Value of Surgical Cytoreduction in Patients with Small Intestinal Neuroendocrine Tumors Metastatic to the Liver and Peritoneum.

BACKGROUND: Cytoreductive hepatectomy can improve survival and symptoms of hormonal excess in patients with small intestinal neuroendocrine tumor (siNET) liver metastases, but whether to proceed when peritoneal metastases are encountered at the time of planned cytoreductive hepatectomy is controversial. METHODS: This was a retrospective review of patients who underwent surgical management of metastatic siNETs at Mayo Clinic between 2000 and 2020. Patients who underwent cytoreductive operation for isolated liver metastases or both liver and peritoneal metastases were compared. RESULTS: Of 261 patients who underwent cytoreductive operation for siNETs, 211 had isolated liver metastases and 50 had liver and peritoneal metastases. Complete cytoreduction was achieved in 78% of patients with isolated liver metastases and 56% of those with liver and peritoneal metastases (p = 0.002). After complete cytoreduction, median overall survival (OS) was 11.5 years for isolated liver metastases and 11.2 years for liver and peritoneal metastases (p = 0.10), and relief of carcinoid syndrome was ≥ 97% in both groups. After incomplete cytoreduction with debulking of > 90% of hepatic disease and/or closing Lyon score of 1-2, median OS was 6.4 years for isolated liver metastases and 7.1 years for liver and peritoneal metastases (p = 0.12). CONCLUSIONS: Patients with siNETs metastatic to both the liver and peritoneum have favorable outcomes after aggressive surgical cytoreduction, with the best outcomes observed after complete cytoreduction. Therefore, the presence of peritoneal metastases should not by itself preclude surgical cytoreduction in this population.

Outcomes of Neoadjuvant Chemotherapy for Invasive Intraductal Papillary Mucinous Neoplasm Compared with de Novo Pancreatic Adenocarcinoma.

BACKGROUND: The management of invasive intraductal papillary mucinous cystic neoplasm (I-IPMN) does not differ from de novo pancreatic ductal adenocarcinoma (PDAC); however, I-IPMNs are debated to have better prognosis. Despite being managed similarly to PDAC, no data are available on the response of I-IPMN to neoadjuvant chemotherapy. METHODS: All patients undergoing pancreatic resection for a pancreatic adenocarcinoma from 2011 to 2022 were included. The PDAC and I-IPMN cohorts were compared to evaluate response to neoadjuvant therapy (NAT) and overall survival (OS). RESULTS: This study included 1052 PDAC patients and 105 I-IPMN patients. NAT was performed in 25% of I-IPMN patients and 65% of PDAC patients. I-IPMN showed a similar pattern of pathological response to NAT compared with PDAC (p = 0.231). Furthermore, positron emission tomography (PET) response (71% vs. 61%; p = 0.447), CA19.9 normalization (85% vs. 76%, p = 0.290), and radiological response (32% vs. 37%, p = 0.628) were comparable between I-IPMN and PDAC. A significantly higher OS and disease-free survival (DFS) of I-IPMN was denoted by Kaplan-Meier analysis, with a p-value of < 0.001 in both plots. In a multivariate analysis, I-IPMN histology was independently associated with lower risk of recurrence and death. CONCLUSIONS: I-IPMN patients have a longer OS and DFS after surgical treatment when compared with PDAC patients. The more favorable oncologic outcome of I-IPMNs does not seem to be related to early detection, as I-IPMN histological subclass is independently associated with a lower risk of disease recurrence. Moreover, neoadjuvant effect on I-IPMN was non-inferior to PDAC in terms of pathological, CA19.9, PET, and radiological response and thus can be considered in selected patients.

Implications of pregnancy on MCN of the pancreas: A multicentric case-control study.

BACKGROUND: Mucinous cystic neoplasms (MCN) of the pancreas express estrogen and progesterone receptors. Several case reports describe MCN increasing in size during gestation. The aim of this study is to assess if pregnancy is a risk factor for malignant degeneration of MCN. METHODS: All female patients who underwent pancreatic resection of a MCN between 2011 and 2021 were included. MCN resected or diagnosed within 12 months of gestation were defined perigestational. MCN with high grade dysplasia or an invasive component were classified in the high grade (HG) group. The primary outcome was defined as the correlation between exposure to gestation and peri-gestational MCN to development of HG-MCN. RESULTS: The study includes 176 patients, 25 (14 %) forming the HG group, and 151 (86 %) forming the low grade (LG) group. LG and HG groups had a similar distribution of systemic contraceptives use (26 % vs. 16 %, p = 0.262), and perigestational MCN (7 % vs 16 %, p = 0.108). At univariate analysis cyst size ≥10 cm (OR 5.3, p < 0.001) was associated to HG degeneration. Peri gestational MCN positively correlated with cyst size (R = 0.18, p = 0.020). In the subgroup of 14 perigestational MCN patients 29 % had HG-MCN and 71 % experienced cyst growth during gestation with an average growth of 55.1 ± 18 mm. CONCLUSIONS: Perigestational MCN are associated to increased cyst diameter, and in the subset of patients affected by MCN during gestation a high rate of growth was observed. Patients with a MCN and pregnancy desire should undergo multidisciplinary counselling.

Non-anatomical liver resection for hepatocellular carcinoma: the SegSubTe classification to overcome the problem of heterogeneity.

BACKGROUND: The superiority of anatomical resection (AR) vs. non-anatomical resection (NAR) in the surgical management of hepatocellular carcinoma (HCC) is debated. ARs are well-defined procedures, whereas the lack of NAR standardization results in heterogeneous outcomes. This study aimed to introduce the SegSubTe classification for NAR detailing the appropriateness of the level of surgical section of the Glissonean pedicles feeding the tumor. METHODS: A single-center retrospective analysis of pre- and postoperative imaging of consecutive patients treated with NAR for single HCC between 2012 and 2020 was conducted. The quality of surgery was assessed classifying the type of vascular supply and the level of surgical section (segmental, subsegmental or terminal next to the tumor) of vascular pedicles feeding the HCCs; then, the population was divided in "SegSubTe-IN" or "SegSubTe-OUT" groups, and the tumor recurrence and survival were analyzed. RESULTS: Ninety-seven patients who underwent NAR were included; 76% were SegSubTe-IN and 24% were SegSubTe-OUT. Total disease recurrence, local recurrence and cut-edge recurrence in the SegSubTe-IN vs. SegSubTe-OUT groups were 50% vs. 83% (P = 0.006), 20% vs. 52% (P = 0.003) and 16% vs. 39% (P = 0.020), respectively. SegSubTe-OUT odds ratio for local recurrence was 4.1 at univariate regression analysis. One-, three-, and five-year disease-free survival rates in the SegSubTe-IN vs. SegSubTe-OUT groups were 81%, 58% and 35% vs. 46%, 21% and 11%, respectively (P < 0.001). CONCLUSIONS: The SegSubTe classification is a useful tool to stratify and standardize NAR for HCC, aiming at improving long-term oncological outcomes and reducing the heterogeneity of quality of NAR for HCC.

The use of ace inhibitors influences the risk of progression of BD-IPMNs under follow-up.

BACKGROUND: Chemoprevention's ability to slow down or prevent the progression of BD-IPMNs is extremely appealing. Aspirin (ASA), Ace Inhibitors/Angiotensin Receptor Blockers (ACEIs/ARBs) and Statins (STATs) are frequently prescribed drugs with a possible beneficial effect on different cancer types. Their effect on IPMNs is largely unknown. AIM: To evaluate the association between the use of ASA, ACEIs/ARBs and STATs and the risk of progression of BD-IPMNs in follow-up. MATERIALS AND METHODS: multicenter, retrospective cohort study on patients with presumed BD-IPMNs without relative or absolute indication for surgery. Pharmacological exposures and risk factors were collected. We identified clinically relevant progression (occurrence of radiological absolute or relative indication for surgery) and any progression (occurrence of clinically relevant progression OR any dimension increase OR the occurrence of new cysts). RESULTS: Overall 594 patients were included. ACEIs were associated with a lower occurrence of any progression (HR = 0.70; 95% CI 0.49-0.98, p = 0.04) and clinically relevant progression, HR = 0.42 (95% CI 0.20-0.88; p = 0.02). No significant effect was shown for factors associated with the occurrence of pancreas cancer such as smoking, alcohol consumption and 1st degree family history of pancreas cancer. Among pharmacological exposures, no convincing effect was shown for the chronic use of ASA, ARB and STAT. CONCLUSIONS: ACEIs might have an effect in slowing the progression of BD-IPMNs. ASA, STAT and ARBs show no convincing effect on the progression of BD-IPMNs. Further, prospective, and long-term multicenter studies are needed to verify such association and to define the potential underlying mechanisms.

Skeletal muscle wasting and long-term prognosis in patients undergoing rectal cancer surgery without neoadjuvant therapy.

BACKGROUND: Derangement of body composition has been associated with dismal long-term survival in several gastrointestinal cancers including rectal tumors treated with neoadjuvant therapies. The role of specific preoperative anthropometric indexes on the oncologic outcomes of patients undergoing upfront surgery for rectal cancer has not been investigated. The aim of the study is to evaluate the association of body composition and overall survival in this specific cohort. METHODS: Lumbar computed tomography images, obtained within the 30 days previous to surgery, between January 2009 and December 2016, were used to calculate population-specific thresholds of muscle mass (sarcopenia), subcutaneous and visceral adiposity, visceral obesity, sarcopenic obesity, and myosteatosis. These body composition variables were related with overall survival (OS), tumor-specific survival (TSS), and disease-free survival (DFS). OS, TSS, and DFS were evaluated by the Kaplan-Meier method. Cox regression analysis was used to identify independent predictors of mortality, tumor-specific mortality, and recurrence, and data were presented as hazard ratio (HR) and 95% confidence interval (CI). RESULTS: During the study period, 411 patients underwent rectal resection for cancer, and among these, 129 were without neoadjuvant chemoradiation. The median follow-up was 96.7 months. At the end of the follow-up, 41 patients (31.8%) had died; of these, 26 (20.1%) died for tumor-related reasons, and 36 (27.1%) experienced disease recurrence. One-, three-, and five-year OS was 95.7%, 86.0%, and 76.8% for non-sarcopenic patients versus 82.4%, 58.8%, and 40.0% for sarcopenic ones respectively (p < 0.001). Kaplan-Meier survival curves comparing sarcopenic and non-sarcopenic patients showed a significant difference in terms of OS (log-rank < 0.0001). Through multivariate Cox regression, overall mortality risk was associated only with sarcopenia (HR 1.96; 95%CI 1.03-3.74; p = 0.041). Disease stage IV and III (HR 13.75; 95% CI 2.89-65.6; p < 0.001 and HR 4.72; 95% CI 1.06-21.1; p = 0.043, respectively) and sarcopenia (HR 2.62; 95% CI 1.22-5.6; p = 0.013) were independently associated with TSS. The other body composition indexes investigated showed no significant association with prognosis. CONCLUSIONS: These results support the inclusion of body composition assessment for prognostic stratification of rectal cancer patients undergoing upfront resection.

Functional liver imaging score (FLIS) can predict adverse events in HCC patients.

PURPOSE: To assess the performance of FLIS in predicting adverse outcomes, namely post-hepatectomy liver failure (PHLF) and death, in patients who underwent liver surgery for malignancies. METHODS: All consecutive patients who underwent liver resection and 1.5 T gadoxetic acid MR were enrolled. PHLF and overall survival (OS) were collected. Two radiologists with 18 and 8 years of experience in abdominal imaging, blinded to clinical data, evaluated all images. Radiologists evaluated liver parenchymal enhancement (EnQS), biliary contrast excretion (ExQS), and signal intensity of the portal vein relative to the liver parenchyma (PVsQs). Reliability analysis was computed with Cohen's Kappa. Cox regression analysis was calculated to determine which factors are associated with PHLF and OS. Area Under the Receiver Operating Characteristic curve (AUROC) was computed. RESULTS: 150 patients were enrolled, 58 (38.7 %) in the HCC group and 92 (61.3 %) in the non-HCC group. The reliability analysis between the two readers was almost perfect (κ = 0.998). The multivariate Cox analysis showed that only post-surgical blood transfusions and major resection were associated with adverse events [HR=8.96 (7.98-9.88), p = 0.034, and HR=0.99 (0.781-1.121), p = 0.032, respectively] in the whole population. In the HCC group, the multivariable Cox analysis showed that blood transfusions, major resection and FLIS were associated with adverse outcomes [HR=13.133 (2.988-55.142), p = 0.009, HR=0.987 (0.244-1.987), p = 0.021, and HR=1.891 (1.772-3.471), p = 0.039]. The FLIS AUROC to predict adverse outcomes was 0.660 (95 %CIs = 0.484-0.836), with 87 % sensitivity and 33.3 % specificity (81.1-94.4 and 22.1-42.1). CONCLUSIONS: FLIS can be considered a promising tool to preoperative depict patients at risk of PHLF and death.

Cancer "Avatars": Patient-Derived Xenograft Growth Correlation with Postoperative Recurrence and Survival in Pancreaticobiliary Cancer.

BACKGROUND: Pancreaticobiliary (PB) cancers are a diverse group of cancers with poor prognoses and high rates of recurrence after resection. Patient-derived xenografts (PDX), created from surgical specimens, provide a reliable preclinical research platform and high-fidelity cancer model from which to study these malignancies with consistent recapitulation of their original patient tumors in vivo. However, the relationship between PDX engraftment success (growth or no growth) and patient oncologic outcomes has not been well studied. We sought to evaluate the correlation between successful PDX engraftment and survival in several PB exocrine carcinomas, including the pancreatic and biliary tract. STUDY DESIGN: In accordance with IRB and Institutional Animal Care and Use Committee protocols and with appropriate consent and approval, excess tumor tissue obtained from surgical patients was implanted into immunocompromised mice. Mice were monitored for tumor growth to determine engraftment success. PDX tumors were verified to recapitulate their tumors of origin by a hepatobiliary pathologist. Xenograft growth was correlated with clinical recurrence and overall survival data. RESULTS: A total of 384 PB xenografts were implanted. The successful engraftment rate was 41% (158/384). We found that successful PDX engraftment was highly associated with both recurrence-free survival (p < 0.001) and overall survival (p < 0.001) outcomes. Successful PDX tumor generation occurs significantly in advance of clinical recurrences in their corresponding patients (p < 0.001). CONCLUSIONS: Successful PB cancer PDX models predict recurrence and survival across tumor types and may provide critical lead time to alter patients' surveillance or treatment plans before cancer recurrence.

Technical Outcomes of Porto-Mesenteric Venous Reconstruction in Pancreatic Resection Using Autologous Left Renal Vein Graft as Conduit.

BACKGROUND: Portal or superior mesenteric vein (PV-SMV) resection and reconstruction is sometimes required during pancreatic tumor resection. In patients requiring segmental venous resection with interposition grafting, the left renal vein (LRV) is an accessible autologous solution. However, long-term patency outcomes of the LRV as an interposition conduit in this setting have not been analyzed. STUDY DESIGN: We conducted a retrospective analysis of patients undergoing pancreatic resection with PV-SMV reconstruction using LRV between 2002 and 2022. The primary outcome was PV-SMV patency at last follow-up, assessed with postoperative CT scans and analyzed using Kaplan-Meier survival methods that account for variation in follow-up duration. Development of any postoperative acute kidney injury within 7 days of surgery and morbidity were secondary outcomes. RESULTS: The study cohort includes 65 patients who underwent LRV harvest; 60 (92%) ultimately underwent successful reconstruction with harvested LRV graft. Kaplan-Meier 2-year estimated patency rate of the LRV graft was 88%, with no cases of complete occlusion. Six (10%) patients experienced graft stenosis. Nine of 61 (15%) patients experienced grade II or III acute kidney injury, 6 of 9 returning to normal renal function before discharge. No difference in median serum creatinine was observed at baseline, 6 and 12 months from surgery. LRV remnant thrombosis was seen in 7 of 65 (11%) patients. Only 3 of 61 (5%) patients had persistent acute kidney injury caused by complications unrelated to LRV harvesting. CONCLUSIONS: Autologous LRV graft was a reliable conduit for segmental PV-SMV reconstruction, resulting in a high patency rate and marginal impact on renal function. LRV harvest is a safe and potentially ideal surgical option for PV-SMV reconstruction in pancreatic surgery.

Mixed Acinar Neuroendocrine Carcinoma of the Pancreas: Comparative Population-Based Epidemiology of a Rare and Fatal Malignancy in The United States.

Mixed acinar neuroendocrine carcinoma of the pancreas (MANEC-P) is an extremely rare malignancy with a poor prognosis. However, epidemiological estimates of MANEC-P remain unknown. This study aimed to estimate and compare the incidence, prevalence, and cancer-specific survival (CSS) of MANEC-P in the United States (US). Patients with MANEC-P were identified through the Surveillance, Epidemiology, and End Results (SEER) and National Program of Cancer Registries databases between 2000-2017. The primary outcomes included age-adjusted incidence rate, limited-duration prevalence, and CSS. A total of 630 patients were identified for the incidence analysis and 149 for the prevalence and CSS analyses. The MANEC-P incidence rate was 0.011 per 100,000 individuals, which was the lowest among pancreatic cancer histologic subtypes. The incidence rate was significantly higher in men and Black races and peaked at 75-79 years of age. The incidence rate was the lowest in the midwestern region (0.009) and the highest in the northeastern US (0.013). The 17-year prevalence was 0.00005%, indicating that 189 patients were alive in the United States at the beginning of 2018. The median CSS of MANEC-P was estimated to be 41 (23, 69) months. In conclusion, MANEC-P is very rare, and its incidence rate has been steady in the US over the last two decades. MANEC-P has a poor prognosis and is the 5th leading cause of pancreatic cancer-related death in the US.

COVID-19 and Liver Surgery: How the Pandemic Affected an Italian Medium-Volume HBP Center.

Introduction: While the COVID-19 pandemic is still ongoing, it is even more evident that victims of the pandemic are not only those who contract the virus, but also the countless patients suffering from other serious diseases (i.e., tumor) who have undergone delayed potentially life-saving surgery due to a lack of beds. Like many hospitals, ours also initially blocked all elective oncologic surgery, but these operations were "recovered" and reintegrated in a relatively short time, thanks to the establishment of COVID-free wards and operating rooms with staff dedicated to oncological surgery. In tis context, our aim is to assess whether and how the severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) pandemic has impacted our hepatobiliary surgery unit. Methods: From our prospective database, we retrospectively took data from patients undergoing liver surgery in 2018-2019 (pre-COVID) and 2020-2021 (COVID period). Patients admitted to COVID-free wards must necessarily have a negative nasal swab from the previous 24 h. Results: Between January 1, 2018, and December 31, 2019 (Group 1), 101 patients were treated; during the pandemic [January 1, 2020, and December 31, 2021 (Group 2)], 126 patients were treated. There was no statistical difference between the groups. The median postoperative hospital stay was 7 days for both groups; 7 patients had major complications (Clavien-Dindo > 3) in Group 1 and 11 in Group 2 (p = 0.795). A total of 4 patients died in Group 1 and 6 during the pandemic (p = 0.754). Tumor burden was significantly greater in Group 2 where nodule size, lymphadenectomy, and extrahepatic disease were significantly greater (p = 0.011, p = 0.004, and p = 0.026, respectively). Conclusion: During the COVID pandemic, our HPB unit managed to offer a volume of tertiary-center hepatobiliary surgery without a significant impact in terms of length of stay, morbidity, or mortality despite the increase in tumor burden during the pandemic years.

Impact of the Proactive Rounding Team on Rapid Response System During COVID-19 Pandemic: A Retrospective Study From an Italian Medical Center.

OBJECTIVE: During the coronavirus disease 2019 (COVID-19) pandemic a proactive rounding (PR) team was introduced in our clinical practice in order to recognize the clinical deterioration of the patient as soon as possible. This study aimed to evaluate the impact of the PR team on the rapid response system (RRS) workload with particular regard to the activity carried out, the mode of intervention, and the outcome of patients. METHODS: In this retrospective study, the first period before the activation of the PR team (March 1, 2019, to February 29, 2020) and the second period after its activation (March 1, 2020, to March 1, 2021) were compared. RESULTS: A total of 406 inpatient RRS activations were collected. The medical emergency team (MET) dose was 13 and 12.2 activations/1000 admitted patients per year while the incidence of unexpected cardiac arrests was 3.8 and 2.6 events/1000 admitted patients per year (p=0.10). MET response time was longer in the second period (3.5±1.6 minutes vs 4.5±2.6 minutes p<0.01). We recorded more RRS activations for medical patients than surgical ones; MET was activated more frequently by physicians than nurses and for less severe criteria. Patients admitted to the intensive care unit had lower Simplified Acute Physiology Score II (SAPS II) scores. CONCLUSIONS: The PR team introduced during the COVID-19 pandemic did not increase the RRS workload. In addition, it allowed an earlier activation of the MET, especially by physicians.

Pancreatic Cystic Neoplasms and Pregnancy: A Systematic Review of Surgical Cases and a Case Report of a Fully Laparoscopic Distal Pancreatectomy.

BACKGROUND: Mucinous cystic neoplasms and solid pseudopapillary neoplasms are the most common pancreatic tumors occurring in women of fertile age and in pregnant women. The aim of this study is to provide an updated literature review on this association and to present a fully laparoscopic resection of a pregnancy-associated pancreatic cystic neoplasm. MATERIALS AND METHODS: A systematic literature review was performed using PubMed (MEDLINE), Scopus, Ovid, ISI Web of Science, and Google Scholar for searching. The syntax was (pancr*) AND (cyst*) AND (pregn*) AND (tumor). Only English-language articles describing pancreatic surgical resections were included. RESULTS: Forty-seven case reports were included. The mean age of the patients was 29.6±5.3. Nine patients (20%) required emergency surgery, 4 (9%) due to cyst rupture, and 5 (11%) due to hemorrhage. Four patients (9%) suffered a miscarriage, and 2 (5%) opted for pregnancy termination; the rest of the women delivered a healthy newborn (86%, n=36). Thirty percent (n=14) of the resected neoplasms were malignant, and among mucinous cystic lesions, this raised to 45% (n=11). All patients diagnosed during the third trimester were resected postpartum, whereas 26/34 (76%) of patients diagnosed during the first 2 trimesters underwent surgery before delivery. CONCLUSIONS: The most worrisome complications in pregnancy-associated pancreatic cysts are bleeding or rupture. Mucinous cystic neoplasm has a tendency to grow during pregnancy. A postpartum resection was generally preferred when the cystic neoplasm was diagnosed during the third trimester. This report is the first to describe a fully laparoscopic pancreatic resection.

A tug-of-war in intraductal papillary mucinous neoplasms management: Comparison between 2017 International and 2018 European guidelines.

BACKGROUND: 2017 International and 2018 European guidelines are the most recent guidelines for intraductal papillary mucinous neoplasms management. AIM: to evaluate the diagnostic accuracy of these guidelines in identifying malignant IPMN. METHODS: data from resected patients with IPMN were collected in two referral centers. Features of risk associated to cancerous degeneration described in International and European guidelines were retrospectively applied. Sensitivity, specificity, positive and negative predictive value in detecting malignant disease were calculated. RESULTS: the study includes 627 resected patients. European guidelines suggest resection in any patient with at least one feature of moderate-risk. International guidelines suggest that patients with moderate-risk features undergo endoscopic ultrasound before surgery. European guidelines had a higher sensitivity (99.2% vs. 83%) but a lower positive predictive value (59.5% vs. 65.8%) and Specificity (2% vs. 37.5%). European guidelines detected almost all malignancies, but 40% of resected patients had low-grade dysplasia. 297 patients underwent endoscopic ultrasound before surgery. 31/116 (26.7%) tumors radiologically classified as "worrisome features" were reclassified as "high-risk stigmata" by endoscopic ultrasound and 24/31 were malignant IPMN. CONCLUSIONS: European and International guidelines have a relatively low diagnostic accuracy, being European guidelines more aggressive. Endoscopic ultrasound can improve guidelines accuracy in patients with moderate-risk features.

Pancreatic cystic neoplasms: What is the most cost-effective follow-up strategy?

Pancreatic cystic neoplasms are one of the most frequent incidental findings in the field of pancreatic diseases, estimated to be present in up to 45% of the general population. They represent an heterogeneous group of tumors with different biological behavior and variable risk of progression to malignancy. While serous cystadenomas (SCAs) have no risk of malignant progression, mucinous cyst adenoma are malignant in 20% of cases and this risk is higher in intraductal papillary mucinous neoplasms (IPMN). Nonsurgical management could be applied in patients with a SCA and in low-risk IPMN and these patients could be managed with follow-up strategies. While follow-up could be interrupted in patients unfit for surgery due to comorbidities or age, and in SCA stable over time, recent evidences do not support surveillance discontinuation in patients with IPMNs fit for surgery.