Analysis of prognostic factors for borderline resectable pancreatic cancer after neoadjuvant chemotherapy: the importance of CA19-9 decrease in patients with elevated pre-chemotherapy CA19-9 levels.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is widely used to treat borderline resectable pancreatic cancer. This study aimed to evaluate the serum carbohydrate antigen (CA)19-9 response, in association with survival, after four cycles of NAC-gemcitabine plus nab-paclitaxel. METHODS: From 2015 to 2018, patients with borderline resectable pancreatic cancer were treated with NAC. Patients were stratified into two groups after excluding CA19-9 non-secretor: Group L (CA19-9 ≥2 and ≤500 U/mL) and Group H (CA19-9 >500 U/mL). The CA19-9 decrease during NAC was evaluated as a response of NAC and was assessed in association with survival concomitant with other prognosis factors. RESULTS: Eighty-seven patients were evaluated (Group L: n = 43, Group H: n = 44). In intention-to-treat-based analysis, Group L exhibited significantly better progression-free survival (PFS) than Group H (median PFS: 24 vs 14months). In resection cohort, no correlation was detected between the CA19-9 decrease and survival in Group L. In Group H, the CA19-9 decrease ≤80% was associated with unfavorable survival in multivariate analysis [Hazard ratio: 4.738 (P = 0.007)]. CONCLUSION: In patients with pre-treatment CA19-9 >500 U/mL, the CA19-9 decrease ≤80% was strongly associated with poor survival and new strategy should be reconsidered for these patients.

Perivascular epithelioid cell tumor (PEComa) of the cystic duct.

Perivascular epithelioid cell tumors, also known as PEComas, are rare mesenchymal tumors composed mainly of epithelioid cells found in perivascular tissue. PEComas occur most frequently in the kidney, uterus, the gastrointestinal tract, liver, and retroperitoneum; those originating in the biliary tree are extremely rare. We report a case of benign PEComa of the cystic duct with positive TFE3 staining on immunohistochemistry.A 66-year-old woman was referred for a 20 mm mass adjacent to the common bile duct discovered incidentally on abdominal ultrasound. Laboratory data including tumor markers were unremarkable. The tumor appeared to arise from the cystic duct, showed early enhancement, and compressed the common bile duct on imaging studies. Endoscopic ultrasound-guided fine-needle aspiration revealed round- and spindle-shaped atypical cells with eosinophilic cytoplasm and brown deposits suggestive of melanin granules. Histological examination of the resected specimen revealed a tumor consisting of epithelioid cells forming an alveolar structure, with melanin pigmentation. Immunohistochemistry was positive for HMB-45 and TFE3, consistent with benign pigmented PEComa of the cystic duct. Melanotic, myogenic, and TFE3 staining are helpful when diagnosing PEComas arising in unusual locations.

Non-operative management after chemoradiotherapy plus consolidation or sandwich (induction with bevacizumab and consolidation) chemotherapy in patients with locally advanced rectal cancer: a multicentre, randomised phase II trial (NOMINATE trial).

INTRODUCTION: Total mesorectal excision (TME) and postoperative adjuvant chemotherapy following neoadjuvant chemoradiotherapy (CRT) is the standard treatment for locally advanced rectal cancer (LARC). However, neoadjuvant CRT has no recognised impact on reducing distant recurrence, and patients suffer from a long-lasting impairment in quality of life (QOL) associated with TME. Total neoadjuvant therapy (TNT) is an alternative approach that could reduce distant metastases and increase the proportion of patients who could safely undergo non-operative management (NOM). This study is designed to compare two TNT regimens in the context of NOM for selecting a more optimal regimen for patients with LARC. METHODS AND ANALYSIS: NOMINATE trial is a prospective, multicentre, randomised phase II selection design study. Patients must have clinical stage II or III (T3-T4Nany) LARC with distal location (≤5 cm from the anal verge or for those who are candidates for abdominoperineal resection or intersphincteric resection). Patients will be randomised to either arm A consisting of CRT (50.4 Gy with capecitabine) followed by consolidation chemotherapy (six cycles of CapeOx), or arm B consisting of induction chemotherapy (three cycles of CapeOx plus bevacizumab) followed by CRT and consolidation chemotherapy (three cycles of CapeOx). In the case of clinical complete response (cCR) or near cCR, patients will progress to NOM. Response assessment involves a combination of digital rectal examination, endoscopy and MRI. The primary endpoint is the proportion of patients achieving pathological CR or cCR≥2 years, defined as the absence of local regrowth within 2 years after the start of NOM among eligible patients. Secondary endpoints include the cCR rate, near cCR rate, rate of NOM, overall survival, distant metastasis-free survival, locoregional failure-free survival, time to disease-related treatment failure, TME-free survival, permanent stoma-free survival, safety of the treatment, completion rate of the treatment and QOL. Allowing for a drop-out rate of 10%, 66 patients (33 per arm) from five institutions will be accrued. ETHICS AND DISSEMINATION: The study protocol was approved by Wakayama Medical University Certified Review Board in December 2020. Trial results will be published in peer-reviewed international journals and on the jRCT website. TRIAL REGISTRATION NUMBER: jRCTs051200121.

Oncologic impact of lateral lymph node metastasis at the distal lateral compartment in locally advanced low rectal cancer after neoadjuvant (chemo)radiotherapy.

INTRODUCTION: The frequency and oncologic outcomes of lateral lymph node (LLN) metastasis at the most distal lateral compartment (DLC) among clinical stage II-III low rectal cancer patients treated with neoadjuvant (chemo)radiotherapy (nCRT) are poorly understood. The aim was to investigate the oncologic impact of LLN metastasis in the DLC versus the proximal lateral compartment (PLC). MATERIALS AND METHODS: Consecutive patients with low rectal cancer treated with nCRT followed by total mesorectal excision and selective LLN dissection including the DLC were analyzed retrospectively. DLC was defined as the area distal to the infra-piriformis foramen on axial MRI images. Size and location of LLN metastasis on MRI, and survival were retrospectively assessed. RESULTS: Of the 718 patients, 72 (10.0%) had pathological LLN metastasis. Thirty-two (44.4%) had metastasis in the DLC (DLC group), while 40 (55.6%) had metastasis in the PLC without metastasis in the DLC (PLC group). The proportion of ypN2 category tended to be lower in the DLC group (15.6% vs 35.0%, P = 0.105). The median number of metastatic LLN was similar (1 vs. 1, P = 0.691). The median short-axis size of metastatic LLN was smaller in the DLC group than in the PLC group on pre-treatment (P < 0.001) and re-staging (P = 0.004) MRI. By multivariable analysis, LLN metastasis in the DLC was predictive of better disease-free survival (HR, 0.412; 95% CI, 0.159-0.958, P = 0.039). CONCLUSION: LLN metastasis in the DLC is frequent and has favorable oncologic outcomes after surgical dissection with nCRT.

Sinistral Portal Hypertension Prediction During Pancreatoduodenectomy With Splenic Vein Resection.

BACKGROUND: Pancreaticoduodenectomy with porto-mesenterico-splenic confluence resection can cause sinistral portal hypertension (SPH), which may lead to gastrointestinal bleeding. Nevertheless, it remains difficult to predict SPH development during surgery. The aim of this study is to assess the feasibility of measuring splenic vein (SV) pressure to predict SPH. METHODS: The patients who underwent pancreaticoduodenectomy with porto-mesenterico-splenic confluence resection between January 2016 and December 2017 were included in this study. SV pressure was measured before SV clamping (SVP1) and after SV clamping (SVP2). SPH was defined as varicose vein formation detected by follow-up computed tomography. Incidence of SPH was assessed in patients who had no SV drainage after surgery. RESULTS: SV pressure was measured in 41 patients. Among them, 24 had no SV drainage (13 patients had occluded SV reconstruction, and 11 had SV ligation without an attempt at reconstruction) and were included for the analysis. SPH was observed in 16 of 24 patients (67%). The median ΔSVP (SPV2-SVP1) in patients with SPH was higher than that in patients without SPH (13.5 mmHg versus 7.5 mmHg, P = 0.0237). Most patients with SVP2 >20 mmHg (12/14 [86%]) or ΔSVP >10 mmHg (10/11 [91%]) developed SPH. CONCLUSIONS: For the patients with SV resection, high SV pressure after clamping (≥20 mmHg) and a large SV pressure difference (≥10 mmHg) before and after clamping are feasible indication criteria for SV reconstruction to prevent SPH.

Clinical significance of subcentimeter pulmonary nodules in patients undergoing hepatectomy for colorectal liver metastases.

BACKGROUND AND OBJECTIVES: The clinical significance of lung metastases regarded as subcentimeter pulmonary nodules (SPN) before hepatectomy for colorectal liver metastases (CLM) has not been assessed well. METHODS: The data from 569 patients undergoing hepatectomy for CLM from 2010 to 2016 were reviewed. The presence and final diagnosis of SPN were analyzed for their association with overall survival (OS). RESULTS: A total of 143 patients had SPN (25.1%). SPN were proved to be lung metastases in 43 patients (30.1%). Before hepatectomy, lung metastases were suspected in 25 patients (sensitivity: 58%; specificity: 100%). The 5-year OS of patients with lung metastases (45.4%) was worse than that of those with no pulmonary nodules (60.9%, P = .003). There was no significant difference in the 5-year OS between the patients with lung metastases diagnosed after hepatectomy (48.7%) and before hepatectomy (41.2%, P = .432). The 5-year OS of patients who underwent surgery for lung metastases after hepatectomy (60.5%) was similar to that of those with no pulmonary nodules and benign pulmonary nodules (60.9%, P = .6310; 44.0%, P = .899). CONCLUSION: Although diagnostic sensitivity for SPN before hepatectomy is low, timing of diagnosis does not affect OS. Conclusive lung resection offers OS similar to that of patients without lung metastases.

Three-Dimensional Fixation: Pathological Protocol Following Pancreaticoduodenectomy with Portal Vein Resection for Pancreatic Cancer.

BACKGROUND: Although existing histopathologic protocols for pancreatic cancer have been standardized, the relevance between prognosis and resection margin clearance is still controversial. Reconstruction of specimens as in situ to appropriately assess the margin is desirable in these protocols. METHODS: The three-dimensional fixation protocol defined specimen handling of pancreaticoduodenectomy (PD) with portal vein (PV) resection. The superior mesenteric artery (SMA) margin of the specimen was tidily fixed around an artificial SMA as if in an in situ setting. In this prospective study, patients undergoing PD with PV resection for pancreatic cancer in 2016 were enrolled. To evaluate the feasibility of the three-dimensional fixation protocol, the SMA margin distance and PV involvement of tumor assessed by computed tomography (CT) were compared with those assessed by pathology. RESULTS: Thirty-three patients with/without preoperative chemotherapy were enrolled. The entire cohort did not present with high-quality diagnostic assessment of the medial margins around SMA and PV (correct estimation, 58% and 73%, respectively). In contrast, in 16 patients undergoing upfront surgery, the concordance value of the SMA margin, which assesses the agreement between CT and pathology measures, was 0.48 (moderate agreement). The PV involvement examined by imaging was significantly associated with that by pathology (P = 0.013). CONCLUSIONS: The three-dimensional fixation protocol was applicable to all cases undergoing PD with PV resection. Focusing on the patients with upfront surgery demonstrated the feasibility of accurate pathological assessment of medial margins. We propose this protocol as a promising standard for the assessment of true surgical margin status.

Encapsulating fibrosis following neoadjuvant chemotherapy is correlated with outcomes in patients with pancreatic cancer.

Pathological assessments of the treatment effect are critical for predicting patient outcomes after surgery. This study included 82 localized pancreatic cancer, 40 of whom were treated with neoadjuvant therapy (NAT) using four courses of gemcitabine plus nab-paclitaxel (GnP) followed by pancreatectomy (GnP group). The remaining 42 patients were treated with upfront pancreatectomy (UP) followed by adjuvant chemotherapy (UP group). We reviewed clinicopathological data of these patients to assess differences between the GnP and UP groups and further evaluate the prognostic impact of residual tumors after GnP treatment. Adjuvant treatment (S1, GnP or gemcitabine) was administered for 36 patients in the GnP group and 33 patients in the UP group. Compared to the UP group, the GnP group showed lower serum CA19-9 levels, microscopic tumor volume, and tumor-stroma ratio and decreased number of lymph node metastasis and vascular invasion. Higher incidence of encapsulating fibrosis was observed in the GnP group than in the UP group. Relative to the UP group (69%), a higher R0 rate was observed in the GnP group (85%). As for prognosis, encapsulating fibrosis was correlated with the overall survival of patients in the GnP group. However, overall survival did not show any correlation with other clinicopathological factors, including tumor reduction ratio (determined by computed tomography) and tumor regression grade (determined following criteria of Evans' grading system or those of the College of American Pathologists). In conclusion, the present study revealed that GnP-induced encapsulating fibrosis could predict patients' outcome. Nevertheless, large cohort studies are warranted to further evaluate the prognostic value of fibrosis, possibly with the help of imaging and biomarkers.

Techniques for splenic vein reconstruction after pancreaticoduodenectomy with portal vein resection for pancreatic cancer.

BACKGROUND: Pancreaticoduodenectomy (PD) with splenic vein (SV) ligation may result in sinistral portal hypertension (SPH). The aim of this study was to compare the outcomes of various types of SV reconstruction to prevent SPH and to define the optimal reconstruction method. METHODS: This study included patients who underwent PD with SV resection and reconstruction for pancreatic cancer between December 2013 and June 2017. The patency of various types of SV anastomosis and SPH was evaluated by follow up computed tomography. RESULTS: The type of SV reconstruction was divided into two groups: (i) end-to-side anastomosis (n = 10), in which the SV was anastomosed with either the left renal vein (LRV; n = 8) or portal vein (n = 2); and (ii) end-to-end anastomosis (n = 20), in which the SV was anastomosed with another smaller vein or graft. The patency rate for Group 1 was 90% (9/10), compared with 45% (9/20) for Group 2 (P = 0.024). Half the patients in whom the SV anastomosis was occluded (6/12) developed gastrointestinal varices, whereas only 11% of patients with a patent SV anastomosis (2/9) had varices (P = 0.034). CONCLUSION: SV-LRV reconstruction is widely applicable, effectively reduces the risk of SPH, and should be considered for the case of extended PD.

Impact of portal vein resection with splenic vein reconstruction after pancreatoduodenectomy on sinistral portal hypertension: Who needs reconstruction?

BACKGROUND: Resection of the porto-mesenterico-splenic confluence is at times necessary during pancreatoduodenectomy with portal vein resection for pancreatic cancer. Although splenic vein ligation can cause sinistral portal hypertension, the incidence of clinically relevant sinistral portal hypertension remains unknown, and the roles of the preservation of potential collateral veins and splenic vein reconstruction are controversial. METHODS: Patients with pancreatic cancer who underwent pancreatoduodenectomy with porto-mesenterico-splenic confluence resection were assessed for incidence of development of varices by computed tomography at 6 months after pancreatoduodenectomy. We evaluated the risk factors for sinistral portal hypertension and the impact of splenic vein reconstruction on sinistral portal hypertension. RESULTS: Of the 118 patients who underwent pancreatoduodenectomy with porto-mesenterico-splenic confluence resection, 31 (26%) underwent splenic vein reconstruction, 44 patients (37%) developed gastroesophageal varices, and 5 (11%) experienced varix rupture. Sacrifice of all 3 potential collateral veins (what we refer to as the critical veins: left gastric vein, middle colic vein, and superior right colic vein arcade) and absence of any spontaneous splenorenal shunt had a substantial impact on formation of varices. The risk of variceal formation could be stratified based on the number of preserved critical veins, and patent splenic vein reconstruction was associated with a decreased incidence of varices (60% versus 100%, P = .018) among the patients without preservation of the critical veins. In contrast, patients with multiple intact critical veins developed no varices, regardless of splenic vein reconstruction. CONCLUSIONS: Sinistral portal hypertension is not uncommon after pancreatoduodenectomy with porto-mesenterico-splenic confluence resection, and the number of preserved critical veins helps to predict the risk of sinistral portal hypertension. Thus, the indication for splenic vein reconstruction should be tailored according to individual risk factors.

Clinical implications of disappearing colorectal liver metastases have changed in the era of hepatocyte-specific MRI and contrast-enhanced intraoperative ultrasonography.

BACKGROUND: Clinical implication of disappearing liver metastases (DLMs) from colorectal cancer after chemotherapy needs to be reviewed in the era of modern imaging studies. METHODS: Between 2010 and 2015, 184 patients underwent curative hepatectomy for colorectal liver metastases following preoperative chemotherapy. The sites of metastases detected on pre-chemotherapy CE-CT were examined post-chemotherapy using CE-CT, gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI), and contrast-enhanced intraoperative ultrasonography (CE-IOUS). DLMs were defined as tumors that disappeared on CE-CT post chemotherapy. The detection rate of DLMs with EOB-MRI and CE-IOUS were assessed, and the outcome of DLMs resected and those left in place were reviewed. RESULTS: A total of 275 DLMs were noted in 59 patients. On EOB-MRI, 71 lesions (26%) were visible and were resected, 92% (65/71) of which contained viable disease. Using CE-IOUS, an additional 94 lesions were identified. A total of 165 DLMs (60%) were identified and resected by sequential use of EOB-MRI and CE-IOUS, 77% (127/165) of which contained viable disease. Of 110 DLMs not identified, 68 were resected, 4% (3/68) of which contained viable disease. Among 42 lesions left in place, 6 (14%) recurred during the median follow-up period of 27 (9-72) months. DISCUSSION: EOB-MRI and CE-IOUS exploration identified clinically relevant DLMs containing viable disease with a high level of accuracy.

Indications for Lateral Pelvic Lymph Node Dissection Based on Magnetic Resonance Imaging Before and After Preoperative Chemoradiotherapy in Patients with Advanced Low-Rectal Cancer.

BACKGROUND: We assessed the magnetic resonance imaging (MRI) findings of lateral pelvic lymph node (LPLN) metastasis in patients with advanced low-rectal cancer treated with preoperative chemoradiotherapy (CRT) and LPLN dissection (LPLD) for clinically suspected LPLN metastasis. Our aim was to identify the optimal indications for LPLD. METHODS: The study population consisted of 77 patients with advanced low-rectal cancer who underwent LPLD for clinically suspicious LPLN metastasis after preoperative CRT. MRI findings before/after CRT, clinical factors, and LPLN metastasis were evaluated. RESULTS: LPLN metastasis was confirmed in 31 patients (40.3 %). Metastasis was significantly higher in patients with LPLNs with a short-axis diameter ≥8 mm than in patients with LPLNs with a short-axis diameter <8 mm before CRT (75 vs. 20 %, P < 0.0001). LPLN metastasis was also significantly higher in patients with LPLNs with a short-axis diameter >5 mm than in patients with LPLNs with a short-axis diameter ≤5 mm after CRT (75 vs. 20 %, P < 0.0001). Multivariate analysis showed the independent association of female sex [P = 0.0192; odds ratio (OR) 5.616; 95 % confidence interval (CI) 1.315-28.942], pre-CRT short-axis diameter of the LPLN ≥8 mm (P = 0.0047; OR 9.188; 95 % CI 1.948-54.366), and CRT without induction systemic chemotherapy (P = 0.0285; OR 9.235; 95 % CI 1.241-106.947) with LPLN metastasis. CONCLUSIONS: MRI before CRT is useful to predict LPLN metastasis and to determine the indications for LPLD.

Hemosuccus pancreaticus in a patient with iodine allergy: successful diagnosis with magnetic resonance imaging and treatment with transarterial embolization using carbon dioxide as the contrast medium.

Hemosuccus pancreaticus (HP) is defined as gastrointestinal bleeding via the pancreatic duct and duodenal papilla. Since the bleeding is usually intermittent, it often remains undetected by endoscopy. Most cases are diagnosed by contrast-enhanced computed tomography (CT) or angiography, and the first-line treatment is transarterial embolization (TAE). However, in general, these modalities require a large amount of iodinated contrast medium. Here, we report the case of a 50-year-old female with HP due to chronic pancreatitis. Contrast-enhanced CT and ordinary angiography were contraindicated for her, as she was allergic to iodine. She was diagnosed with HP following gadolinium-enhanced magnetic resonance imaging and successfully treated by TAE of the splenic artery with metallic coils using carbon dioxide as the contrast medium.

Detection of hepatic metastases using ferucarbotran-enhanced MR imaging: feasibility and diagnostic accuracy of three-dimensional sensitivity-encoding water-excitation multishot echo-planar sequence (3D-SWEEP).

PURPOSE: To evaluate the diagnostic accuracy of a ferucarbotran-enhanced three-dimensional sensitivity-encoding water-excitation multishot echo-planar sequence (3D-SWEEP) for detecting hepatic metastases compared to a T2*-weighted fast field-echo (FFE) sequence. MATERIALS AND METHODS: Twenty-five consecutive patients with hepatic metastases underwent ferucarbotran-enhanced MRI on a 1.5-T unit before hepatic resections. Eighty-two foci of metastases were confirmed by histopathology or intraoperative ultrasonography (US). Signal-intensity decay (SID), tumor-to-liver contrast (TLC), and image quality were compared between T2*-weighted FFE and 3D-SWEEP. Three independent observers reviewed three imaging sets: set 1, without 3D-SWEEP or T2*-weighted FFE; set 2, with T2*-weighted FFE; and set 3, with 3D-SWEEP. The mean values of areas under alternative free response receiver operating characteristic curves (Az) and sensitivities were compared among the three sets. RESULTS: SID and TLC were significantly greater for 3D-SWEEP than T2*-weighted FFE, although 3D-SWEEP had poorer image quality. The mean Az and sensitivity were significantly greater for set 3 compared to set 1 for detecting overall lesions, and compared to sets 1 and 2 for detecting lesions of 1-2 cm in diameter. CONCLUSION: Despite relatively prominent artifacts, ferucarbotran-enhanced 3D-SWEEP was more sensitive and accurate than T2*-weighted FFE for detecting hepatic metastases.