Minimal Residual Disease using a Plasma-Only Circulating Tumor DNA Assay to Predict Recurrence of Metastatic Colorectal Cancer Following Curative Intent Treatment.

PURPOSE: Minimal residual disease (MRD) detection identifies patients with colorectal adenocarcinoma (CRC) likely to recur following definitive treatment. We evaluated a plasma only MRD assay to predict recurrence and survival in metastatic CRC patients undergoing curative intent procedures (surgery and/or radiotherapy), with or without (neo)adjuvant chemotherapy. The primary objective of this study was to assess the correlation of post-procedure tumor cfDNA detection status with radiographic disease recurrence (RFS). EXPERIMENTAL DESIGN: Pre- and post-procedure longitudinal samples were collected from 53 patients and analyzed with a multiomic MRD assay detecting circulating tumor DNA (ctDNA) from genomic and epigenomic signals. Pre- and post-procedure ctDNA detection correlated with recurrence-free and overall survival. RESULTS: 230/233 samples from 52 patients were successfully analyzed. At the time of data cutoff, 36 (69.2%) patients recurred with median follow-up of 31 months. 19/42 patients (45.2%) with ctDNA analyzed 3 weeks post-procedure had detectable ctDNA. ctDNA detection 3 weeks post-procedure was associated with shorter median RFS (HR 5.27; 95% CI, 2.31-12.0, p<0.0001) and overall survival (OS) (HR 12.83; 95% CI, 3.6-45.9, p<0.0001). Pre-procedure ctDNA detection status was not associated with RFS but was associated with improved OS (HR 4.65; 95% CI, 1.4-15.2, p=0.0111). Undetectable ctDNA pre-procedure had notable long-term overall survival, >90% 3 years post-procedure. CONCLUSION: In this cohort of oligometastatic CRC, detection of ctDNA pre- or post-procedure was associated with inferior outcomes even after accounting for prognostic clinicopathologic variables. This suggests ctDNA may enhance current risk stratification methods helping evaluate novel treatments and surveillance strategies toward improving patient outcomes.

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.

Portal Vein Thrombosis After Transarterial Embolization for Hepatocellular Carcinoma.

This cross-sectional study assesses the association between venous thrombosis and embolization in patients with hepatocellular carcinoma.

Conditional Survival After Hepatectomy for Colorectal Liver Metastasis: Results from the Colorectal Liver Operative Metastasis International Collaborative (COLOMIC).

INTRODUCTION: Complete resection of colorectal liver metastasis (CLM) improves long-term survival in colorectal cancer. However, there is limited recent data on conditional survival (CS) as postoperative survival milestones are achieved post-hepatectomy. METHODS: A retrospective analysis was performed on the penta-institutional Colorectal Liver Operative Metastasis International Collaborative (COLOMIC), with 906 consecutive CLM hepatectomy cases. CS was calculated using Bayes' theorem and Kaplan-Meier analysis. Additional CS analyses were performed on additional clinicopathologic risk factors, including colon cancer laterality, KRAS mutation status, and extrahepatic disease. RESULTS: The 5-year CS was 40.6%, 45.3%, 52.8%, and 65.3% at 0, 1, 2, and 3 years postoperatively, with significant improvements each year (p < 0.005). CS was not significantly different between right-sided and left-sided colorectal cancers by 3 years postoperatively. Patients with KRAS mutations had worse CS at all timepoints (p < 0.001). Extrahepatic disease was a poor prognostic factor for OS and CS (p < 0.001). However, CS for patients with KRAS mutations or extrahepatic disease improved significantly as 2-year, postoperative survival was achieved (p < 0.05). CONCLUSIONS: Five-year CS after hepatectomy for CLM improved with each passing year of survival postoperatively. Although extrahepatic disease and KRAS mutations are poor prognostic factors for OS, these populations still had improved CS after 2 years postoperatively.

Machine Learning Models for Predicting the Outcomes of Surgical Treatment of Colorectal Liver Metastases.

BACKGROUND: Surgical intervention remains the cornerstone of a multidisciplinary approach in the treatment of colorectal liver metastases (CLM). Nevertheless, patient outcomes vary greatly. While predictive tools can assist decision-making and patient counseling, decades of efforts have yet to result in generating a universally adopted tool in clinical practice. STUDY DESIGN: An international collaborative database of CLM patients who underwent surgical therapy between 2000 and 2018 was used to select 1,004 operations for this study. Two different machine learning methods were applied to construct 2 predictive models for recurrence and death, using 128 clinicopathologic variables: gradient-boosted trees (GBTs) and logistic regression with bootstrapping (LRB) in a leave-one-out cross-validation. RESULTS: Median survival after resection was 47.2 months, and disease-free survival was 19.0 months, with a median follow-up of 32.0 months in the cohort. Both models had good predictive power, with GBT demonstrating a superior performance in predicting overall survival (area under the receiver operating curve [AUC] 0.773, 95% CI 0.743 to 0.801 vs LRB: AUC 0.648, 95% CI 0.614 to 0.682) and recurrence (AUC 0.635, 95% CI 0.599 to 0.669 vs LRB: AUC 0.570, 95% CI 0.535 to 0.601). Similarly, better performances were observed predicting 3- and 5-year survival, as well as 3- and 5-year recurrence, with GBT methods generating higher AUCs. CONCLUSIONS: Machine learning provides powerful tools to create predictive models of survival and recurrence after surgery for CLM. The effectiveness of both machine learning models varies, but on most occasions, GBT outperforms LRB. Prospective validation of these models lays the groundwork to adopt them in clinical practice.

Survival Outcomes of Optimally Treated Colorectal Metastases: The Importance of R0 Status in Surgical Treatment of Hepatic and Peritoneal Surface Disease.

BACKGROUND: Although colorectal hepatic metastases (HM) and peritoneal surface disease (PSD) are distinct biologic diseases, they may have similar long-term survival when optimally treated with surgery. METHODS: This study retrospectively reviewed prospectively managed databases. Patients undergoing R0 or R1 resections were analyzed with descriptive statistics, the Kaplan-Meier method, and Cox regression. Survival was compared over time for the following periods: 1993-2006, 2007-2012, and 2013-2020. RESULTS: The study enrolled 783 HM patients undergoing liver resection and 204 PSD patients undergoing cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC). Compared with PSD patients, HM patients more often had R0 resections (90.3% vs. 32.4%), less often had pre-procedure chemotherapy (52.4% vs. 92.1%), and less often were functionally independent (79.7% vs. 95.6%). The 5-year overall survival for HM was 40.9%, with a median survival period of 45.8 months versus 25.8% and 33.4 months, respectively, for PSD (p < 0.05). When stratified by resection status, R0 HM and R0 PSD did not differ significantly in median survival (49.0 vs. 45.4 months; p = 0.83). The median survival after R1 resection also was similar between HM and PSD (32.6 vs. 26.9 months; p = 0.59). Survival between the two groups again was similar over time when stratified by resection status. The predictors of survival for HM patients were R0 resection, number of lesions, intraoperative transfusion, age, and adjuvant chemotherapy. For the PSD patients, the predictors were peritoneal cancer index (PCI) score, estimated blood loss (EBL), and female gender. CONCLUSION: The study showed that R0 resections are associated with improved outcomes and that median survival is similar between HM and PSD patients when it is achieved. Surveillance and treatment strategies that facilitate R0 resections are needed to improve results, particularly for PSD.

Primary Cutaneous Malignant Perivascular Epithelioid Cell Tumor Mimicking Undifferentiated Pleomorphic Sarcoma: A Report of a Rare Entity.

ABSTRACT: Primary cutaneous malignant perivascular epithelioid cell tumor (PEComa) is a rare and potentially aggressive neoplasm. In this article, we report the case of a 34-year-old man who initially presented with a 3-cm mass involving the skin and soft tissue of the right shoulder that, over 3 months, enlarged to 12 cm. Histologic examination of the mass revealed an infiltrative neoplasm with features resembling an undifferentiated pleomorphic sarcoma, including sheets of pleomorphic cells with abundant atypical mitoses and necrosis. Immunohistochemical evaluation showed features suggestive of PEComa. Next-generation sequencing revealed pathogenic homozygous deletions of TSC2 and TP53 genes and numerous large-scale copy number changes. Taken together, the findings supported malignant PEComa. This case demonstrates only the seventh example of malignant cutaneous PEComa. Although cutaneous PEComa is chiefly a benign mesenchymal neoplasm, in rare cases, it can rapidly transform into a malignant and infiltrative sarcoma, requiring prompt surgical management.

Outcomes after repeat hepatectomy for colorectal liver metastases from the colorectal liver operative metastasis international collaborative (COLOMIC).

BACKGROUND: Resection of colorectal liver metastasis (CLM) is beneficial when feasible. However, the benefit of second hepatectomy for hepatic recurrence in CLM remains unclear. METHODS: The Colorectal Liver Operative Metastasis International Collaborative retrospectively examined 1004 CLM cases from 2000 to 2018 from a total of 953 patients. Hepatic recurrence after initial hepatectomy was identified in 218 patients. Kaplan-Meier analysis was performed for overall survival (OS) and recurrence-free survival (RFS). Propensity score matching (PSM) was performed to offset selection bias. Cox proportional-hazards regression was performed to identify risk factors associated with OS. RESULTS: A total of 51 patients underwent second hepatectomy. Unadjusted median OS was 60.1 months in repeat-hepatectomy versus 38.3 months in the single-hepatectomy group (p = 0.015). In the PSM population, median OS remained significantly better in the repeat-hepatectomy group (60.1 vs. 33.1 months; p = 0.0023); median RFS was 12.4 months for the repeat-hepatectomy group, versus 9.8 months in the single-hepatectomy group (p = 0.0050). Repeat hepatectomy was associated with lower risk of death (hazard ratio: 0.283; p = 0.000012). Obesity, tobacco use, and high intraoperative blood loss were associated with significant risk of death (p < 0.05). CONCLUSION: In CLM with hepatic recurrence, second hepatectomy was beneficial for OS. With PSM, the OS benefit of performing a second hepatectomy remained significant.

Perioperative chemotherapy for resectable colorectal liver metastases: Analysis from the Colorectal Operative Liver Metastases International Collaborative (COLOMIC).

BACKGROUND: Chemotherapy has been increasingly combined with surgery as multimodality treatment for resectable colorectal-liver metastases (CLM). There is paucity of clinical data addressing optimal timing of chemotherapy relative to surgery. We examined outcomes of patients undergoing hepatectomy for resectable CLM. METHODS: Seven hundred and eighteen patients treated with hepatectomy for CLM were analyzed from five hepatobiliary institutions between 2000 and 2018. Overall survival (OS) was measured from time of hepatectomy for patients receiving: surgery alone, neoadjuvant, adjuvant, and neoadjuvant-plus-adjuvant (perioperative) chemotherapy. Kaplan-Meier analysis was performed to detect differences in OS between treatment groups. Single- and multi-variable analysis with Cox proportional hazards were run for OS between groups. RESULTS: One hundred and thirty-seven patients (19.08%) received surgery, 104 (14.48%) received neoadjuvant-only, 214 (29.81%) received adjuvant-only, and 263 (36.63%) received perioperative chemotherapy; with median OS of 48.20, 46.83, 56.27, and 49.93 months, respectively. No differences in median OS were seen between groups on Kaplan-Meier analysis. No significant difference in Charlson-Deyo comorbidity status was seen between groups (p = 0.853), while significant difference was seen in maximum tumor size (p = 0.0023). On multivariate analysis, adjuvant (p = 0.010) and perioperative (p = 0.020) chemotherapy were independently associated with OS compared to surgery alone. DISCUSSION: Despite group differences, chemotherapy after surgery was independently associated with improved OS in CLM.

Association of primary tumor laterality with surgical outcomes for colorectal liver metastases: results from the Colorectal Liver Operative Metastasis International Collaborative (COLOMIC).

BACKGROUND: Primary laterality of colorectal cancer is thought to be associated with differences in outcomes. Liver metastasis is the most common site of solitary colorectal cancer spread. However, how primary colorectal cancer laterality affects outcomes in colorectal liver metastasis remains unclear. METHODS: The Colorectal Liver Operative Metastasis International Collaborative (COLOMIC) of operative hepatectomy cases for colorectal liver metastasis was compiled from five participating institutions. This included consecutive cases from 2000 to 2018 at all sites. A total of 884 patients were included in this study. Univariate, multivariate, and Kaplan-Meier analyses were performed. RESULTS: Patients with left-sided versus right-sided cancers had significantly better overall survival: 49.4 vs. 41.8 months (p < 0.05). Patients with KRAS mutations had significantly worse median overall survival compared to KRAS wild-type (43.6 vs 56.1 months; p < 0.001). In left-sided cancers, KRAS mutations were associated with significantly worse median overall survival compared to KRAS wild-type cancers (43.6 vs 56.6 months; p < 0.01). This association was absent in patients with right-sided primary tumors. Multivariate Cox regression analysis revealed different variable sets (non-overlapping) were associated with overall survival, when comparing left-sided and right-sided cancers. CONCLUSION: Understanding how primary tumor laterality and related biological aspects affect long-term outcomes can potentially inform treatment decisions for patients with colorectal liver metastases.

Contemporary Management of Hepatic Cyst Disease: Techniques and Outcomes at a Tertiary Hepatobiliary Center.

BACKGROUND: Hepatic cyst disease is often asymptomatic, but treatment is warranted if patients experience symptoms. We describe our management approach to these patients and review the technical nuances of the laparoscopic approach. METHODS: Medical records were reviewed for operative management of hepatic cysts from 2012 to 2019 at a single, tertiary academic medical center. RESULTS: Fifty-three patients (39 female) met the inclusion criteria with median age at presentation of 65 years. Fifty cases (94.3%) were performed laparoscopically. Fourteen patients carried diagnosis of polycystic liver disease. Dominant cyst diameter was median 129 mm and located within the right lobe (30), left lobe (17), caudate (2), or was bilobar (4). Pre-operative concern for biliary cystadenoma/cystadenocarcinoma existed for 7 patients. Operative techniques included fenestration (40), fenestration with decapitation (7), decapitation alone (3), and excision (2). Partial hepatectomy was performed in conjunction with fenestration/decapitation for 15 cases: right sided (7), left sided (7), and central (1). One formal left hepatectomy was performed in a polycystic liver disease patient. Final pathology yielded simple cyst (52) and one biliary cystadenoma. Post-operative complications included bile leak (2), perihepatic fluid collection (1), pleural effusion (1), and ascites (1). At median 7.1-month follow-up, complete resolution of symptoms occurred for 34/49 patients (69.4%) who had symptoms preoperatively. Reintervention for cyst recurrence occurred for 5 cases (9.4%). CONCLUSIONS: Outcomes for hepatic cyst disease are described with predominantly laparoscopic approach, approach with minimal morbidity, and excellent clinical results.

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.

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.

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.

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.

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.