Distinct Indications for Adjuvant Therapy in Resected Invasive Mucinous Cystic Neoplasms of the Pancreas Compared with Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Surgical and adjuvant management of mucinous cystic neoplasms (MCNs) lacks formal guidelines and data is limited to institutional studies. Factors associated with receipt of adjuvant therapy and any associated impact on survival remain to be clarified. In the absence of other data, guidelines that recommend adjuvant chemotherapy for invasive pancreatic adenocarcinoma have been extrapolated to MCN. PATIENTS AND METHODS: The National Cancer Database (2004-2019) was utilized to identify all patients that underwent pancreatic resection for invasive MCNs. Patients that received neoadjuvant therapy or did not undergo lymphadenectomy were excluded. Patient, tumor, and treatment factors associated with survival were assessed. RESULTS: For 161 patients with invasive MCN, median overall survival (OS) was 133 months and 45% of patients received adjuvant therapy. Multivariable analysis demonstrated that poorly differentiated tumors [odds ratio (OR) 4.19, 95% confidence interval (CI) 1.47-11.98; p = 0.008] and positive lymph node status (OR 2.67, 95% CI 1.02-6.98; p = 0.042) were independent predictors of receiving adjuvant therapy. Lymph node positivity [hazard ratio (HR) 2.90, 95% CI 1.47-5.73; p = 0.002], positive margins (HR 5.28, 95% CI 2.28-12.27; p < 0.001), and stage III disease (HR 12.46, 95% CI 1.40-111.05; p = 0.024) were associated with worse OS. Receipt of adjuvant systemic therapy was independently associated with decreased risk of mortality in node positive patients (HR 0.23, 95% CI 0.10-0.69; p = 0.002). Survival was not associated with adjuvant therapy in patients with negative lymph nodes or margin negative status. CONCLUSION: In contrast to pancreatic ductal adenocarcinoma (PDAC), where adjuvant therapy improves OS for every tumor stage, surgery alone for invasive MCN is not associated with improved OS compared with surgery plus adjuvant therapy in node-negative patients. Surgery alone is likely sufficient for a subset of invasive MCN.

Long-Term Survival Outcomes After Minimally Invasive Surgery for Ileal Neuroendocrine Tumors.

BACKGROUND: Ileal neuroendocrine tumors (i-NETs) are characterized by their multifocality and bulky mesenteric mass. Having shown that minimally invasive surgery (MIS) utilizing a hand-access port device has favorable short-term outcomes and achieves the goals of surgery for i-NETs, we sought to analyze long-term survival outcomes of MIS. METHODS: One hundred and sixty-eight patients who underwent resection of primary i-NETs at a single institution between January 2007 and February 2023 were retrospectively studied. Patients were categorized into the MIS or open surgery cohorts on an intention-to-treat basis. Open surgery was selected mainly based on the need for hepatectomy or bulky mesenteric mass resection. Overall survival was analyzed using log-rank tests with propensity score matching (PSM) and Cox proportional hazards regression. PSM was performed to reduce standardized mean differences of the variables to <0.2. RESULTS: Overall, 129 (77%) patients underwent MIS and 39 (23%) underwent open surgery. Twenty-seven MIS patients were converted to an open procedure. The median follow-up time was 49 months (interquartile range 23-87 months). In the PSM cohorts, overall survival did not differ significantly between the MIS and open surgery cohorts {median 99 months (95% confidence interval [CI] 91-not applicable [NA]) vs. 103 months (95% CI 86-NA), p = 0.77; hazard ratio 0.87 (95% CI 0.33-2.2), p = 0.77}. CONCLUSIONS: MIS is an alternative to open surgery for i-NETs, achieving similar short- and long-term oncological outcomes. Bulky mesenteric mass and a plan for concurrent liver resection are potential criteria for open surgery.

Long-Duration Neoadjuvant Therapy with FOLFIRINOX Yields Favorable Outcomes for Patients Who Undergo Surgery for Pancreatic Cancer.

BACKGROUND: In 2023 alone, it's estimated that over 64,000 patients will be diagnosed with PDAC and more than 50,000 patients will die of the disease. Current guidelines recommend neoadjuvant therapy for patients with borderline resectable and locally advanced PDAC, and data is emerging on its role in resectable disease. Neoadjuvant chemotherapy may increase the number of patients able to receive complete chemotherapy regimens, increase the rate of microscopically tumor-free resection (R0) margin, and aide in identifying unfavorable tumor biology. To date, this is the largest study to examine surgical outcomes after long-duration neoadjuvant chemotherapy for PDAC. METHODS: Retrospective analysis of single-institution data. RESULTS: The routine use of long-duration therapy in our study (median cycles: FOLFIRINOX = 10; gemcitabine-based = 7) is unique. The majority (85%) of patients received FOLFIRINOX without radiation therapy; the R0 resection rate was 76%. Median OS was 41 months and did not differ significantly among patients with resectable, borderline-resectable, or locally advanced disease. CONCLUSIONS: This study demonstrates that in patients who undergo surgical resection after receipt of long-duration neoadjuvant FOLFIRINOX therapy alone, survival outcomes are similar regardless of pretreatment resectability status and that favorable surgical outcomes can be attained.

Metastatic melanoma to small bowel: metastasectomy is supported in the era of immunotherapy and checkpoint inhibitors.

BACKGROUND: Metastatic melanoma to the small bowel is an aggressive disease often accompanied by obstruction, abdominal pain, and gastrointestinal bleeding. With advancements in melanoma treatment, the role for metastasectomy continues to evolve. Inclusion of novel immunotherapeutic agents, such as checkpoint inhibitors, into standard treatment regimens presents potential survival benefits for patients receiving metastasectomy. CASE PRESENTATION: We report an institutional experience of 15 patients (12 male, 3 female) between 2014-2022 that underwent small bowel metastasectomy for metastatic melanoma and received perioperative systemic treatment. Median age of patients was 64 years (range: 35-83 years). No patients died within 30 days of their surgery, and the median hospital length of stay was 5 days. Median overall survival in these patients was 30.1 months (range: 2-115 months). Five patients died from disease (67 days, 252 days, 426 days, 572 days, 692 days postoperatively), one patient died of non-disease related causes (1312 days postoperatively), six patients are alive with disease, and three remain disease free. CONCLUSIONS: This case series presents an updated perspective of the utility of metastasectomy for small bowel metastasis in the age of novel immunotherapeutic agents as standard systemic treatment. Small bowel metastasectomy for advanced melanoma performed in conjunction with perioperative systemic therapy is safe and appears to promote long-term survival and enhanced quality of life.

Ampullary Adenocarcinoma, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology.

Ampullary cancers refer to tumors originating from the ampulla of Vater (the ampulla, the intraduodenal portion of the bile duct, and the intraduodenal portion of the pancreatic duct), while periampullary cancers may arise from locations encompassing the head of the pancreas, distal bile duct, duodenum, or ampulla of Vater. Ampullary cancers are rare gastrointestinal malignancies, and prognosis varies greatly based on factors such as patient age, TNM classification, differentiation grade, and treatment modality received. Systemic therapy is used in all stages of ampullary cancer, including neoadjuvant therapy, adjuvant therapy, and first-line or subsequent-line therapy for locally advanced, metastatic, and recurrent disease. Radiation therapy may be used in localized ampullary cancer, sometimes in combination with chemotherapy, but there is no high-level evidence to support its utility. Select tumors may be treated surgically. This article describes NCCN recommendations regarding management of ampullary adenocarcinoma.

Preoperative risk stratification of lymph node metastasis for non-functional pancreatic neuroendocrine neoplasm: An international dual-institutional study.

BACKGROUND: /Objectives: Although the presence of lymph node metastasis (LNM) defines malignant potential, preoperative prediction of LNM has not been established for non-functional pancreatic neuroendocrine neoplasm (NF-PNEN). We sought to develop a prediction system using only preoperatively available factors that would stratify the risk of LNM for NF-PNEN. METHODS: We retrospectively reviewed patients who underwent R0/1 resection of NF-PNEN at Kyoto University (2007-2019) and the University of California, San Francisco (2010-2019). Risk stratification of LNM was developed using preoperative factors by the logistic regression analysis. Long-term outcomes were compared across the risk groups. RESULTS: A total of 131 patients were included in this study. Lymph nodes were pathologically examined in 116 patients, 23 (20%) of whom had LNM. Radiological tumor size [1.5-3.5 cm (odds ratio: 13.5, 95% confidence interval: 1.77-398) and >3.5 cm (72.4, 9.06-2257) against ≤1.5 cm], <50% cystic component (8.46 × 10^6, 1.68 × 10^106-), and dilatation of main pancreatic duct ≥5 mm (31.2, 3.94-702) were independently associated with LNM. When patients were classified as the low-risk (43 patients), intermediate-risk (44 patients), and high-risk groups (29 patients), proportions of LNM differed significantly across the groups (0%, 14%, and 59%, respectively). Recurrence-free survival (RFS) of the low- and intermediate-risk groups were significantly better than that of the high-risk group (5-year RFS rates of 92.2%, 85.4%, and 47.1%, respectively). CONCLUSIONS: The prediction system using preoperative radiological factors stratifies the risk of LNM for NF-PNEN. This stratification helps to predict malignant potential and determine the surgical procedure and necessity of regional lymphadenectomy.

Pancreatic Adenocarcinoma, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

Pancreatic cancer is the fourth leading cause of cancer-related death among men and women in the United States. A major challenge in treatment remains patients' advanced disease at diagnosis. The NCCN Guidelines for Pancreatic Adenocarcinoma provides recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pancreatic cancer. Although survival rates remain relatively unchanged, newer modalities of treatment, including targeted therapies, provide hope for improving patient outcomes. Sections of the manuscript have been updated to be concordant with the most recent update to the guidelines. This manuscript focuses on the available systemic therapy approaches, specifically the treatment options for locally advanced and metastatic disease.

Synchronous Versus Metachronous Colorectal Liver Metastasis Yields Similar Survival in Modern Era.

BACKGROUND: Synchronous colorectal cancer liver metastasis (CRLM) has been viewed as being more aggressive and having shorter survival than metachronous disease. Advances in CRLM management led us to examine differences in treatment characteristics of synchronous versus metachronous CRLM patients along with survival and recurrence. MATERIALS AND METHODS: A retrospective review of hepatic resection for CRLM at a tertiary academic medical center was performed for two periods: a historic cohort from 1992 to 2010 (n = 121), and a modern cohort (n = 179) from 2012 to 2018. Clinical variables were compared between the patient groups, and survival outcomes were characterized. RESULTS: Five-year disease-specific survival for the modern synchronous group compared to the historic synchronous group was 71.7% versus 44.3% (P = 0.02). Modern metachronous versus modern synchronous 5-y disease-specific survival rates were 49.8% versus 71.7% (P = 0.31). Compared to the historic cohort, the modern one had significantly different timing of hepatic resection (P < 0.01) with increased use of liver-first (30.1% versus 7.5%) and simultaneous liver-colon resections (24.1% versus 10.4%), along with greater use of neoadjuvant chemotherapy (96.4% versus 65.6%; P < 0.01). Significantly more patients in the modern synchronous cohort had disease-free or alive-with-disease status at last follow-up, compared to the historic group (P < 0.01), and experienced less disease recurrence (62.7% versus 77.6%; P < 0.05). CONCLUSIONS: Modern synchronous CRLM patients who underwent hepatic resection experienced significantly improved survival compared to a historic cohort. We postulate that increased use of neoadjuvant chemotherapy and liver-first/simultaneous liver-colon resections in the modern synchronous cohort contributed to improved survival.

Residual tumor volume discriminates prognosis after surgery for neuroendocrine liver metastasis.

BACKGROUND AND OBJECTIVES: We developed objective measurements of preoperative and residual tumor volume, and debulking rate, to evaluate their prognostic value for neuroendocrine liver metastasis (NELM). METHODS: Seventy-three patients who underwent surgery for NELM were analyzed retrospectively. Indices of preoperative and postoperative residual tumor volume (pre-volume index [VI] and post-VI) were calculated as the sum of the cubes of individual tumor diameters on preoperative and postoperative imaging, respectively. The debulking rate (%) was calculated as 100 - 100 × post-VI/pre-VI. The classification and regression trees method was used to classify pre-VI and post-VI. RESULTS: Overall survival (OS) was discriminated by preoperative tumor volume (5-year OS rates, 87.8% for low pre-VI and 60.1% for high pre-VI; P = .037) and residual tumor volume (5-year OS rates, 88.1% for low post-VI and 24.8% for high post-VI; P < .001). In contrast, debulking rates of 100%, ≥90%, and <90% did not discriminate OS (5-year OS rates, 88.0%, 61.9%, and 58.9%, respectively, not significant). In multivariate analysis, residual tumor volume (high post-VI, hazard ratio, 6.40; 95% confidence interval, 1.45-32.3) was an independent prognostic factor for OS. CONCLUSIONS: Objective measurement of tumor volume demonstrates that residual tumor volume is prognostic after surgery for NELM.

A novel stratification of mesenteric mass involvement as a predictor of challenging mesenteric lymph node dissection by minimally invasive approach for ileal neuroendocrine tumors.

BACKGROUND AND OBJECTIVES: We classified the extent of mesenteric mass (MM) involvement that predicts challenging mesenteric lymph node dissection (mLND) by minimally invasive surgery (MIS) for ileal neuroendocrine tumors (i-NETs). METHODS: Patients who underwent surgery for i-NETs were retrospectively reviewed. MM involvement was classified as region-0: no MM; region-1: >2 cm from the origins of the ileocolic artery/vein; region-2: ≤2 cm from the origins; and region-3: more proximal superior mesenteric artery/vein. Logistic regression analysis was used to evaluate the predictive value of MM regions for gross positive mesenteric margin (mR2) and/or conversion among the MIS cohort. The open surgery cohort was used as a reference for mR2 rates. RESULTS: Of 108 patients, 83 patients (77%) underwent MIS. MMs in region-2 and region-3 were independent risk factors for mR2 and/or conversion (odds ratio [95% confidence interval]: 4.25 [1.17-16.4] and 8.51 × 107 [11.0-], respectively, against regions-0 and 1]. mR2 rates of MIS and open surgery cohorts per region did not differ significantly (4% and 7% for regions-0 and 1; 17% and 25% for region-2; and 100% and 83% for region-3). CONCLUSIONS: The novel stratification of MM regions was predictive of challenging mLND by MIS. Surgeons should have a low threshold for conversion for MMs in proximal regions.

Ampullary stenosis and choledocholithiasis post Roux-En-Y gastric bypass: challenges of biliary access and intervention.

BACKGROUND: Ampullary stenosis following Roux-en-Y gastric bypass (RYGB) is increasingly encountered. We describe cases of biliary obstruction from ampullary stenosis and choledocholithiasis to illustrate the associated diagnostic and interventional challenges with this condition. METHODS: We reviewed medical records of patients with prior RYGB who underwent a biliary access procedure or surgery for non-malignant disease from January 2012-December 2018. RESULTS: We identified 15 patients (4 male, 11 female; mean age 53.7 years) who had RYGB on average 11.7 years (range 1-32) years before diagnosis of biliary obstruction. Fourteen patients reported abdominal pain, 5 had nausea/emesis, 12 had elevated liver function tests, and 6 had ascending cholangitis. Mean common bile duct (CBD) diameter at presentation was 16.9 mm (range 4.0-25.0 mm). Operations included 3 transduodenal ampullectomies (2 with biliary bypass), 2 CBD explorations with stone extraction, 1 laparoscopic cholecystectomy alone, 1 Whipple procedure, 1 balloon enteroscopy with sphincterotomy, and 7 transgastric endoscopic retrograde cholangiopancreatography. All ampulla pathology was benign in patients who underwent resection. At follow-up (mean 15.4 months; range 0.23-44.5 months), 12/15 (80%) reported symptom resolution or improvement. DISCUSSION: Ampullary stenosis after RYGB presents challenges for diagnostic evaluation and intervention, often requiring multi-disciplinary expertise. The underlying pathology remains to be elucidated.

Pancreatic Adenocarcinoma, Version 1.2019.

The NCCN Guidelines for Pancreatic Adenocarcinoma discuss the diagnosis and management of adenocarcinomas of the exocrine pancreas and are intended to assist with clinical decision-making. These NCCN Guidelines Insights discuss important updates to the 2019 version of the guidelines, focusing on postoperative adjuvant treatment of patients with pancreatic cancers.

Prognostic impact of a large mesenteric mass >2 cm in ileal neuroendocrine tumors.

BACKGROUND AND OBJECTIVES: Ileal neuroendocrine tumors (i-NETs) frequently metastasize to mesenteric lymph nodes and the liver. Regional lymphadenopathy is associated with desmoplasia of the mesentery forming a large mesenteric mass (LMM). Although the latest American Joint Committee on Cancer TNM staging (8th edition) defined LMM >2 cm as N2, the prognostic impact of LMM is ill-defined. We evaluated whether LMM is prognostic for patients with i-NETs. METHODS: This single-institution, retrospective cohort study included 106 patients who underwent resection of i-NETs between 2007 and 2018. Overall survival (OS) and liver progression-free survival (LPFS) were compared between patients with and without LMM. RESULTS: LMM was present in 66 patients (62%) and was not associated with the presence or absence of liver metastasis (P = .969) or the extent of liver involvement (P = .938). OS and LPFS differed significantly between patients with and without LMM (5-year OS rates of 64.8% and 92.9%, respectively, P = .011; 3-year LPFS rates of 45.3% and 67.5%, respectively, P = .025). In multivariate analysis, LMM was an independent prognostic factor for both OS (hazard ratio: 4.69, 95% confidence interval: 1.63-17.6) and LPFS (1.99, 1.08-3.88). CONCLUSION: LMM >2 cm is prognostic for OS and LPFS and represents aggressive tumor biology.

Outcomes of arterial bypass preceding resection of retroperitoneal masses involving major vessels.

BACKGROUND: Current surgical management of retroperitoneal masses involving major vessels now includes complete en bloc resection with in situ venous, arterial, or combined reconstruction. No studies have investigated preresection arterial bypass for continuous lower extremity perfusion during definitive resection. Here, we characterize and compare the outcomes of surgery for retroperitoneal masses with major vascular involvement by a two-stage approach (femoral-femoral bypass preceding resection) and the traditional one-stage approach (consecutive resection and in situ vascular reconstruction). MATERIALS AND METHODS: We retrospectively reviewed patients who underwent resection of retroperitoneal masses and reconstruction of major arterial or venous structures from 2004 to 2016. Outcomes were compared with unpaired t-tests, chi-squared tests, and Kaplan-Meier analysis. RESULTS: Eight patients underwent a two-stage procedure, and seven underwent a one-stage procedure for retroperitoneal masses with vascular involvement. Mean (±SD) oncologic resection time (443 ± 215 versus 648 ± 128 min, P = 0.047) and postoperative ICU stay (0.9 ± 1.3 versus 4.4 ± 2.9 d, P = 0.018) were significantly shorter for the two-stage approach. CONCLUSIONS: To our knowledge, this is the first report of a two-stage approach for resection of retroperitoneal masses with major vessel involvement. Femoral-femoral arterial bypass before definitive resection could be a viable option for improving intraoperative vascular control and decreasing perioperative complications in these complex procedures.

Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology.

Ductal adenocarcinoma and its variants account for most pancreatic malignancies. High-quality multiphase imaging can help to preoperatively distinguish between patients eligible for resection with curative intent and those with unresectable disease. Systemic therapy is used in the neoadjuvant or adjuvant pancreatic cancer setting, as well as in the management of locally advanced unresectable and metastatic disease. Clinical trials are critical for making progress in treatment of pancreatic cancer. The NCCN Guidelines for Pancreatic Adenocarcinoma focus on diagnosis and treatment with systemic therapy, radiation therapy, and surgical resection.

MicroRNA dynamics in the stages of tumorigenesis correlate with hallmark capabilities of cancer.

While altered expression of microRNAs (miRs) in tumors has been well documented, it remains unclear how the miR transcriptome intersects neoplastic progression. By profiling the miR transcriptome we identified miR expression signatures associated with steps in tumorigenesis and the acquisition of hallmark capabilities in a prototypical mouse model of cancer. Metastases and a rare subset of primary tumors shared a distinct miR signature, implicating a discrete lineage for metastatic tumors. The miR-200 family is strongly down-regulated in metastases and met-like primary tumors, thereby relieving repression of the mesenchymal transcription factor Zeb1, which in turn suppresses E-cadherin. Treatment with a clinically approved angiogenesis inhibitor normalized angiogenic signature miRs in primary tumors, while altering expression of metastatic signature miRs similarly to liver metastases, suggesting their involvement in adaptive resistance to anti-angiogenic therapy via enhanced metastasis. Many of the miR changes associated with specific stages and hallmark capabilities in the mouse model are similarly altered in human tumors, including cognate pancreatic neuroendocrine tumors, implying a generality.