Robotic versus open pancreaticoduodenectomy in elderly patients: a propensity score-matched analysis.

BACKGROUND: Pancreaticoduodenectomy (PD) is complex procedure with high morbidity in the elderly. This retrospective study aimed to compare post-operative outcomes in patients ≥75 years of age who underwent robot-assisted (RA)PD and open PD. METHODS: We analyzed 2502 patients ≥75 years of age who underwent PD from 2015 to 2018 in the National Surgical Quality Improvement Program (NSQIP) database. RAPD and open PD patients were propensity score matched 1:5 to assess the 30-day outcomes of interest: postoperative complications, length of stay, discharge destination, and readmissions. RESULTS: Of 725 matched patients, 110 underwent RAPD, 615 OPD, and 12 were converted to an open operation. Post-operative outcomes were largely similar between cohorts. RAPD was associated a shorter length of stay (median 8 days, interquartile range [IQR] 6 to 11) than OPD (median 8 days, IQR 7 to 13) (p = 0.003). However, RAPD was associated with more readmissions (28.1% vs. 17.7%; p = 0.02). CONCLUSIONS: RAPD in patients ≥75 years of age appears to be safe and has a similar complication profile to open PD. Randomized or well-designed prospective matched studies are needed to confirm these findings.

Oncologic Outcomes After Robotic Pancreatic Resections Are Not Inferior to Open Surgery.

OBJECTIVE: Compare oncologic outcomes after open and robotic pancreatic resections for pancreatic adenocarcinoma (PDAC). SUMMARY OF BACKGROUND DATA: Receipt of adjuvant chemotherapy improves survival after resected PDAC. Complications after pancreatectomy have been shown to prohibit the administration of adjuvant chemotherapy and survival. We examined the effect of surgical approach on receipt of adjuvant chemotherapy, complications, and overall survival after pancreatectomy. METHODS: A single-institution retrospective review of all patients with PDAC who underwent robotic or open pancreatectomy from 2011 to 2016 with 24-month follow-up. RESULTS: Four hundred fifty-six patients underwent resection: 226 robotic and 230 open. No significant difference was identified in major complications or receipt of adjuvant chemotherapy between robotic and open pancreatectomy, nor was approach an independent predictor of these outcomes. Robotic pancreatectomy patients had a shorter length of stay than patients who underwent open pancreatectomy (7 days vs 9 days; P < 0.001). Additionally, wound infection rate (32.3% vs 12.4%, P < 0.0001) and transfusion (39.6% vs 12.4%, P < 0.0001) was improved in robotic pancreatectomy group with no differences in perioperative mortality. Improved median overall survival approached statistical significance for the robotic cohort (25.6 months vs 23.9 months; P = 0.055); however, on multivariable analysis the robotic approach predicted overall survival, (hazard ratio 0.77, P = 0.041). Robotic approach was an independent predictor of decreased blood loss and less transfusions than the open approach. CONCLUSIONS: Robotic pancreatectomy was not inferior compared to open pancreatectomy in a high-volume experienced center for oncologic outcomes and due to decreased blood loss and transfusion may have improved survival.

Reviews on Current Liquid Biopsy for Detection and Management of Pancreatic Cancers.

Pancreatic cancer is the fourth leading cause of cancer death in the United States. Pancreatic cancer presents dismal clinical outcomes in patients, and the incidence of pancreatic cancer has continuously increased to likely become the second most common cause of cancer-related deaths by as early as 2030. One of main reasons for the high mortality rate of pancreatic cancer is the lack of tools for early-stage detection. Current practice in detecting and monitoring therapeutic response in pancreatic cancer relies on imaging analysis and invasive endoscopic examination. Liquid biopsy-based analysis of genetic alterations in biofluids has become a fundamental component in the diagnosis and management of cancers. There is an urgent need for scientific and technological advancement to detect pancreatic cancer early and to develop effective therapies. The development of a highly sensitive and specific liquid biopsy tool will require extensive understanding on the characteristics of circulating tumor DNA in biofluids. Here, we have reviewed the current status of liquid biopsy in detecting and monitoring pancreatic cancers and our understanding of circulating tumor DNA that should be considered for the development of a liquid biopsy tool, which will greatly aid in the diagnosis and healthcare of people at risk.

Readmission and Resource Use After Robotic-Assisted versus Open Pancreaticoduodenectomy: 2010-2017.

BACKGROUND: Unplanned rehospitalization is considered an adverse quality of care indicator. Minimally invasive operations carry the potential to reduce resource use while enhancing recovery. Robotic-assisted pancreaticoduodenectomy (RAPD) has been used to improve outcomes of its morbid open counterpart. We sought to identify factors associated with readmission between RAPD and open pancreaticoduodenectomy (OPD). MATERIALS AND METHODS: We used the 2010-17 National Readmissions Database to identify adults who underwent RAPD or OPD. The primary outcome was 30-day readmission. Secondary outcomes included readmission diagnosis: index, readmission, and total (index + readmission) length of stay, costs, and mortality. RESULTS: Of an estimated 84,036 patients undergoing pancreaticoduodenectomy, 96.9% survived index hospitalization. Frequency of both RAPD and OPD increased during the study period with similar mortality (2.5% versus 3.2%, P = 0.46). Compared with OPD, RAPD was not an independent predictor of 30-day readmission (adjusted odds ratio (AOR): 1.0, P = 0.98). Disposition with home health care (AOR: 1.1, P < 0.001) or to a skilled nursing facility (AOR: 1.5, P < 0.001) was significantly associated with increased 30-day readmission. CONCLUSIONS: Readmission after pancreaticoduodenectomy is common, regardless of surgical approach. Although RAPD saves in-patient days on index admission, readmission rates and length of stay are similar between the two modalities. Neither RAPD nor OPD is a risk factor for readmission, highlighting the complexity of pancreaticoduodenectomy, with complications that may result from factors independent of the operative approach.

National Trends in Readmission and Resource Utilization After Pancreatectomy in the United States.

INTRODUCTION: Pancreatectomy is a complex operation that has been associated with excess morbidity and mortality. Although acute index outcomes have been characterized, there are limited data available on nonelective readmission after pancreatic surgery. We sought to identify factors associated with 30-day and 30- to 90-day readmission after pancreatectomy. MATERIAL AND METHODS: We utilized the National Readmissions Database between 2010 and 2016 to identify adults who underwent a pancreatectomy. The primary outcomes were 30-day (30DR) and 30- to 90-day (90DR) readmission. Secondary outcomes included nonelective readmission trends, diagnosis, length of stay, charges, and mortality. RESULTS: Of an estimated 130,267 subjects undergoing pancreatectomy, 97% survived index hospitalization. Eighteen percent of patients had nonelective 30DR while 5.6% experienced 90DR. Readmission at the two time points remained stable during the study period. After adjusting for institution, pancreatectomy volume, mortality (2.0% versus 4.9%, P < 0.001), 30DR length of stay (7.3 d versus 7.8 d, P < 0.001), and 90DR rates (6.9% versus 8.1%, P = 0.003) were significantly decreased at high-volume pancreatectomy centers compared to low-volume hospitals. Discharge to a skilled nursing facility (AOR: 1.52) or with home health care (AOR: 1.2) was associated with 30DR (P < 0.001). Patients undergoing total pancreatectomy (AOR: 1.3) or those with a substance use disorder (AOR: 1.4) among others were associated with 90DR (P ≤ 0.01). CONCLUSIONS: Readmissions are common and costly after pancreatectomy. Approximately 20% of patients experience readmission within 30 d. 30DR and 90DR rates remained stable during the study. Pancreatectomy at a high-volume center was associated with decreased mortality and 90DR. The present analysis confirms associations between pancreatectomy volume, postsurgical complications, comorbidities, and readmission.

Epidural Analgesia Improves Postoperative Pain Control but Impedes Early Discharge in Patients Undergoing Pancreatic Surgery.

OBJECTIVES: The aim of this study was to evaluate the impact of epidural analgesia (EA) on postoperative length of stay (LOS), expeditious discharge, and pain relief after pancreaticoduodenectomy (PD) and distal pancreatectomy (DP). METHODS: Retrospective reviews of 2014-2015 American College of Surgeons National Surgical Quality Improvement Program databases and our institutional pancreatic surgery database were conducted. RESULTS: On univariate analysis, EA was associated with statistically significant longer lengths of stay for both PD and DP. On comparative analysis at mode LOS, discharged before versus after 7 days for PD and 6 days for DP, EA was a significant predictor for the longer groups for both procedures on multivariable analysis (PD, odds ratio of 1.465, P < 0.001; DP, odds ratio of 1.471, P = 0.004). On review of our institution's pancreatic surgery database, patient-reported pain scores were significantly lower in the EA groups than intravenous narcotics groups on the day of surgery only for both PD and DP. CONCLUSIONS: Epidural analgesia was associated with longer LOS with a most pronounced effect on early discharge after surgery for patients undergoing open PD and DP. It only resulted in superior pain control on the day of surgery.

Emerging Evidence for the Clinical Relevance of Pancreatic Cancer Exosomes.

The last 5 years have seen a dramatic increased interest in the field of exosome biology. Although much is unknown about the role of exosomes in human health and disease, disparate scientific disciplines are recognizing the highly conserved role that exosomes play in fundamental biological processes. Recently, there have been intriguing discoveries defining the role of exosomes in cancer biology. We performed a structured review of the English-language literature using the PubMed database searching for articles relating to exosomes and pancreatic ductal adenocarcinoma (PDAC). Articles were screened for relevance and content to judge for inclusion. Evidence implicates exosomes in the pathogenesis, local progression, metastasis, immune evasion, and intercellular communication of PDAC. Basic science discoveries in exosome biology have the potential to change the clinical management of PDAC, where, despite advances in early detection, diagnosis, staging, chemotherapy, and surgery, survival rates have been stagnant for decades and PDAC remains the most deadly human gastrointestinal malignancy.

Pasireotide does not prevent postoperative pancreatic fistula: a prospective study.

BACKGROUND: Pancreatic fistula is a major cause of morbidity after pancreas surgery. In 2014, a single-center, randomized-controlled trial found pasireotide decreased pancreatic fistula rates. However, this finding has not been validated, nor has pasireotide been widely adopted. METHODS: A single-arm study in 111 consecutive patients undergoing pancreatic resection April 2015-October 2016 was conducted. Beginning immediately before surgery, patients received 900 µg subcutaneous pasireotide twice daily for up to seven days. Fistula rates were compared to 168 historical controls from July 2013 to March 2015. The primary outcome was Grade B/C fistula, as defined by the International Study Group on Pancreatic Fistula (ISGPF). RESULTS: There were no significant differences between the pasireotide group and historical controls in demographics, comorbidities, operation type, malignancy, gland texture, or pancreatic duct size. Pasireotide did not reduce fistula rate (15.5% control versus 17.1% pasireotide, p = 0.72). In subgroup analyses of pancreaticoduodenectomy or distal pancreatectomy, or patients with soft gland texture and/or small duct size, there was no decrease in fistulas. Thirty-nine patients (38%) experienced dose-limiting nausea. CONCLUSIONS: In an appropriately-powered, single-institution prospective study, pasireotide was not validated as a preventive measure for pancreatic fistula.

Robotic-assisted spleen preserving distal pancreatectomy: a technical review.

Minimally-invasive spleen-preserving distal pancreatectomy is indicated for benign or borderline malignant lesions confined to the pancreatic body and tail. With the introduction of the da Vinci robotic system, preliminary case series have suggested an improved spleen preservation rate, higher rate of margin negative resections and improved lymph node yield versus the standard laparoscopic approach. In this article, we described our approach to robotic-assisted distal pancreatectomy with both vessel-conserving (Kimura) and vessel-sacrificing (Warshaw) variations.

Deviations from Expected Treatment of Pancreatic Cancer in Octogenarians: Analysis of Patient and Surgeon Factors.

BACKGROUND: Morbidity and mortality of pancreatectomy has improved and chemotherapeutic options for pancreatic cancer (PC) are growing, yet there is reluctance to treat octogenarians. This study examined the reasons for failure to treat and analyzes outcomes in octogenarians with PC. METHODS: Retrospective chart review 2005-2013. Demographics, tumor characteristics, treatment, reason for lack of treatment, Charlson comorbidity index (CCI), and survival were analyzed. Expected treatment for early-stage patients (I/II) included surgery ± chemotherapy ± radiation. Expected treatment for advanced stage patients (III/IV) was chemotherapy. RESULTS: A total of 431 octogenarians were analyzed. Mean age was 84.0 ± 3.4, 59.6 % female, and 44.1 % received no treatment. Patients with operable tumors (I = 31 [7.2 %]/II = 214 [49.7 %]) had surgery 39.2 % of the time. Age was a predictor of not receiving surgery (odds ratio [OR] 0.78; 95 % confidence interval [CI] 0.70-0.86; p = 0.0001), whereas CCI was not. The most common reason for no surgery was contraindication despite similar CCI. Median overall survival for early-stage patients was better in the surgical group (15.8 vs. 5.5 months) than nonsurgical group (p < 0.0001). Advanced patients (III = 54 [12.5 %]/IV = 132 [30.6 %]) had similarly low treatment rates (n = 65 [34.9 %]). Survival for advanced disease was best for treated patients (6.9 vs. 1.8 months; p < 0.0001). CCI did not differ between those receiving chemotherapy and not, although age was significantly different (p < 0.0001). CONCLUSIONS: There is significant deviation from expected treatment for octogenarians with PC. While no correlation existed between CCI and treatment, age correlated with therapy for nearly all stages. Chronological age, not comorbidity, may drive recommendation for treatment in elderly patients.

Safety in Numbers: Progressive Implementation of a Robotics Program in an Academic Surgical Oncology Practice.

Background Robotic-assisted surgery has potential benefits over laparoscopy yet little has been published on the integration of this platform into complex surgical oncology. We describe the outcomes associated with integration of robotics into a large surgical oncology program, focusing on metrics of safety and efficiency. Methods A retrospective review of a prospectively maintained database of robotic procedures from July 2009 to October 2014 identifying trends in volume, operative time, complications, conversion to open, and 90-day mortality. Results Fourteen surgeons performed 1236 cases during the study period: thyroid (246), pancreas/duodenum (458), liver (157), stomach (56), colorectal (129), adrenal (38), cholecystectomy (102), and other (48). There were 38 conversions to open (3.1%), 230 complications (18.6%), and 13 mortalities (1.1%). From 2009 to 2014, operative volume increased (7 cases/month vs 24 cases/month; P < .001) and procedure time decreased (471 ± 166 vs 211 ± 140 minutes; P < .001) with statistically significant decreases for all years except 2014 when volume and time plateaued. Conversion to open decreased (12.1% vs 1.7%; P = .009) and complications decreased (48.5% vs 12.3%; P < .001) despite increasing complexity of cases performed. There were 13 deaths within 90 days (5/13 30-day mortality) and 2 (15.4%) were from palliative surgeries. Conclusions Implementation of a diverse robotic surgical oncology program utilizing multiple surgeons is safe and feasible. As operative volume increased, operative time, complications, and conversions to open decreased and plateaued at approximately 3 years. No unanticipated adverse events attributable to the introduction of this platform were observed.

Complete encasement of the peroneal tendons by the peroneal tubercle.

The peroneal tubercle is an osseous structure on the lateral side of the calcaneus present in 90% of individuals. Hypertrophy of the peroneal tubercle resulting in stenosing peroneal tenosynovitis has been well described in the literature. Repair of this condition involves operative treatment to remove the hypertrophied peroneal tubercle and repair any resulting tendon pathology. The authors report a unique case of a hypertrophied peroneal tubercle with an associated tarsal coalition, resulting in complete bony encasement of the peroneal tendons. In this case, a 50-year-old white man presented with worsening bilateral foot and ankle pain for several years. On examination, he had fixed hindfoot varus and bilateral equinocavovarus feet. Magnetic resonance imaging and weight-bearing radiographs showed a calcaneonavicular coalition. Intraoperatively, the authors discovered complete bony encasement of the peroneal longus and brevis tendons. On examination, the peroneal longus and brevis were severely stenotic, with the peroneal brevis to the point of near laceration. This painful condition was repaired by takedown of the calcaneonavicular coalition, the peroneal tubercle was resected, and the peroneal tendons were freed from their bony encasement. Tenodesis of the peroneus brevis to longus was performed and the hindfoot varus was corrected with wedge osteotomy of the calcaneus. The patient reported excellent postoperative results. At 3 months postoperatively, he was pain-free and his calcaneal osteotomy was well healed. This case appears to be the first of its type to be reported in the literature. The details of the case are presented along with a review of the relevant literature.

Cardiac preconditioning with sphingosine-1-phosphate requires activation of signal transducer and activator of transcription-3.

AIM: Sphingosine-1-phosphate (S1P) is a cardioprotective agent. Signal transducer and activator of transcription 3 (STAT-3) is a key mediator of many cardioprotective agents. We aimed to explore whether STAT-3 is a key mediator in S1P-induced preconditioning. METHODS: Langendorff-perfused hearts from Wistar rats and wild-type or cardiomyocyte-specific STAT-3 knockout mice were pre-treated with S1P (10 nmol/l), with or without the STAT-3 pathway inhibitor AG490, before an ischaemia-reperfusion insult. Triphenyltetrazolium chloride and Evans blue staining were used for the determination of infarct size. Western blot analysis was carried out on the S1P pre-treated hearts for detection of cytosolic, nuclear and mitochondrial phosphorylated and total STAT-3 proteins. RESULTS: Pre-treatment with S1P decreased the infarct size in isolated rat (5 ± 3% vs control 26 ± 8%, p < 0.01) and wild-type mouse hearts (13 ± 1% vs control 33 ± 3%, p < 0.05). This protective effect was abolished in the rat hearts pre-treated with AG490 (30 ± 10%, p = ns vs control) and in the hearts from STAT-3 knockout mice (35 ± 4% vs control 30 ± 3%, p = ns). Levels of phosphorylated STAT-3 were significantly increased in both the nuclear (p < 0.05 vs control) and mitochondrial (p < 0.05 vs control) fractions in the S1P pre-treated hearts, but remained unchanged in the cytosolic fraction (p = ns vs control). CONCLUSION: These novel results demonstrate that pharmacological preconditioning with S1P in the isolated heart is mediated by activation of mitochondrial and nuclear STAT-3, therefore suggesting that S1P may be a novel therapeutic target to modulate mitochondrial and nuclear function in cardiovascular disease in order to protect the heart against ischaemia-reperfusion.

Evidence for activation of mutated p53 by apigenin in human pancreatic cancer.

Pancreatic cancer is an exceedingly lethal disease with a five-year survival that ranks among the lowest of gastrointestinal malignancies. Part of its lethality is attributable to a generally poor response to existing chemotherapeutic regimens. New therapeutic approaches are urgently needed. We aimed to elucidate the anti-neoplastic mechanisms of apigenin-an abundant, naturally-occurring plant flavonoid-with a particular focus on p53 function. Pancreatic cancer cells (BxPC-3, MiaPaCa-2) experienced dose and time-dependent growth inhibition and increased apoptosis with apigenin treatment. p53 post-translational modification, nuclear translocation, DNA binding, and upregulation of p21 and PUMA were all enhanced by apigenin treatment despite mutated p53 in both cell lines. Transcription-dependent p53 activity was reversed by pifithrin-α, a specific DNA binding inhibitor of p53, but not growth inhibition or apoptosis suggesting transcription-independent p53 activity. This was supported by immunoprecipitation assays which demonstrated disassociation of p53/BclXL and PUMA/BclXL and formation of complexes with Bak followed by cytochrome c release. Treated animals grew smaller tumors with increased cellular apoptosis than those fed control diet. These results suggest that despite deactivating mutation, p53 retains some of its function which is augmented following treatment with apigenin. Cell cycle arrest and apoptosis induction may be mediated by transcription-independent p53 function via interactions with BclXL and PUMA. Further study of flavonoids as chemotherapeutics is warranted.

Baicalein, a component of Scutellaria baicalensis, induces apoptosis by Mcl-1 down-regulation in human pancreatic cancer cells.

Scutellaria baicalensis (SB) and SB-derived polyphenols possess anti-proliferative activities in several cancers, including pancreatic cancer (PaCa). However, the precise molecular mechanisms have not been fully defined. SB extract and SB-derived polyphenols (wogonin, baicalin, and baicalein) were used to determine their anti-proliferative mechanisms. Baicalein significantly inhibited the proliferation of PaCa cell lines in a dose-dependent manner, whereas wogonin and baicalin exhibited a much less robust effect. Treatment with baicalein induced apoptosis with release of cytochrome c from mitochondria, and activation of caspase-3 and -7 and PARP. The general caspase inhibitor zVAD-fmk reversed baicalein-induced apoptosis, indicating a caspase-dependent mechanism. Baicalein decreased expression of Mcl-1, an anti-apoptotic member of the Bcl-2 protein family, presumably through a transcriptional mechanism. Genetic knockdown of Mcl-1 resulted in marked induction of apoptosis. The effect of baicalein on apoptosis was significantly attenuated by Mcl-1 over-expression, suggesting a critical role of Mcl-1 in this process. Our results provide evidence that baicalein induces apoptosis in pancreatic cancer cells through down-regulation of the anti-apoptotic Mcl-1 protein.

A modern review of the operative management of chronic pancreatitis.

Chronic pancreatitis is a debilitating disease resulting in pain, intestinal malabsorption, endocrine dysfunction, and poor quality of life (QoL). Our aim was to analyze surgical outcomes for patients with chronic pancreatitis. Data for patients undergoing operations for chronic pancreatitis between 1990 and 2009 were reviewed. Demographics, operative and perioperative data, and survival were catalogued. QoL was determined (Short Form 36 and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire + PAN-26) and compared with historical controls. The mean age was 51 +/- 2 years, 38 patients were male (53%), the most common indication was pain (71%), the etiology of pancreatitis often was alcohol, and most patients underwent a Whipple procedure (56%). Operative time was 316 +/- 17 minutes and blood loss was 363 +/- 75 mL. There were 34 complications in 30 patients (42%) and one death. QoL surveys were administered for 25 of 55 (45%) surviving patients at a mean follow-up of 72 +/- 16 months. Mean survival was 99 +/- 9 months, whereas 5- and 10-year survival were 86 and 75 per cent. QoL scores were uniformly better than historical controls. Our data demonstrate that operations for chronic pancreatitis can be performed with acceptable morbidity and mortality. Patients have excellent survival and improved QoL compared with historical controls. Surgery is an effective and durable treatment option for patients with chronic pancreatitis.

Pancreatic-pleural fistula is best managed by early operative intervention.

BACKGROUND: Pancreatic-pleural fistula is an uncommon complication of chronic pancreatitis occurring as a result of disruption of the main pancreatic duct and tracking of pancreatic fluid through the retroperitoneum into 1 or both thoracic cavities. The optimal treatment strategy for pancreatic-pleural fistula is unknown; it has traditionally been medical management followed by operative therapy for patients who fail to respond to conservative treatment. Our objective was to compile the case reports of pancreatic-pleural fistula in the literature in order to better define clinical management strategy. METHODS: The case management of pancreatic-pleural fistula was reviewed and a structured MEDLINE search for published studies was performed. Descriptive statistical analysis was performed on compiled data. RESULTS: Review of the literature revealed 63 adult patients with pancreatic-pleural fistula published in English between 1970 and 2008. The majority of patients were male (71%) and there was a predominance of alcohol-associated chronic pancreatitis (51%). There were 10 complications (16%) and 2 deaths (3%) reported. Most patients were treated initially with medical therapy (87%). Medical therapy was deemed to have failed after an average period of 35+/-5 days. Total duration of therapy for patients in whom operative intervention was required after attempted medical management was 40+/-6 days, which was greater than the surgery alone cohort. In total, operative treatment was successful more often than medical therapy (94% vs 31%). CONCLUSION: Analysis from this series indicates that a majority of patients recover from pancreatic-pleural fistula without sequelae (81%). Attempts at prolonged periods of medical therapy tend to delay the resolution of the fistula compared with patients who undergo definitive operative intervention early in the course of treatment.