Pathologic tumor response to neoadjuvant therapy in resected pancreatic cancer: does it affect prognosis?

Neoadjuvant therapy (NAT) + surgical resection for pancreatic cancer (PC) has gained consensus in recent years. Pathological response (PR) is generally assessed according to the College of American Pathologists grading system, ranging from 0 (complete response) to 3 (no response). The aim of our study is to evaluate the PR in a series of resections for PC after NAT and its prognostic implication. 112 patients undergone NAT and resection for PC between 2011 and 2020 were retrospectively evaluated. PR was 0/1, 2 and 3 in 18 (15%), 79 (61%) and 29 (24%) cases, respectively. Chemotherapy regimens different from FOLFIRINOX and gemcitabine + nab-paclitaxel (OR 11.61 (2.53-53.36), p = 0.002) and lymphovascular invasion (OR 11.28 (1.89-67.23), p = 0.008) were associated to PR-3. Median follow-up was 25.8 (3.6-130.5) months. For PR-0/1, PR-2 and PR-3, median DFS was 45.8, 11.5, 4.6 months (p < 0.0001), respectively, while median OS was not reached, 27.1 and 17.5 months (p = 0.0006), respectively. At univariate analysis, PR-0/1 was significantly associated to better DFS and OS (HR 0.33 (0.17-0.67), p = 0.002; HR 0.20 (0.07-0.54), p = 0.002, respectively). At multivariate analysis, pancreaticoduodenectomy (HR 0.50 (0.30-0.84), p = 0.009), LNR (HR 27.14 (1.21-608.9), p = 0.038) and lymphovascular invasion (HR 1.99 (1.06-3.76), p = 0.033) were independently associated to DFS; pre-treatment CA 19.9 value (HR 1.00 (1.00-1.00), p = 0.025), post-treatment resectability status (HR 0.51 (0.28-0.95), p = 0.035), pancreaticoduodenectomy (HR 0.56 (0.32-0.99), p = 0.050), severe morbidity (2.99 (1.22-7.55), p = 0.017), LNR (HR 56.8 (2.08-1548.3), p = 0.017), lymphovascular invasion (HR 2.18 (1.08-4.37), p = 0.029) were independently associated to OS. PR did not reach statistical significance at multivariate analysis. A favorable PR is observed only in a limited number of cases. The prognostic role of PR, despite being promising, remains unclear and further multicentric studies are needed.

Long-term outcomes after pancreatoduodenectomy for ampullary cancer: The influence of the histological subtypes and comparison with the other periampullary neoplasms.

BACKGROUND: Ampullary carcinoma (AC) is histologically classified as intestinal (In-AC), pancreaticobiliary (Pb-AC) or mixed-AC. The prognostic role of AC subtypes has been debated and remains unclear. The aims of this study were to evaluate outcomes after pancreatoduodenectomy (PD) for each subtype of AC and to compare these with pancreatic ductal adenocarcinoma [PDAC] and distal cholangiocarcinoma [DCC]. METHODS: PDs performed for AC between 2010 and 2018 were retrospectively evaluated. Histological subtype was obtained for all patients. One-year, 3-year and 5-year disease-free-survival (DFS) and overall survival (OS) rates were calculated. Kaplan-Meier survival analysis was performed to compare Pb-AC, In-AC and mixed-AC. Comparison with PDs performed for PDAC and DCC during the same period was also performed. RESULTS: A total of 97 patients undergoing PD for AC were evaluated: 34 (35.1%) In-AC, 54 (55.7%) Pb-AC and 9 mixed-AC (9.3%). DFS and OS rates for Pb-AC were significantly lower compared to In-AC (p < 0.05 and p < 0.01), but similar to mixed-AC (p = 0.3 and p = 0.4). Adjuvant therapy was not associated with increased survival, regardless of the histological subtype (p > 0.05). During the same period, 337 and 53 PDs for PDAC and DCC, respectively, were performed. In-AC was associated with significantly better outcomes compared to PDAC and DCC (p < 0.001); DFS and OS rates for Pb-AC and mixed AC were significantly higher compared to PDAC (p < 0.001), but similar to DCC (p > 0.05). CONCLUSIONS: Pb-AC has significantly worse survival compared to In-AC. Moreover, mixed-AC should be considered as Pb-AC. Pb-AC and mixed-AC seem to have better prognosis compared to PDAC, but similar to DCC.

Robotic versus laparoscopic distal pancreatectomy: multicentre analysis.

BACKGROUND: The role of minimally invasive distal pancreatectomy is still unclear, and whether robotic distal pancreatectomy (RDP) offers benefits over laparoscopic distal pancreatectomy (LDP) is unknown because large multicentre studies are lacking. This study compared perioperative outcomes between RDP and LDP. METHODS: A multicentre international propensity score-matched study included patients who underwent RDP or LDP for any indication in 21 European centres from six countries that performed at least 15 distal pancreatectomies annually (January 2011 to June 2019). Propensity score matching was based on preoperative characteristics in a 1 : 1 ratio. The primary outcome was the major morbidity rate (Clavien-Dindo grade IIIa or above). RESULTS: A total of 1551 patients (407 RDP and 1144 LDP) were included in the study. Some 402 patients who had RDP were matched with 402 who underwent LDP. After matching, there was no difference between RDP and LDP groups in rates of major morbidity (14.2 versus 16.5 per cent respectively; P = 0.378), postoperative pancreatic fistula grade B/C (24.6 versus 26.5 per cent; P = 0.543) or 90-day mortality (0.5 versus 1.3 per cent; P = 0.268). RDP was associated with a longer duration of surgery than LDP (median 285 (i.q.r. 225-350) versus 240 (195-300) min respectively; P < 0.001), lower conversion rate (6.7 versus 15.2 per cent; P < 0.001), higher spleen preservation rate (81.4 versus 62.9 per cent; P = 0.001), longer hospital stay (median 8.5 (i.q.r. 7-12) versus 7 (6-10) days; P < 0.001) and lower readmission rate (11.0 versus 18.2 per cent; P = 0.004). CONCLUSION: The major morbidity rate was comparable between RDP and LDP. RDP was associated with improved rates of conversion, spleen preservation and readmission, to the detriment of longer duration of surgery and hospital stay.

Immune infiltrating cells in duodenal cancers.

BACKGROUND: Duodenal adenocarcinoma (DA) is a rare yet aggressive malignancy, with increasing incidence in the last decades. Its low frequency has hampered a thorough understanding of the pathogenesis of the disease and of its biology, limiting the identification of tailored therapeutic options. A large body of evidence has clearly shown the clinical relevance of immune cells in solid tumors, correlating immune features with post-surgical prognosis. The aim of this study was to analyze the immune contexture in a cohort of duodenal adenocarcinomas surgically resected at our Institution and define its correlation with clinical variables. METHODS: Tissue slides from paraffin-embedded tumor specimens of 15 consecutive DA and 3 adenomas that underwent a pancreaticoduodenectomy in our center between 2010 to 2018 were immunohistochemically stained. The density (percentage of immune reactive area, IRA%) of immune markers CD45RO, CD8, CD20, IL-17, PD-1, CD68 was quantified by computer-assisted image analysis. Demographic, clinical, histopathological data were collected. RESULTS: In our population, median IRA % (IQR) of immune subsets was respectively CD45RO-TILs 2.19 (2.14), CD8-TIL 0.42 (0.81), CD20-TILs 0.22 (0.51), CD20-TLT 2.84 (4.64), CD68-TAM 2.19 (1.56), IL17+ cells 0.39 (0.39), PD1-TILs 0.19 (0.41). The median follow-up was 47.5 (22.4-63.3) months. At statistical analysis, the density of CD8-TILs inversely correlated with lymph node ratio (p = 0.013), number of metastatic lymph nodes (p = 0.019), and was lower in N+ adenocarcinomas compared to N0 (1.07 vs 0.29; p = 0.093), albeit not significantly. Stratifying patients for the N status, the density of CD8-TILs decreased with the increasing of the N stage (p = 0.065) and was lower in patients who experienced recurrence and died for the disease (0.276 vs 0.641; p = 0.044). Notably, also CD68-TAM distribution was different in patients who had recurrence versus patients who did not (1.028 vs 2.276; p = 0.036). CONCLUSIONS: Immune cells showed variable expression in correlation with common prognostic factors, suggesting T cell infiltration may play a protective role towards lymphatic spread of disease and nodal metastatization. Furthermore, T cell density and macrophage infiltration were associated to a lower risk of recurrence and disease related death. A multicentric approach may be indicated to allow analysis of larger cohorts of patients, potentially increasing the power of our observations.

The Number of Metastatic Lymph Nodes is a Useful Predictive Factor for Recurrence after Surgery for Nonmetastatic Nonfunctional Neuroendocrine Neoplasm of the Pancreas.

Nodal involvement (actually categorized as positive or negative) is an important prognostic factor after surgery for pancreatic neuroendocrine neoplasms (pNENs). We aim to evaluate the predictive role of the number of nodal metastases after pancreatic resection for pNENs. We analyzed from a prospectively maintained database all pancreatic resections for nonmetastatic nonfunctioning pNENs performed in our institution from 2011 to 2016. According to the number of nodal metastases, enhancing the actual categorization, we distinguished the following: N0, no nodal metastases; N1, 1-3 metastatic lymph nodes; and N2, metastases in 4 or more regional lymph nodes. Recurrence and disease-free survival (DFS) were evaluated. The predictive value in terms of recurrence for each clinicopathological data, including the number of metastatic lymph nodes, was calculated. Univariate and multivariate analyses were conducted. 77 patients underwent pancreatic surgery for pNENs. N0, N1, and N2 resections were found in 52 (67.5%), 16 (20.8%), and 9 (11.7%) cases, respectively. Mean follow-up of the entire cohort was 48 (±25) months. The recurrence rate was 11.8%, and the mean time of recurrence was 12 (±14) months. DFS was 83.7 months (76.0 - 91.5). At a univariate analysis, factors associated with recurrence were mitotic count (OR 1.19, p = 0.001), Ki67 value (OR 1.06, p = 0.001), the presence of nodal metastases (OR 11.54, p = 0.002), and metastases in 4 or more regional lymph nodes (N2) (OR 30.19, p = 0.002). At a multivariate analysis, only mitotic count (OR 1.51, p = 0.005) and N2 resection (OR 134.74, p = 0.002) were found to be predictive factors of recurrence. The number of metastatic lymph nodes and mitotic count is the most significant predictive factors of recurrence after pancreatic surgery for nonmetastatic nonfunctioning pNENs.

Differences in Treatment and Outcome of Pancreatic Adenocarcinoma Stage I and II in the EURECCA Pancreas Consortium.

BACKGROUND: The EUropean REgistration of Cancer CAre (EURECCA) consortium aims to investigate differences in treatment and to improve cancer care through Europe. The purpose of this study was to compare neo- and adjuvant chemotherapy (ACT) and outcome after tumor resection for pancreatic adenocarcinoma stage I and II in the EURECCA Pancreas consortium. METHODS: The eight, collaborating national, regional, and single-center partners shared their anonymized dataset. Patients diagnosed in 2012-2013 who underwent tumor resection for pancreatic adenocarcinoma stage I and II were investigated with respect to treatment and survival and compared using uni- and multivariable logistic and Cox regression analyses. All comparisons were performed separately per registry type: national, regional, and single-center registries. RESULTS: In total, 2052 patients were included. Stage II was present in the majority of patients. The use of neo-ACT was limited in most registries (range 2.8-15.5%) and was only different between Belgium and The Netherlands after adjustment for potential confounders. The use of ACT was different between the registries (range 40.5-70.0%), even after adjustment for potential confounders. Ninety-day mortality was also different between the registries (range 0.9-13.6%). In multivariable analyses for overall survival, differences were observed between the national and regional registries. Furthermore, patients in ascending age groups and patients with stage II showed a significant worse overall survival. CONCLUSIONS: This study provides a clear insight in clinical practice in the EURECCA Pancreas consortium. The differences observed in (neo-)ACT and outcome give us the chance to further investigate the best practices and improve outcome of pancreatic adenocarcinoma.

Ampullary neuroendocrine neoplasms: surgical experience of a rare and challenging entity.

PURPOSE: Ampullary neuroendocrine neoplasms (NENs) account for < 0.3% of gastrointestinal NENs. Surgical options include transduodenal ampullectomy/tumour excision or pancreaticoduodenectomy (PD). We report the experience of two high-volume pancreatic surgical centres of ampullary NENs. METHODS: Clinical records of patients who underwent surgery for ampullary NENs (January 2007-November 2017) in the study centres were retrieved retrospectively. We evaluated clinical-pathological features, post-operative outcome and follow-up (FU). RESULTS: Eighteen patients (9 M/9 F, averaging 62 years) were enrolled. All but one were non-functioning NENs; four (22%) patients presented with jaundice. Seven (39%) of the patients underwent ampullectomy/excision (median tumour size 1.5 cm), and 11 (61%) patients underwent PD (median tumour size 2.4 cm). The median operation time of ampullectomy/excision was 221 min with operative blood loss of 75 ml (vs. 506 min and 425 ml in PD). The median hospital stay was 10 days in both groups. Overall surgical morbidity was 33%, due to four biochemical leaks, one pancreatic fistula and one abdominal haemorrhage. No reoperations were needed. The median tumour size was 1.8 (range 0.5-6.7) cm. All G2-G3 NENs were N1 (vs. 1/7 in G1 NENs). Three (17%) cases were mixed exocrine/G3 NECs. After a median FU of 45 (up to 124) months, recurrence occurred in four G3 NEC (31%) patients (median disease-free survival 14 months) after an R0 PD. Disease-related survival was 93, 77 and 66% at 1, 3 and 5 years, respectively. CONCLUSION: Ampullary NENs are mostly G1-G2 neoplasms. Lymph node metastases rarely occur in G1 NENs < 2 cm in size, which may be treated with ampullectomy/excision. Survival is 66% 5 years after surgery.

Parenchyma-sparing surgery for pancreatic endocrine tumors.

Enucleation (EN) and middle pancreatectomy (MP) have been proposed as a treatment for G1 and G2 pancreatic neuroendocrine tumors (PNET). The aim of this study is to analyze the outcomes of parenchyma-sparing surgery (PSS) for PNET in an Italian high-volume center. All patients with a histological diagnosis of PNET who underwent surgical resection in our center between January 2010 and January 2016 were included in the study. Demographic, perioperative, and discharge data were collected in a prospective database. Follow-up was considered until March 31, 2016. 99 patients were included. PSS was performed in 22 cases (22.2 %), 18 EN (82 %), and 4 MP (18 %). 89.8 % patients were staged with CT scan, 69.6 % with endoscopic ultrasonography, 48.4 % with MRI, and 47.4 % with 68Ga-PET. Pre-operative histological diagnosis was obtained in 68.6 %. Most of PSS tumors were G1 (n = 15; 68 %) and there were no G3. Nodal sampling was performed in every PSS. Only two patients showed nodal metastatic disease. The median post-operative length of stay was 7 days after PSS. Eleven (50 %) of these patients developed a complication; two (18.2 %) were major complications. Pancreatic fistula developed in ten patients (45.5 %); two (20 %) were type B. There were no type C fistula and no re-operations after PSS. Readmission rate was 9 %. All patients submitted to PSS are alive and free of recurrence. PSS is a safe technique for G1 and G2 PNETs, but it has to be conducted in experienced centers and an extensive nodal sampling and a long follow-up are required for the best oncologic outcome.

Effect of hospital volume on outcome of pancreaticoduodenectomy in Italy.

BACKGROUND: An inverse relationship between hospital volume and death following pancreatico duodenectomy (PD) has been reported from several countries. The aim of this study was to assess the volume-outcome effect of PD in Italy. METHODS: The study group comprised 1576 patients who underwent PD in 2003. Hospitals were allocated to four volume groups: low volume, five PDs or fewer; medium volume, six to 13 PDs; high volume, 14 to 51 PDs; and very high volume, two hospitals that performed 89 and 104 PDs. RESULTS: Some 221 hospitals performed at least one PD in 2003; hospital volume was low in 74.7 per cent, medium in 17.6 per cent, high in 6.8 per cent and very high in 0.9 per cent. The overall mortality rate was 8.1 per cent. Increasing hospital volume was associated with a significantly reduced mortality rate: 12.4 per cent (adjusted odds ratio (OR) 1.000) for low-volume, 7.8 per cent (OR 0.611) for medium-volume, 5.9 per cent (OR 0.466) for high-volume and 2.6 per cent (OR 0.208) for very high-volume hospitals. Length of postoperative stay was reduced in very high-volume hospitals (P < 0.001). CONCLUSION: The outcome of PD in Italy is dependent on hospital volume and a policy of centralization may therefore be appropriate.

[Radical peritonectomy in 37 patients with stage II and III ovarian cancer]. / Peritonectomia radicale in 37 pazienti affette da neoplasia ovarica II e III stadio.

AIM: Radical peritonectomy followed by intraperitoneal early chemotherapy and systemic chemotherapy is the treatment of choice of stage II C and III ovarian cancer, due to the low 5-years survival rate (20%) of stage III and IV. METHODS: The authors present a 5-years experience in 37 patients affected by stage II C and III ovarian cancer treated by Sugarbaker's radical peritonectomy with some surgical technical differences. Intraperitoneal chemotherapy with adriamycin and cisplatin is started and followed after 25 days by a systemic chemotherapy with taxol and carboplatin. A 6-months second-look is performed. RESULTS: All the patients have been treated with radical peritonectomy with tumoral residual lesser than 2.5 mm; we performed 4 minor hepatectomies, 5 radical cystectomies, 35 resections of rectum and sigmoid colon with hysterectomies, bilateral salpingo-oophorectomies and pelviperitonectomies, 14 right hemicolectomies. We had no postoperative mortality, but we recorded a 40% minor morbidity rate. During the second look we found 7 recurrences (18%), 6 lesser than 6 mm, often located on the mesentery and treated with radical resections. The follow-up range is 2-60 months, 27 patients are still alive. Actually, 22 patients (80% of live patients) are in good health and disease free. CONCLUSION: Radical surgery associated with early postoperative chemotherapy followed by systemic chemotherapy in the treatment of ovarian cancer makes it possible to achieve the best survival results and long periods of disease free.