Distal Pancreatectomy: Extent of Resection Determines Surgical Risk Categories.

BACKGROUND: Recently, subclassification of pancreatoduodenectomy in 4 differing types has been reported, because additional major vascular and multivisceral resections have been shown to be associated with an increased risk of postoperative morbidity and mortality. OBJECTIVE: To classify distal pancreatectomy (DP) based on the extent of resection and technical difficulty and to evaluate postoperative outcomes with regards to this classification system. METHODS: All consecutive patients who had undergone DP between 2001 and 2020 in a high-volume pancreatic surgery center were included in this study. DPs were subclassified into 4 distinct categories reflecting the extent of resection and technical difficulty, including standard DP (type 1), DP with venous (type 2), multivisceral (type 3), or arterial resection (type 4). Patient characteristics, perioperative data, and postoperative outcomes were analyzed and compared among the 4 groups. RESULTS: A total of 2135 patients underwent DP. Standard DP was the most frequently performed procedure (64.8%). The overall 90-day mortality rate was 1.6%. Morbidity rates were higher in patients with additional vascular or multivisceral resections, and 90-day mortality gradually increased with the extent of resection from standard DP to DP with arterial resection (type 1: 0.7%; type 2: 1.3%; type 3: 3%; type 4: 8.7%; P <0.0001). Multivariable analysis confirmed the type of DP as an independent risk factor for 90-day mortality. CONCLUSIONS: Postoperative outcomes after DP depend on the extent of resection and correlate with the type of DP. The implementation of the 4-type classification system allows standardized reporting of surgical outcomes after DP improving comparability of future studies.

Impact of EGFR and EGFR ligand expression on treatment response in patients with metastatic colorectal cancer.

Up to 50% of patients with colorectal cancer (CRC) have either synchronous or metachronous hepatic metastases in the course of their disease. Patients with metastatic CRC (mCRC) whose tumors express wild-type KRAS benefit from treatment with monoclonal antibodies (such as cetuximab or panitumumab) that target the epidermal growth factor receptor (EGFR). However, the therapeutic response to these antibodies is variable, and further predictive models are required. The present study examined whether expression of different EGFRs or their ligands in tumors was associated with the response to cetuximab treatment. Tumor tissues, collected during liver resection in 28 patients with mCRC, were analyzed. The protein expression levels of EGFR/ErbB1, ErbB2, ErbB3 and the EGFR ligands heregulin and amphiregulin were determined using Luminex 200® and enzyme-linked immunosorbent assays. Computed tomography or magnetic resonance imaging was performed 4 weeks before and 6-8 weeks after treatment with cetuximab. Response to treatment was assessed using the response evaluation criteria for solid tumors (RECIST). The association between the protein expression levels of different EGFRs and their ligands with RECIST criteria was then analyzed to determine whether these protein levels could predict the treatment response to cetuximab. A total of 12 patients exhibited a partial response, 9 exhibited stable disease and 7 exhibited progressive disease after cetuximab therapy according to RECIST. The expression levels of EGFRs (EGFR/ErbB1, ErbB2 and ErbB3) and their ligands (heregulin and amphiregulin) were not significantly associated with the response to cetuximab therapy. Therefore, the present study indicated that EGFR or EGFR ligand expression did not predict treatment response in patients with CRC with liver metastases following cetuximab therapy.

Outcome and prognosis after pancreatectomy in patients with solid pseudopapillary neoplasms.

BACKGROUND: Solid pseudopapillary neoplasms (SPN) are rare and represent approximately 4% of all cystic pancreatic tumors. The prognosis is excellent, although 10-15% of SPN patients show metastasis at the time of surgery or tumor recurrence during follow-up after pancreatectomy. Aim of the study was to analyze surgical management, risk factors for malignancy as well as long-term outcome and prognosis of this distinct tumor entity. METHOD: All patients with pancreatic resection for SPN between 10/2001 and 07/2018 in the authors' institution were identified from a prospective database. Clinicopathologic details, perioperative data and long-term follow-up results were retrospectively analyzed. RESULTS: Fifty-two patients were identified, 44 (85%) of them were female and the median age was 29 years (IQR 9-71). Seven (13%) patients showed a malignant behaviour of SPN with N1 (n = 2) or M1 (n = 1) disease at resection; 5 patients developed tumor recurrence, after a median of 21 months. During follow-up time (median 54 months) all patients were alive, the 5- and 10-year rates for disease-free survival were 89.0% and 81.6%, respectively. Significant risk factors for recurrence were age <18 years (p = 0.0087) and parenchyma-preserving surgical approaches (p = 0.0006). The postoperative long-term outcome showed ECOG = 0-1 in all patients, with resection related exocrine insufficiency in 20 (41%) and diabetes mellitus in 2 (4%) patients. CONCLUSIONS: Age < 18 years is a significant risk factor for malignancy in SPN, and parenchyma preserving resections harbor a significant risk for tumor recurrence. As recurrence may occur late, a systematic life-long follow-up should be performed.

Minimally Invasive versus Open Distal Pancreatectomy for Ductal Adenocarcinoma (DIPLOMA): A Pan-European Propensity Score Matched Study.

OBJECTIVE: The aim of this study was to compare oncological outcomes after minimally invasive distal pancreatectomy (MIDP) with open distal pancreatectomy (ODP) in patients with pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Cohort studies have suggested superior short-term outcomes of MIDP vs. ODP. Recent international surveys, however, revealed that surgeons have concerns about the oncological outcomes of MIDP for PDAC. METHODS: This is a pan-European propensity score matched study including patients who underwent MIDP (laparoscopic or robot-assisted) or ODP for PDAC between January 1, 2007 and July 1, 2015. MIDP patients were matched to ODP patients in a 1:1 ratio. Main outcomes were radical (R0) resection, lymph node retrieval, and survival. RESULTS: In total, 1212 patients were included from 34 centers in 11 countries. Of 356 (29%) MIDP patients, 340 could be matched. After matching, the MIDP conversion rate was 19% (n = 62). Median blood loss [200 mL (60-400) vs 300 mL (150-500), P = 0.001] and hospital stay [8 (6-12) vs 9 (7-14) days, P < 0.001] were lower after MIDP. Clavien-Dindo grade ≥3 complications (18% vs 21%, P = 0.431) and 90-day mortality (2% vs 3%, P > 0.99) were comparable for MIDP and ODP, respectively. R0 resection rate was higher (67% vs 58%, P = 0.019), whereas Gerota's fascia resection (31% vs 60%, P < 0.001) and lymph node retrieval [14 (8-22) vs 22 (14-31), P < 0.001] were lower after MIDP. Median overall survival was 28 [95% confidence interval (CI), 22-34] versus 31 (95% CI, 26-36) months (P = 0.929). CONCLUSIONS: Comparable survival was seen after MIDP and ODP for PDAC, but the opposing differences in R0 resection rate, resection of Gerota's fascia, and lymph node retrieval strengthen the need for a randomized trial to confirm the oncological safety of MIDP.

Hypercoagulability after distal pancreatectomy: Just meaningless alterations?

BACKGROUND: Perioperative and short-term postoperative parameters are similar comparing spleen-preserving distal pancreatectomy (SPDP) and distal pancreatectomy with splenectomy (DPS). But there are no sound data evaluating the long term risk of postoperative thromboses and infectious complications after splenectomy. The present study evaluated whether the coagulation status differs in patients after SPDP and DPS, and whether that matters clinically. METHODS: A total of 41 patients after DP (SPDP = 20; DPS = 21) were followed up, focusing on alterations of patient coagulation and immune status. To assess kinetics of the coagulation process, qualitative tests (multiple platelet function analyzer, rotational thrombelastography) were used in addition to global coagulation tests. RESULTS: Coagulation tests revealed a significant enhanced tendency for blood-platelet aggregation and coagulation activation in patients after DPS compared to patients after SPDP. No septic or thromboembolic events were observed in any patient. CONCLUSION: Hypercoagulability in splenectomized patients persists over years. Thus, a correlation of this finding with thromboembolic events and mortality years after splenectomy should to be performed in a large cohort.

Teres Ligament Patch Reduces Relevant Morbidity After Distal Pancreatectomy (the DISCOVER Randomized Controlled Trial).

OBJECTIVE: The aim of this study was to analyze the impact of teres ligament covering on pancreatic fistula rate after distal pancreatectomy (DP). BACKGROUND: Postoperative pancreatic fistula (POPF) represents the most significant complication after DP. Retrospective studies suggested a benefit of covering the resection margin by a teres ligament patch. METHODS: This prospective randomized controlled study (DISCOVER trial) included 152 patients undergoing DP, between October 2010 and July 2014. Patients were randomized to undergo closure of the pancreatic cut margin without (control, n = 76) or with teres ligament coverage (teres, n = 76). The primary endpoint was the rate of POPF, and the secondary endpoints included postoperative morbidity and mortality, length of hospital stay, and readmission rate. RESULTS: Both groups were comparable regarding epidemiology (age, sex, body mass index), operative parameters (operation time [OP] time, blood loss, method of pancreas transection, additional operative procedures), and histopathological findings. Overall inhospital mortality was 0.6% (1/152 patients). In the group of patients with teres ligament patch, the rate of reoperations (1.3% vs 13.0%; P = 0.009), and also the rate of readmission (13.1 vs 31.5%; P = 0.011) were significantly lower. Clinically relevant POPF rate (grade B/C) was 32.9% (control) versus 22.4% (teres, P = 0.20). Multivariable analysis showed teres ligament coverage to be a protective factor for clinically relevant POPF (P = 0.0146). CONCLUSIONS: Coverage of the pancreatic remnant after DP is associated with less reinterventions, reoperations, and need for readmission. Although the overall fistula rate is not reduced by the coverage procedure, it should be considered as a valid measure for complication prevention due to its clinical benefit.

Fluid collection after distal pancreatectomy: a frequent finding.

BACKGROUND: Fluid collections (FC) at the resection margin of the pancreatic stump after distal pancreatectomy (DP) are common radiological findings in follow-up scans. No recommendations exist regarding the management of such findings. The aim was to characterise incidence, risk factors, clinical impact and therapy of FC. METHOD: Data of 209 patients who underwent DP between 07/2009 and 06/2011 were prospectively collected and analysed, regarding follow-up CT or MRI scan findings of FC at the resection margin. FC was defined as a cyst-like lesion >1 cm in diameter. RESULTS: A follow-up with at least two cross-sectional images was available in 159/209 patients. In the first postoperative control, 68 patients showed an FC (43%). FC size was classified as <5 cm (n = 38 pat.), 5-10 cm (n = 24 pat.) and >10 cm (n = 6 pat.). 20 patients (30%) showed clinical symptoms. Six patients (9%) required specific treatment, all other FC showed spontaneous regression. No correlation with stump closure techniques or preceding postoperative pancreatic fistula was found (4/68 patients, 6%). Multivariate analysis revealed standard resections as the only significant factor for FC. CONCLUSIONS: FCs at the resection margin after DP are frequent and harmless findings. Therapeutic interventions are required in only 9% of all FC patients.

Characterization of myeloid leukocytes and soluble mediators in pancreatic cancer: importance of myeloid-derived suppressor cells.

Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers in the world. PDAC cells activate tumor-specific immune responses but simultaneously trigger a strong immunosuppression. We showed that PDAC cells produce high amount of chronic inflammatory mediators and PDAC tumors build an immunosuppressive cytokine milieu, which correlates with tumor progression. We observed a low frequency of dendritic cells (DC) and a pronounced accumulation of macrophages and myeloid-derived suppressor cells (MDSC) in murine PDAC tumors. A strong accumulation of MDSC has also been demonstrated in the peripheral blood of resected PDAC patients. While DC and macrophages seem not to play a significant role in this PDAC model in the context of immunosuppression, MDSC are highly suppressive, and their accumulation is associated with an increase in intratumoral VEGF concentration during the PDAC progression. Application of the phosphodiesterase-5 inhibitor sildenafil led to a prolonged survival of PDAC-bearing female mice, which was due to the decrease in MDSC frequencies and in the systemic VEGF level. This led to a restoration of anticancer immune responses, manifested in the recovery of T lymphocyte functions and in an increase in the frequency of conventional CD4+ T cells in tumors and IFNγ level in serum of PDAC-bearing mice. Thus, MDSC are strongly involved in the PDAC-associated immunosuppression and that their depletion could create new approaches for therapy of PDAC.

DISCOVER trial- Distal resection of the pancreas with or without coverage of the pancreatic remnant: study protocol of a randomised controlled trial.

BACKGROUND: Distal pancreatectomy for benign and malignant tumours is the second most common surgical procedure on the pancreas. Postoperative pancreatic fistulas (POPF) represent the most significant clinical complication, causing prolongation of hospital stay and the need for additional diagnostic and therapeutic procedures. Although various techniques for preventing POPF have been evaluated, to date, there is no available technique that ensures closure of the pancreatic remnant. METHODS/DESIGN: DISCOVER will aim to investigate differences in the postoperative course after a distal pancreatectomy comparing the standard surgical technique with an alternative technique that provides additional coverage of the pancreatic remnant by the falciform ligament. The primary endpoint of this trial will be the rate of POPF. As secondary endpoints, incidence of postoperative morbidity and mortality, length of hospital stay, and quality of life will be assessed.DISCOVER is a single-centre, randomised, controlled surgical trial. For statistical analysis, a binary logistic regression model will be used. With a level of significance of 5% and a power of 80%, a sample size of 75 patients per group has been identified as necessary. DISCUSSION: The findings of this trial will help to evaluate the usefulness of the coverage procedure at reducing the rate of POPF. The results could influence the standard procedure for remnant closure after distal pancreatectomy. TRIAL-REGISTRATION: Clinical trials register (DRKS-ID: DRKS00000546).

Decrease in clinically relevant pancreatic fistula by coverage of the pancreatic remnant after distal pancreatectomy.

BACKGROUND: Pancreatic fistulas after distal pancreatectomy occur in up to 60% of patients with distal pancreatectomy. Several techniques for closure of the pancreatic stump have been advocated, but the best management of stump closure remains controversial. Our aim was to evaluate the clinical benefits of coverage of the pancreatic resection margin by autologous tissue. METHODS: One hundred seventeen consecutive patients underwent distal pancreatectomy at the university hospital in Heidelberg between May 2009 and September 2010. A coverage procedure was performed in 73 of these patients. All patients were recorded prospectively, and the clinical course was evaluated focusing on the occurrence of pancreatic fistula as defined by the International Study Group on Pancreatic Fistula. A treatment cost analysis was performed. RESULTS: The rate of clinically relevant pancreatic fistulas (types B and C) was decreased in patients with coverage compared to the standard controls (type B, 7% vs 9%; type C, 7% vs 25%; P < .002). Patients with a coverage procedure had a shorter duration of stay in the hospital (P < .02), and treatment costs were lower (P < .001) compared to patients without coverage. CONCLUSION: Coverage of the pancreatic remnant after distal pancreatectomy decreases the rate of clinically relevant pancreatic fistulas, duration of stay, and treatment costs. A randomized trial is needed to verify these results.

Multivisceral resection for pancreatic malignancies: risk-analysis and long-term outcome.

OBJECTIVE: To evaluate the safety and outcome of multivisceral pancreatic resections for primary pancreatic malignancies. BACKGROUND: Curative resection is the only potential cure for patients with pancreatic cancer, but some patients present with advanced tumors that are not resectable by a standard pancreatic resection. Data on risk and survival analysis of extended pancreatic resections is limited. METHODS: One hundred one patients who had a multivisceral pancreatic resection between 10/2001 and 12/2007 were identified from a prospective database, and perioperative and long-term results were compared with those of 202 matched patients with a standard pancreatic resection. Uni- and multivariate regression analysis were performed to identify parameters that are associated with perioperative morbidity. Long-term survival was evaluated. RESULTS: Colon, stomach, adrenal gland, liver, hepatic or celiac artery, kidney, or small intestine were resected in 37.6%, 33.7%, 27.7%, 18.8%, 16.8%, 11.9%, and 6.9% of the 101 patients with multivisceral resection, respectively. Additional portal vein resection was performed in 20.8% of patients. Overall and surgical morbidity but not mortality was significantly increased compared with standard pancreatic resections (55.5% vs. 42.8%, 37.6 vs. 25.3%, and 3.0% vs. 1.5%, respectively). Uni- and multivariate analysis identified a long operative time and the extended multivisceral resection of 2 or more additional organs as independent risk factors for intraabdominal complications or need for relaparotomy. Median survival was comparable to that of standard pancreatic resections. CONCLUSIONS: Multivisceral resections can be performed with increased morbidity but comparable mortality and long-term prognosis as compared with standard pancreatic resections at high volume centers. Increased morbidity is related to extended multivisceral resections with a long operative time.