 2, K3, k 4) were extracted from dynamic PET data. Receiver-operating curves of static and dynamic PET parameters were calculated. Results: Eleven of the patients had menacing IPMN (high-grade IPMN with [6 cases] or without [5 cases] progression into PDAC) and 11 low-grade IPMN; 3 patients had other benign entities. Menacing IMPN showed significantly elevated 68Ga-FAPI uptake compared with low-grade IPMN and other benign cystic lesions. In dynamic imaging, menacing IPMN showed increasing time-activity curves followed by slow decrease afterward; time-activity curves of low-grade IPMN showed an immediate peak followed by rapid decrease for about 10 min and slower decrease for the rest of the time. Receiver-operating curves showed high sensitivity and specificity (area under the curve greater than 80%) of static and dynamic PET parameters for the differentiation of IPMN subtypes. Conclusion: 68Ga-FAPI PET is a helpful new tool for the differentiation of menacing and low-grade IPMN and shows the potential to avoid unnecessary surgery for nonmalignant pancreatic IPMN.

Distal Bile Duct Cancer: Radical (R0 > 1 mm) Resection Achieves Favorable Survival.

OBJECTIVE: Evaluation of the outcome after resection for distal bile duct cancer (DBC) with focus on the impact of microscopic histopathological resection status R0 (>1 mm) versus R1 (≤1 mm) vs R1 (direct). SUMMARY BACKGROUND DATA: DBC is a rare disease for which oncologic resection offers the only chance of cure. METHODS: Prospectively collected data of consecutive patients undergoing pancreaticoduodenectomy for DBC were analyzed. Histopathological resection status was classified according to the Leeds protocol for pancreatic ductal adeno carcinoma (PDAC) (PDAC; R0 >1 mm margin clearance vs R1 ≤1 mm vs R1 direct margin involvement). RESULTS: A total of 196 patients underwent pancreaticoduodenectomy for DBC. Microscopic complete tumor clearance (R0>1 mm) was achieved in 113 patients (58%). Median overall survival (OS) of the entire cohort was 37 months (5- and 10-year OS rate: 40% and 31%, respectively). After R0 resection, median OS increased to 78 months with a 5-year OS rate of 52%. Negative prognostic factors were age >70 years ( P < 0.0001, hazard ratio (HR) 2.48), intraoperative blood loss >1000 mL ( P = 0.0009, HR 1.99), pN1 and pN2 status ( P = 0.0052 and P = 0.0006, HR 2.14 and 2.62, respectively) and American Society of Anesthesiologists score >II ( P = 0.0259, HR 1.61). CONCLUSIONS: This is the largest European single-center study of surgical treatment for DBC and the first to investigate the prognostic impact of the revised PDAC resection status definition in DBC. The results show that this definition is valid in DBC and that "true" R0 resection (>1 mm) is a key factor for excellent survival. In contrast to PDAC, there was no survival difference between R1 (≤1 mm) and R1 (direct).

Induction Chemotherapy with FOLFIRINOX for Locally Advanced Pancreatic Cancer: A Simple Scoring System to Predict Effect and Prognosis.

BACKGROUND: Effective chemotherapy (CTx) protocols as induction treatment provide increasing opportunities for surgical resection of locally advanced pancreatic cancer (LAPC). Although improved survival after resection of LAPC with CTx has been reported for selected patients, reliable recommendations on the indication for conversion surgery after induction treatment are currently lacking. We investigated the factors predictive of prognosis in resected LAPC after FOLFIRINOX. METHODS: Consecutive patients with LAPC undergoing curative resection after FOLFIRINOX between 2011 and 2018 were identified from a prospectively maintained database. Relevant clinical parameters and CT findings were examined. A scoring system was developed based on the ratio of hazard ratios for overall survival of all significant predictors. RESULTS: A total of 62 patients with LAPC who underwent oncologic resection after FOLFIRINOX were analyzed. Tumor shrinkage, tumor density, and postchemotherapy CA19-9 serum levels were independently associated with overall survival (multivariate analysis: HR = 0.31, 0.17, and 0.18, respectively). One, two, and two points were allocated to these three factors in the proposed scoring system, respectively. The median overall survival of patients with a score from 0 to 2 was significantly shorter than that of patients with a score from 3 to 5 (22.1 months vs. 53.2 months, P < 0.001). CONCLUSIONS: Tumor density is a novel predictive marker for the prognosis of patients with resected LAPC after FOLFIRINOX. A simple scoring model incorporating tumor density, the tumor shrinkage rate, and CA 19-9 levels identifies patients with a low score, who may be candidates for additional treatment.

Myofibroblastic CAF Density, Not Activated Stroma Index, Indicates Prognosis after Neoadjuvant Therapy of Pancreatic Carcinoma.

Neoadjuvant therapy (NT) for advanced PDAC is an emerging concept, affecting both stroma and tumor. The Activated Stroma Index (ASI; ratio of activated cancer-associated fibroblasts (CAF) to collagen deposition) is a prognostic marker in upfront resected pancreatic adenocarcinoma (PDAC). We assessed ASI and its prognostic relevance after NT. Tissue from resection specimens of n = 48 PDAC patients after neoadjuvant chemotherapy with FOLFIRINOX (FOL; n = 31), gemcitabine + nab-paclitaxel (GEM; 7) or combination treatment (COMB; 10) was compared with upfront resected matched controls (RES; 69). Activated CAFs were assessed by immunohistochemistry for α-SMA, and collagen was stained with aniline blue; the stained area was then determined by computational imaging analysis and ASI was calculated. In GEM, ASI was significantly higher and collagen deposition lower than in controls and FOL. The lowest quartile of ASI values had significantly longer overall survival (OS) in RES, whereas in FOL, the highest quartile had the best prognosis. After NT, OS was significantly improved in the α-SMA-high group; in RES, however, survival was independent of α-SMA. Reversed prognostic association of ASI thus points to the differing significance of stromal composition after FOL, while improved prognosis with high CAF abundance suggests a synergistic effect of myofibroblasts with chemotherapy. These divergences impede usability of ASI after NT.

Factors Influencing Overall Survival for Patients with Fibrolamellar Hepatocellular Carcinoma: Analysis of the Surveillance, Epidemiology, and End Results Database.

BACKGROUND: The study aimed to develop a nomogram to predict overall survival (OS) for patients with FLC using a national database. METHODS: The Surveillance, Epidemiology, and End Results database of the National Cancer Institute was reviewed to identify FLC cases with histological confirmation between 2004 and 2014. Cox proportional hazards models were used to identify factors associated with OS. The validation of the nomogram was performed using concordance index (C-index) and calibration curves. RESULTS: Out of 170 cases with complete follow-up, 87 received surgery/ablation and 12 received transplantation with significantly higher OS than chemotherapy alone while transplantation combined with chemotherapy showed better survival than solely transplantation. The combination of surgery and chemotherapy showed worse OS than surgery alone. Survival was negatively influenced by T4 stadium (HR = 5.91), while young age and surgery were positive predictive factors. There was no influence of gender, ethnicity or nodal status on survival. The rate of AFP positivity was comparable with and without the presence of distal metastases. CONCLUSION: FLC survival is greatly dependent upon appropriate surgical management irrespective of tumor stadium.

Can local ablative techniques replace surgery for locally advanced pancreatic cancer?

In the treatment of pancreatic ductal adenocarcinoma (PDAC) the best chance at long term survival or cure has to date always included the complete surgical removal of the tumor. However, locally advanced pancreatic cancer (LAPC), about 25% of all newly diagnosed PDAC, is defined by its primary technical unresectability due to infiltration of visceral arteries and absence of metastasis. Induction therapies, especially FOLFIRINOX treatment, together with technical surgical advancement have increased the numbers for conversion to secondary resectability. Recent data on resections after induction therapy show promising, almost doubled survival compared to palliative treatment. Yet, around 70% of LAPC remain unresectable after induction therapy, often due to persistent local invasion. As locally ablative techniques are becoming more widely available this review examines their possible applicability to substitute for surgery in these cases which we propose to group under the new term "Inconvertible LAPC". The need for defining this novel subgroup who might benefit from ablative treatment is based on the findings in our review that high-level evidence on ablative techniques for PDAC is largely lacking and the latest effective, harmonized treatment guidelines for LAPC are not often incorporated in these studies. The "inconvertible LAPC" label requires persistent unresectability after staging and induction therapy of LAPC according to current guidelines followed by liberal indication for aggressive surgical exploration at a center equipped for extended pancreatic resections. Ideally, this specification of a new, distinct patient group will also put it in the spotlight more, hopefully prompt more trials designed to generate robust evidence and optimize transferability of study results.

Open irreversible electroporation for isolated local recurrence of pancreatic ductal adenocarcinoma after primary surgery.

BACKGROUND/OBJECTIVES: Irreversible electroporation (IRE) is an emerging treatment for locally advanced pancreatic cancer (LAPC) which in some cohorts has been associated with severe complications. Additionally, re-resection of isolated local recurrence (ILR) after pancreatic ductal adenocarcinoma (PDAC) can improve survival. We investigated safety, feasibility and oncologic outcomes in the first report on open IRE for unresectable ILR of PDAC in a staged surgical approach. METHODS: Records of the prospectively documented institutional database were screened for patients undergoing laparotomy in IRE-standby due to questionable resectability. Endpoints were morbidity, mortality and overall (OS) and progression free survival (PFS). Data of LAPC and ILR were compared statistically for safety and feasibility analysis. RESULTS: Intraoperative IRE was performed in 11 ILR and 14 LAPC. Six (54.5%) ILR and 10 (71.4%) LAPC patients had postoperative complications, type and frequency did not differ significantly. Major complications occurred in one ILR and two LAPC patients. Median OS was 20.0 months (95% CI: 2.7-37.3) after IRE for ILR and 28 (17.4-38.6) for LAPC. Median PFS after IRE was seven months for both ILR (4.1-9.9; n = 9) and LAPC (2.3-11.7; n = 13). CONCLUSION: Open IRE for unresectable ILR was associated with acceptable perioperative risk. In this small, highly selected subset of patients with limited therapeutic options ancillary treatment with IRE might improve survival. Randomized treatment studies are required to establish the definitive role of IRE as compared to palliative standards of care in unresectable recurrence of PDAC and inconvertible LAPC.

68Ga-FAPI-PET/CT in patients with various gynecological malignancies.

PURPOSE: 68Ga-FAPI (fibroblast activation protein inhibitor) is a novel and highly promising radiotracer for PET/CT imaging. The aim of this retrospective analysis is to explore the potential of FAPI-PET/CT in gynecological malignancies. We assessed biodistribution, tumor uptake, and the influence of pre- or postmenopausal status on tracer accumulation in hormone-sensitive organs. Furthermore, a comparison with the current standard oncological tracer 18F-FDG was performed in selected cases. PATIENTS AND METHODS: A total of 31 patients (median age 59.5) from two centers with several gynecological tumors (breast cancer; ovarian cancer; cervical cancer; endometrial cancer; leiomyosarcoma of the uterus; tubal cancer) underwent 68Ga-FAPI-PET/CT. Out of 31 patients, 10 received an additional 18F-FDG scan within a median time interval of 12.5 days (range 1-76). Tracer uptake was quantified by standardized uptake values (SUV)max and (SUV)mean, and tumor-to-background ratio (TBR) was calculated (SUVmax tumor/ SUVmean organ). Moreover, a second cohort of 167 female patients with different malignancies was analyzed regarding their FAPI uptake in normal hormone-responsive organs: endometrium (n = 128), ovary (n = 64), and breast (n = 147). These patients were categorized by age as premenopausal (<35 years; n = 12), postmenopausal (>65 years; n = 68), and unknown menstrual status (35-65 years; n = 87), followed by an analysis of FAPI uptake of the pre- and postmenopausal group. RESULTS: In 8 out of 31 patients, the primary tumor was present, and all 31 patients showed lesions suspicious for metastasis (n = 81) demonstrating a high mean SUVmax in both the primary (SUVmax 11.6) and metastatic lesions (SUVmax 9.7). TBR was significantly higher in 68Ga-FAPI compared to 18F-FDG for distant metastases (13.0 vs. 5.7; p = 0.047) and by trend for regional lymph node metastases (31.9 vs 27.3; p = 0.6). Biodistribution of 68Ga-FAPI-PET/CT presented significantly lower uptake or no significant differences in 15 out of 16 organs, compared to 18F-FDG-PET/CT. The highest uptake of all primary lesions was obtained in endometrial carcinomas (mean SUVmax 18.4), followed by cervical carcinomas (mean SUVmax 15.22). In the second cohort, uptake in premenopausal patients differed significantly from postmenopausal patients in endometrium (11.7 vs 3.9; p < 0.0001) and breast (1.8 vs 1.0; p = 0.004), whereas no significant difference concerning ovaries (2.8 vs 1.6; p = 0.141) was observed. CONCLUSION: Due to high tracer uptake resulting in sharp contrasts in primary and metastatic lesions and higher TBRs than 18F-FDG-PET/CT, 68Ga-FAPI-PET/CT presents a promising imaging method for staging and follow-up of gynecological tumors. The presence or absence of the menstrual cycle seems to correlate with FAPI accumulation in the normal endometrium and breast. This first investigation of FAP ligands in gynecological tumor entities supports clinical application and further research in this field.

68Ga-FAPI-PET/CT improves diagnostic staging and radiotherapy planning of adenoid cystic carcinomas - Imaging analysis and histological validation.

BACKGROUND: Adenoid cystic carcinomas (ACCs) are rare epithelial tumors mostly situated in the head and neck region and characterized by infiltrative growth. The tumor stroma of ACCs includes cancer-associated fibroblasts (CAFs) expressing Fibroblast Activation Protein (FAP), a new target for positron emission tomography (PET) imaging. Here we describe the value of PET/ computed tomography (PET/CT) imaging using 68Ga-labelled FAP-Inhibitors (68Ga-FAPI-PET/CT) and their clinical potential for staging and radiotherapy planning in 12 ACC patients (7 primary, 5 recurrent). PATIENTS AND METHODS: Patients underwent contrast enhanced staging CT (ceCT) and magnetic resonance imaging (ceMRI) before 68Ga-FAPI - PET/CT. PET-scans were acquired 10, 60 and 180 minutes after administration of 150-250 MBq of 68Ga-labelled FAPI tracers. SUVmax and SUVmean values of ACCs and healthy organs were obtained using a 60% of maximum iso-contour. FAP and alpha smooth muscle actin (α-SMA) immunohistochemistry was performed in 13 cases (3 with and 10 without 68Ga FAPI-PET/CT). Staging and radiotherapy planning based on 68Ga-FAPI-PET/CT versus ceCT/MRI alone were compared. RESULTS: We observed elevated tracer uptake in all ACCs. Immunohistochemistry showed FAP-expressing CAFs in the tumor. Compared to conventional staging, 68Ga-FAPI-PET/CT led to upstaging in 2/12 patients and to detection of additional metastases in 3 patients, thus in total 42% of patients had their staging altered. Moreover, 68Ga-FAPI PET improved the accuracy of target volume delineation for radiotherapy, as compared to CT and MRI. CONCLUSION: 68Ga-FAPI-PET/CT is a promising imaging modality for ACC, increasing the accuracy of staging exams and radiotherapy planning volumes, as compared conventional to CT and MRI.

Survival Benefit of Resection Surgery for Pancreatic Ductal Adenocarcinoma with Liver Metastases: A Propensity Score-Matched SEER Database Analysis.

Guidelines do not recommend resection surgery for oligometastatic pancreatic ductal adenocarcinoma (PDAC). However, reports in small samples of selected patients suggest that surgery extends survival. Thus, this study aims to gather evidence for the benefits of cancer-directed surgery (CDS) by analyzing a national cohort and identifying prognostic factors that aid the selection of candidates for CDS or recruitment into experimental trials. Data for patients with PDAC and hepatic metastasis were extracted from the population-based Surveillance, Epidemiology, and End Results database (SEER). The bias between CDS and non-CDS groups was minimized with Propensity Score Matching (PSM), and the prognostic role of CDS was investigated by comparing Kaplan-Meier estimators and Cox proportional hazard models. A total of 12,018 patients were extracted from the database, including 259 patients who underwent CDS that were 1:1 propensity score-matched with patients who did not receive CDS. CDS appeared to significantly prolong median overall survival from 5 to 10 months. Multivariate analysis revealed chemotherapy as a protective prognostic, whilst survival was impaired by old age and tumors that were poorly differentiated (Grades III-IV). These factors can be used to select patients likely to benefit from CDS treatment, which may facilitate recruitment into randomized controlled trials.

Prognostic Factors of Survival After Neoadjuvant Treatment and Resection for Initially Unresectable Pancreatic Cancer.

OBJECTIVE: To evaluate the impact of clinical and pathological parameters, including resection margin (R) status, on survival in patients undergoing pancreatic surgery after neoadjuvant treatment for initially unresectable pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Prognostic factors are well documented for patients with resectable PDAC, but have not been described in detail for patients with initially unresectable PDAC undergoing resection after neoadjuvant therapy. METHODS: Prospectively collected data of consecutive patients with initially unresectable pancreatic cancer treated by neoadjuvant treatment and resection were analyzed. The R status was categorized as R0 (tumor-free margin >1 mm), R1 ≤1 mm (tumor-free margin ≤1 mm), and R1 direct (microscopic tumor infiltration at margin). Clinicopathological characteristics and outcomes were compared among these groups and tested for survival prediction. RESULTS: Between January, 2006 and February, 2017, 280 patients with borderline resectable (n = 18), locally advanced (n = 190), or oligometastatic (n = 72) disease underwent tumor resection after neoadjuvant treatment. Median overall survival from the time of surgery was 25.1 months for R0 (n = 82), 15.3 months for R1 ≤1 mm (n = 99), and 16.1 months for R1 direct (n = 99), with 3-year overall survival rates of 35.0%, 20.7%, and 18.5%, respectively (P = 0.0076). The median duration of the neoadjuvant treatment period was 5.1 months. In multivariable analysis, preoperative CA 19-9 levels, lymph node status, metastasis category, and vascular involvement were all significant prognostic factors for overall survival. The R status was not an independent prognostic factor. CONCLUSIONS: In patients undergoing resection after neoadjuvant therapy for initially unresectable PDAC, preoperative CA 19-9 levels, lymph node involvement, metastasis category, and vascular involvement, but not the R status, were independent prognostic factors of overall survival.

Systematic Review and Metaanalysis of Lymph Node Metastases of Resected Pancreatic Neuroendocrine Tumors.

BACKGROUND: The optimal surgical strategy for pancreatic neuroendocrine tumors (PNETs) is unknown. However, current guidelines recommend a watch-and-wait strategy for small nonfunctional PNETs (NF-PNETs). The aim of this study is to investigate the risk stratification and prognostic significance of lymph node metastasis (LNM) of PNETs to guide decision-making for lymphadenectomy. PATIENTS AND METHODS: The MEDLINE and Web of Science databases were systematically searched for studies reporting either risk factors of LNM in resected PNETs or survival of patients with LNM. The weighted average incidence of LNM was calculated according to tumor characteristics. Random-effects metaanalyses were performed, and pooled hazard ratios (HR) and their 95% confidence intervals (CI) were calculated to determine the impact of LNM on overall survival (OS). In subgroup analyses, NF-PNETs were assessed. RESULTS: From a total of 5883 articles, 98 retrospective studies with 13,374 patients undergoing resection for PNET were included. In all PNETs, the weighted median rates of LNM were 11.5% for small (≤ 2 cm) PNETs and 15.8% for G1 PNETs. In NF-PNETs, the rates were 11.2% for small PNETs and 10.3% for G1 PNETs. LNM of all PNETs (HR 3.87, 95% CI 3.00-4.99, P < 0.001) and NF-PNETs (HR 4.98, 95% CI 2.81-8.83, P < 0.001) was associated with worse OS. CONCLUSIONS: LNM is potentially prevalent even in small and well-differentiated PNETs and is associated with worse prognosis. A watch-and-wait strategy for small NF-PNETs should be reappraised, and oncologic resection with lymphadenectomy can be considered. Prospective and controlled studies are needed in the future.

Escherichia coli Bacterobilia Is Associated with Severe Postoperative Pancreatic Fistula After Pancreaticoduodenectomy.

BACKGROUND: The benefit of preoperative biliary stenting in the treatment of pancreatic ductal adenocarcinoma is controversially debated. Data from recent meta-analyses favor primary surgery for the majority of resectable pancreatic cancers. Regardless of this evidence, preoperative biliary stenting via endoscopy (EBS) is commonly performed, often before involvement of a surgeon. The goal of this study was to elucidate the association of bile duct stenting, microbiological dislocation of gut flora to the biliary compartment, and major postoperative complications. METHODS: Patient data was derived from a prospectively maintained database including all pancreatic resections between January 2006 and December 2014. Patients receiving pancreaticoduodenectomy for malignant disease in the head of the pancreas with prior EBS were included. Microbiological data were obtained through conventional culture from intraoperative bile duct swabs. RESULTS: Two hundred ninety-eight patients were enrolled in this study. Severe postoperative complications were associated with stent colonization: Postoperative pancreatic fistula type C occurred more frequently in E. coli-colonized patients (sample estimated odds ratio (OR) = 4.07), and the rate of lymphatic fistula was elevated in Enterococcus-colonized patients (OR = 3.25). Longer stenting duration (> 16 days) was associated with the prevalence of these bacteria. CONCLUSION: Major surgical complications following pancreaticoduodenectomy, including severe pancreatic fistula, are associated with bacterobilia after EBS. The indication for bile duct stenting should be evaluated in a multidisciplinary setting.