PDIA2 has a dual function in promoting androgen deprivation therapy induced venous thrombosis events and castrate resistant prostate cancer progression.

Androgen deprivation therapy (ADT) is the first line of treatment for metastatic prostate cancer (PCa) that effectively delays the tumor progression. However, it also increases the risk of venous thrombosis event (VTE) in patients, a leading cause of mortality. How a pro-thrombotic cascade is induced by ADT remains poorly understood. Here, we report that protein disulfide isomerase A2 (PDIA2) is upregulated in PCa cells to promote VTE formation and enhance PCa cells resistant to ADT. Using various in vitro and in vivo models, we demonstrated a dual function of PDIA2 that enhances tumor-mediated pro-coagulation activity via tumor-derived extracellular vehicles (EVs). It also stimulates PCa cell proliferation, colony formation, and xenograft growth androgen-independently. Mechanistically, PDIA2 activates the tissue factor (TF) on EVs through its isomerase activity, which subsequently triggers a pro-thrombotic cascade in the blood. Additionally, TF-containing EVs can activate the Src kinase inside PCa cells to enhance the AR signaling ligand independently. Androgen deprivation does not alter PDIA2 expression in PCa cells but enhances PDIA2 translocation to the cell membrane and EVs via suppressing the clathrin-dependent endocytic process. Co-recruitment of AR and FOXA1 to the PDIA2 promoter is required for PDIA2 transcription under androgen-deprived conditions. Importantly, blocking PDIA2 isomerase activity suppresses the pro-coagulation activity of patient plasma, PCa cell, and xenograft samples as well as castrate-resistant PCa xenograft growth. These results demonstrate that PDIA2 promotes VTE and tumor progression via activating TF from tumor-derived EVs. They rationalize pharmacological inhibition of PDIA2 to suppress ADT-induced VTE and castrate-resistant tumor progression.

Mucin 1 and venous thrombosis in tumor-bearing mice and patients with cancer.

INTRODUCTION: Mucins released from epithelial tumors have been proposed to play a role in cancer-associated thrombosis. Mucin1 (MUC1) is a transmembrane mucin that is overexpressed in a variety of human malignancies, including breast and pancreatic cancer. We analyzed the association of MUC1 and venous thrombosis in a mouse tumor model and in patients with cancer. MATERIALS AND METHODS: We used a human pancreatic cancer cell line HPAF-II that expresses a high level of MUC1. We grew HPAF-II tumors in the pancreas of Crl:NU-Foxn1nu male mice. MUC1 in plasma and extracellular vesicles (EVs) isolated from plasma was measured using an enzyme-linked immunosorbent assay. MUC1 in EVs and venous thrombi from tumor-bearing mice was assessed by western blotting. We measured MUC1 in plasma from healthy controls and patients with stomach, colorectal or pancreatic cancer with or without venous thromboembolism. RESULTS AND DISCUSSION: MUC1 was detected in the plasma of mice bearing HPAF-II tumors and was associated with EVs. MUC1 was present in venous thrombi from mice bearing HFAP-II tumors. Recombinant MUC1 did not induce platelet aggregation. Levels of MUC1 were higher in patients with pancreatic cancer compared with healthy controls. In contrast to the mouse model, MUC1 was present in EV-free plasma in samples from healthy controls and patients with cancer. There was no significant difference in the levels of MUC1 in cancer patients with or without VTE. Our data did not find any evidence that MUC1 contributed to VTE in patients with cancer.

Advanced Renal Cell Carcinoma With Inferior Vena Cava Thrombus Treated With a Combination of Preoperative Lenvatinib and Pembrolizumab.

BACKGROUND/AIM: Lenvatinib plus pembrolizumab combination therapy is a safe and effective treatment for patients with advanced renal cell carcinoma (RCC). However, there are no reports of the use of lenvatinib and pembrolizumab combination therapy for RCC with an inferior vena cava (IVC) tumor thrombus. Herein, we describe a case in which pembrolizumab and lenvatinib combination therapy was effectively used to treat RCC with the IVC tumor thrombus extending to the right atrium. CASE REPORT: A 73-year-old man was diagnosed with a right renal tumor with the IVC tumor thrombus extending to the right atrium and multiple pulmonary metastases (cT3cN0M1). Using a computed tomography-guided renal tumor biopsy, the tumor was diagnosed as clear cell RCC. The International Metastatic RCC Database Consortium risk classification was poor according to three risk factors, and lenvatinib and pembrolizumab combination therapy was initiated. The primary renal tumor shrunk, the IVC tumor thrombus that reached the right atrium was reduced from level 4 to level 2, and the lung metastases disappeared 4 months after treatment initiation. Thereafter, a robot-assisted deferred cytoreductive nephrectomy was successfully performed. Pathologically, owing to the preoperative combination therapy, most of the tumor tissue was necrotic; however, some viable cells were present in the primary tumor and IVC tumor thrombus. Eight months following the operation, the patient remains recurrence-free. CONCLUSION: Treatment with lenvatinib and pembrolizumab combination therapy led to tumor shrinkage and allowed robot-assisted nephrectomy in a patient with advanced RCC with the IVC tumor thrombus extending to the right atrium, corroborating the efficacy of the treatment.

Management and Outcomes of Wilms Tumor With Suprarenal Intravascular Extension: A Pediatric Surgical Oncology Research Collaborative Study.

OBJECTIVE: The purpose of this study was to describe management and outcomes from a contemporary cohort of children with Wilms tumor complicated by inferior vena caval thrombus. BACKGROUND: The largest series of these patients was published almost 2 decades ago. Since then, neoadjuvant chemotherapy has been commonly used to manage these patients, and outcomes have not been reported. METHODS: Retrospective review of 19 North American centers between 2009 and 2019. Patient and disease characteristics, management, and outcomes were investigated and analyzed. RESULTS: Of 124 patients, 81% had favorable histology (FH), and 52% were stage IV. IVC thrombus level was infrahepatic in 53 (43%), intrahepatic in 32 (26%), suprahepatic in 14 (11%), and cardiac in 24 (19%). Neoadjuvant chemotherapy using a 3-drug regimen was administered in 82% and postresection radiation in 90%. Thrombus level regression was 45% overall, with suprahepatic level showing the best response (62%). Cardiopulmonary bypass (CPB) was potentially avoided in 67%. The perioperative complication rate was significantly lower after neoadjuvant chemotherapy [(25%) vs upfront surgery (55%); P =0.005]. CPB was not associated with higher complications [CPB (50%) vs no CPB (27%); P =0.08]. Two-year event-free survival was 93% and overall survival was 96%, higher in FH cases (FH 98% vs unfavorable histology/anaplastic 82%; P =0.73). Neither incomplete resection nor viable thrombus cells affected event-free survival or overall survival. CONCLUSIONS: Multimodal therapy resulted in excellent outcomes, even with advanced-stage disease and cardiac extension. Neoadjuvant chemotherapy decreased the need for CPB to facilitate resection. Complete thrombectomy may not always be necessary.

Refining MRI-based criteria for portal vein invasion in hepatocellular carcinoma: improving sensitivity beyond portal vein tumor thrombosis.

PURPOSE: To investigate the imaging features indicating portal vein invasion (PVI) of hepatocellular carcinoma (HCC) on gadoxetic acid-enhanced MRI and to create more accurate diagnostic criteria than the presence of portal vein tumor thrombosis (PVTT) on MRI. METHODS: This retrospective study included patients with surgically resected HCC larger than 5 cm, and the presence of PVI was investigated. On MRI, we evaluated the image findings of portal vein occlusion, the parenchymal signal change caused by hemodynamic alterations of the portal vein, and their combination showing the highest odds ratio (OR) to define the diagnostic criteria for radiological PVI detection (rPVI criteria). The diagnostic performance and recurrence-free survival were compared between the rPVI criteria and the presence of PVTT using McNemar's test and Kaplan-Meier method, respectively. Interobserver agreement was evaluated using Cohen's weighted ĸ statistics. RESULTS: Of 189 enrolled patients, 25 (13.2%) had PVI on histology. To diagnose PVI on MRI, either peripheral wedge-shaped arterial peritumoral hyperemia with an abrupt cut-off of a portal vein or the presence of PVTT had the highest OR (41.67, p < 0.001). The sensitivity of PVI was significantly increased under this diagnostic criterion (64.0% to 88.0%; p = 0.031) with comparable accuracy (95.2% vs. 94.7%; p > 0.999). In terms of recurrence-free survival, the patient group with rPVI was significantly worse (p = 0.017) compared with the patients without rPVI. Interobserver agreement of radiologic findings was substantial (ĸ = 0.64). CONCLUSION: Diagnostic criteria for radiologically PVI detection increase the sensitivity more than the only presence of PVTT.

Role of platelet count in a murine stasis model of deep vein thrombosis.

Platelets are core components of thrombi but their effect on thrombus burden during deep vein thrombosis (DVT) has not been fully characterized. We examined the role of thrombopoietin-altered platelet count on thrombus burden in a murine stasis model of DVT. To modulate platelet count compared to baseline, CD1 mice were pretreated with thrombopoietin antisense oligonucleotide (THPO-ASO, 56% decrease), thrombopoietin mimetic (TPO-mimetic, 36% increase), or saline (within 1%). Thrombi and vein walls were examined on postoperative days (POD) 3 and 7. Thrombus weights on POD 3 were not different between treatment groups (p = .84). The mean thrombus weights on POD 7 were significantly increased in the TPO-mimetic cohort compared to the THPO-ASO (p = .005) and the saline (p = .012) cohorts. Histological grading at POD 3 revealed a significantly increased smooth muscle cell presence in the thrombi and CD31 positive channeling in the vein wall of the TPO-mimetic cohort compared to the saline and THPO-ASO cohorts (p < .05). No differences were observed in histology on POD 7. Thrombopoietin-induced increased platelet count increased thrombus weight on POD 7 indicating platelet count may regulate thrombus burden during early resolution of venous thrombi in this murine stasis model of DVT.

Deep vein thrombosis (DVT) is a pathology in which blood clots form in the deep veins of our body. Usually occurring in the legs, these clots can be dangerous if they dislodge and travel to the heart and are pumped into the lungs. Often these clots do not travel and heal where they formed. However, as the body heals the clot it may also cause damage to the vein wall and predispose the patient to future clots, i.e., the biggest risk factor for a second clot is the first clot. DVT can also cause symptoms of pain, swelling, and redness in the long-term, leading to post-thrombotic syndrome where the initial symptoms of the clot persist for a long time. All blood clots have common components of red blood cells, white blood cells, platelets, and fibrin in varying concentrations. Humans maintain a platelet count between 150 and 400 thousand platelets per microliter of our blood. However, diseases like cancer or medications like chemotherapy can cause a change in our body's platelet count. The effect of a changing platelet count on the size (clot burden) of DVT clot and how platelet count could affect DVT as the clot heals is not fully understood. Studying this might help us develop better targets and treat patients with a wide range of platelet counts who experience DVT. In this study, we intentionally decreased, left unchanged, and increased platelet counts in mice and then created a DVT to study what the effect of low, normal, and high platelet counts, respectively, would be on the clot burden. We observed that mice with higher platelet counts had a higher clot burden during the early part of the healing process of the clot. Within this study, we can conclude that higher platelet counts may lead to higher clot burden in DVT which furthers our understanding of how platelet count affects clot burden during DVT.

Relationship between intrathrombotic appearance of HSP27 and HSP70 and thrombus ages in a murine model of deep vein thrombosis.

Heat shock proteins (HSPs) are molecular chaperones whose primary function is cytoprotection, supporting cell survival under (sub) lethal conditions. They have been implicated in various diseases such as inflammatory diseases and cancer due to their cytoprotective and immunomodulatory effects, and their biological mechanisms have been studied. Central family members include, HSP27, which is induced by various stimuli such as heat shock, hypoxia, hyperoxia, ultraviolet exposure, and nutritional deficiency, and HSP70, which is homeostatically expressed in many organs such as the gastrointestinal tract and has anti-cell death and anti-inflammatory effects. In this study, HSP27 and HSP70 were investigated during thrombus formation and dissolution in a deep vein thrombosis model by immunohistochemistry to determine their involvement in this process and whether their expression could be used as a forensic marker. In the process of thrombus formation and lysis, HSP27 and HSP70 were found to be expressed by immunohistochemical analysis. The role of inhibitors of HSP27 and HSP70 in the pathogenesis of thrombosis in mice was also investigated. When HSP27 or HSP70 inhibitors were administered, thrombi were significantly smaller than in the control group on day 5 after inferior vena cava ligation, indicating pro-thrombotic effects HSP27 and HSP70. If HSP27- or HSP70-positive cells were clearly visible and easily identifiable in the thrombus sections, the thrombus was presumed to be more than 10 days old. Thus, the detection of intrathrombotic HSP27 and HSP70 could forensically provide useful information for the estimation of thrombus ages. Collectively, our study implied that both HSP27 and HSP70 might be molecular targets for thrombus therapy and that the detection of HSP-related molecules such as HSP27 and HSP70 could be useful for the determination of thrombus ages.

The Role of Contrast-Enhanced Ultrasound (CEUS) in the Detection of Neoplastic Portal Vein Thrombosis in Patients with Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the principal primary liver cancer and one of the most frequent malignant tumors worldwide in patients with chronic liver disease. When diagnosed at an advanced stage, it is often associated with portal vein tumor thrombosis (PVTT), which heavily affects patients' prognosis. Imaging evaluation is crucial in PVTT detection and staging; computed tomography and magnetic resonance are the principal diagnostic tools. Contrast-enhanced ultrasound (CEUS) is a non-invasive and easily repeatable method that can also be used in patients with impaired renal function. It represents an important means for the identification of PVTT, particularly differentiating neoplastic and non-neoplastic thrombosis through the analysis of ultrasound enhancement characteristics of the thrombosis (arterial hyperenhancement and portal washout), thus allowing more refined disease staging, appropriate treatment planning, and response evaluation, along with prognosis assessment.

Transarterial interventional therapy combined with tyrosine kinase inhibitors with or without anti-PD-1 antibodies as initial treatment for hepatocellular carcinoma with major portal vein tumor thrombosis: a single-center retrospective study.

Transarterial interventional therapy combined with tyrosine kinase inhibitors (TKIs) and anti-Pd-1 antibodies (triplet regimen) has shown promising results in advanced HCC. However, the clinical utility of the triplet regimen in patients with HCC and major portal vein tumor thrombosis (PVTT) remains unclear. This study compared the efficacy and safety of the triplet regimen versus transarterial interventional therapy combined with TKIs (double regimen) for such patients. Thirty-nine patients treated with the triplet regimen were retrospectively compared with 37 patients treated with the double regimen. The objective response rate (ORR), the response rate of PVTT treatment, and safety were observed; progression-free survival (PFS) and overall survival (OS) were assessed using the Kaplan‒Meier method and log-rank test. Predictors of survival were identified using multivariate analysis. Median OS and median PFS were significantly improved in the Triplet Group compared with the Double Group (482 vs. 310 days; 208 vs. 85 days). The ORR and the response rate of PVTT were significantly higher in the Triplet Group than in the Double Group (59% vs. 35%; 62% vs. 35%). There was no significant difference in the incidence of grade 3/4 adverse events between the two groups (33% vs. 21%). The most frequent grade 3/4 adverse events were thrombocytopenia (10%) in the Triplet Group and hand-foot syndrome (14%) in the Double Group. Multivariable analysis showed that treatment method and PVTT treatment response were significant predictors of OS. The triplet regimen showed superiority over the doublet regimen in improving OS and PFS and had acceptable safety in patients with HCC and major PVTT.

Robotic assisted radical nephrectomy with Inferior vena cava tumor thrombus.

PURPOSE: Surgery for renal cell carcinoma (RCC) with an inferior vena cava (IVC) tumor thrombus can be done via a robotic approach. While this approach is thought to minimize blood loss, it may still result in significant losses (1) and current publications indicate that it can require upwards of 3-day hospital stays (1, 2). However, innovative surgical techniques, such as the split and roll, may curtail this. The purpose of this video is to present the case and surgical technique of robotic assisted radical nephrectomy with IVC thrombectomy. MATERIALS AND METHODS: The patient was a 77-year-old male found to have a right upper pole renal mass on CT urogram. On MRI (Figure 1), a renal mass and level II thrombus was seen. For this case, the Da Vinci Xi Intuitive robotic system was used, with four robotic 8-millimeter (mm) metallic trocars, two 5 mm assistant trocars, and one 12 mm air seal port. The split and roll technique were utilized to access the IVC and lumbar veins. This surgical method uses the adventitia of the IVC as a plane of dissection and safely identifies all branches/tributaries of the IVC to minimize the chance of vascular injury (3). RESULTS: Robotic console time was 150 minutes. The patient had an excellent outcome, with all tumor thrombus removed, less than 50cc of blood loss, and was discharged within 24 hours of the operation. The tumor pathology came back as papillary, high grade, and was stage pT3bN1. CONCLUSIONS: The robotic approach with split and roll technique is a great surgical option for urologists to consider in patients with RCC and a level I or II thrombus, which can minimize blood loss and expedite discharge.

Robot Assisted Laparoscopy Combined with Thoracoscopy in the Treatment of Hepatocellular Carcinoma with Inferior Vena Cava Tumor Thrombus.

BACKGROUND: Facing the 0.7-22% incidence rate of hepatocellular carcinoma (HCC) with inferior vena cava tumor thrombus (IVCTT), there are usually no obvious symptoms and signs when the tumor thrombus completely blocks the IVCTT in the early stage.1.J Gastroenterol. 29:41-46;2.Hepatogastroenterology. 41:154-157;3.Clin Cardiol. 19:211-213; Once diagnosed, it is the end-stage manifestation without unified treatment for HCC with IVCTT, bringing poor prognosis. Without active treatment, the median survival time is only 3 months. Previous scholars believed that patients with IVCTT should not adopt active surgical treatment. With the advance of technology, active surgical treatment has significantly lengthened the survival time with IVCTT.4.Ann Surg Oncol. 20:914-22;5.World J Surg Oncol. 11:259;6.Hepatogastroenterology. 58:1694-1699; However, for patients with HCC and IVCTT, open surgery was always selected in the past by opening the diaphragm through the combined thoracoabdominal incision to block the superior and subhepatic vena cava, leading long incision and huge trauma. With the development of minimally invasive techniques, laparoscopy thoracoscopy has showed great advantages in the treatment of HCC with IVCTT. A patient underwent laparoscopic with thoracoscopic resection of tumor and cancer thrombectomy after neoadjuvant therapy and then survived after follow-up.7.Ann Surg Oncol. 29:5548-5549 Therefore, it used as a first reported case of robot-assisted laparoscopic with thoracoscopic treatment of HCC complicated inferior vena cava cancer thrombectomy. METHODS: A 41-year-old man had a liver space-occupying lesion discovered during his medical examination 2 months ago. The diagnosis of HCC with IVCTT was confirmed by enhanced CT and biopsy specimen in the first hospitalization. A combination of TACE, targeted therapy, and immunotherapy plan was applied for the patient after multidisciplinary treatment (MDT). Specifically, Lenvatinib was taken orally 8 mg daily and 160 mg of toripalimab was given intravenously every 3 weeks. His reexamination CT showed that the tumor was more advanced after 2 months of treatment. The surgical operation was performed based on comprehensive consideration. The patient was placed in the left lateral decubitus position, and a thoracoscopic prefabricated the inferior vena cava above diaphragm blocking device was pulled out of the incision. The patient was switched to a supine position with the head of the bed raised 30 degrees. The gallbladder was removed first after entering the abdominal cavity, then prefabricated first hilar blocking band. Sterile rubber glove edges and hemo-lock were used to fabricate the blocking device. The novel hepatic inflow occlusion device is a safe, reliable, and convenient technique that is associated with favorable perioperative outcomes and low risk of conversion.8.Surg Endosc. 34:2807-2813 The liver along the middle hepatic vein was cut to expose the anterior wall of the inferior vena cava, then prefabricated posterior inferior vena cava blocking belt and right hepatic vein blocking belt. Finally, the first portal of liver, right hepatic vein, retrohepatic inferior vena cava, and inferior vena cava above diaphragm were blocked in sequence, so that accomplishing tumor resection and thrombectomy of inferior vena cava. It should be emphasized that before the inferior vena cava is completely sutured, the retrohepatic inferior vena cava blocking device should be released to allow blood flow to flush the inferior vena cava. Moreover, transesophageal ultrasound is required to real-time monitor inferior vena cava blood flow and IVCTT. Some images of the operation are shown in Fig. 1. Fig. 1 (a) Layout of the trocar. ①Make a 3cm small incision between the right anterior axillary line and the midaxillary line, parallel to the fourth and fifth intercostal spaces; a puncture hole in the next intercostal space for endoscope; ②2cm above the intersection of umbilicus horizontal line and axillary front line; ③Intersection of right clavicular midline and umbilical horizontal line; ④Superior margin of umbilicus; ⑤The midpoint of '④ & ⑥'; ⑥2cm below the intersection of left clavicular midline and left costal margin. (b) Prefabricated the inferior vena cava blocking device above diaphragm by thoracoscopic. (c) The smooth tumor thrombus protruding into the inferior vena cava RESULTS: It took 475 min to finish the operation, and the loss of blood was estimated as 300 ml. The patient was discharged from hospital 8 days after the operation without postoperative complication. HCC was confirmed by postoperative pathology. CONCLUSIONS: Robot surgical system reduces the limitations of laparoscopic surgery by offering a stable three-dimensional view, 10-times-enlarged image, restored eye-hand axis, and excellent dexterity with the endowristed instruments, which has several advantages over open operation such as diminished blood loss, reduced morbidity, and shorter hospital stay.9.Chirurg. 88:7-11;10.BMC Surg. 11:2;11.Minerva Chir. 64:135-146; Furthermore, it could favor the operative feasibility of difficult resections reducing the conversion rate and playing a role to extend the indications of liver resection to minimally invasive approaches. It may provide new curative options in patients deemed inoperable with conventional surgery, such as HCC with IVCTT.12.Biosci Trends. 16:178-188;13.J Hepatobiliary Pancreat Sci. 29:1108-1123.

The feasibility of contrast-enhanced CT to identify the adhesive renal venous tumor thrombus of renal cell carcinoma.

OBJECTIVE: To identify adhesive renal venous tumor thrombus (RVTT) of renal cell carcinoma (RCC) by contrast-enhancement CT (CECT). MATERIALS AND METHODS: Our retrospective study included 53 patients who underwent preoperative CECT and pathologically confirmed RCC combined with RVTT. They were divided into two groups based on the intra-operative findings of RVTT adhesion to the venous wall, with 26 cases in the adhesive RVTT group (ARVTT) and 27 cases in the non-adhesive group (NRVTT). The location, maximum diameter (MD) and CT values of tumors, the maximum length (ML) and width (MW) of RVTT, and length of inferior vena cava tumor thrombus were compared between the two groups. The presence of renal venous wall involvement, renal venous wall inflammation, and enlarged retroperitoneal lymph node was compared between the two groups. A receiver operating characteristic curve was used to analyze the diagnostic performance. RESULTS: The MD of RCC and the ML and MW of the RVTT were all larger in the ARVTT group than in the NRVTT group (p = 0.042, p < 0.001, and p = 0.002). The proportion of renal vein wall involvement and renal vein wall inflammation were higher in the ARVTT group than in NRVTT groups (both p < 0.001). The multivariable model including ML and vascular wall inflammation to predict ARVTT could achieve the best diagnostic performance with the area under the curve, sensitivity, specificity, and accuracy of 0.91, 88.5%, 96.3%, and 92.5%, respectively. CONCLUSION: The multivariable model acquired by CECT images could be used to predict RVTT adhesion. CLINICAL RELEVANCE STATEMENT: For RCC patients with tumor thrombus, contrast-enhanced CT could noninvasively predict the adhesion of tumor thrombus, thus predicting the difficulty of surgery and contributing to the selection of an appropriate treatment plan. KEY POINTS: • The length and width of the tumor thrombus could be used to predict its adhesion to the vessel wall. • Adhesion of the tumor thrombus can be reflected by inflammation of the renal vein wall. • The multivariable model from CECT can well predict whether the tumor thrombus adhered to the vein wall.

Prognostic value of preoperative circulating tumor cells for hepatocellular carcinoma with portal vein tumor thrombosis: A propensity score analysis.

PURPOSE: The role of circulating tumor cells (CTCs) in hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is not fully understood. METHODS: In this retrospective analysis, we included 316 HCC patients who underwent hepatectomy and preoperative CTC detection. We selected 41 pairs of matched HCC patients with and without PVTT using propensity score matching (PSM) analysis. We compared the preoperative CTC counts in patients from both the full cohort and the PSM model. We also analyzed their associations with disease-free survival (DFS) and overall survival (OS). RESULTS: Before and after PSM analysis, the preoperative CTC counts in the HCC with PVTT group were substantially higher than in the HCC without PVTT group. In both the full cohort of patients and the PSM model, patients with CTC ≥ 2 had significantly shorter OS and DFS than patients with CTC < 2. The outcomes of HCC patients with PVTT could be well differentiated by preoperative CTC levels. HCC patients with CTC ≥ 2 had noticeably shorter OS (9.9 months vs. 24.6 months, P = 0.0003) and DFS (6.0 months vs. 12.3 months, P = 0.0041) than those with CTC < 2. Moreover, preoperative CTC ≥ 2 remained an independent predictor in all groups' multivariate analysis. CONCLUSION: We discovered a link between preoperative CTC counts and the occurrence of PVTT and confirmed the prognostic significance of preoperative CTC in HCC patients with PVTT. These findings suggest that preoperative CTC counts have the potential to assist in identifying patients with HCC and PVTT who may benefit from surgery.

Systematic review and meta-analysis of preoperative imaging prediction of renal cell carcinoma tumour thrombus inferior vena cava wall invasion.

AIM: To summarise published evidence assessing the preoperative diagnostic performance of identifying inferior vena cava (IVC) wall invasion in patients with renal cell carcinoma (RCC). MATERIALS AND METHODS: A systematic approach was used to identify studies that assessed IVC wall invasion with non-invasive imaging preoperatively. Search limits included English language and human study participants. A meta-analysis was conducted using random effects models to compare radiographic vascular size parameters and the association of IVC wall invasion. RESULTS: A total of 15 studies were identified, which included computed tomography (CT), magnetic resonance imaging (MRI), positron-emission tomography (PET), and ultrasound assessment. In the majority of cases, CT and MRI was utilised with high accuracy in predicting IVC wall invasion. A meta-analysis of commonly reported radiographic vascular size parameters found that IVC wall invasion was associated with greater IVC maximum anteroposterior (AP) diameter (mean difference [MD] = 6.58 mm, 95% confidence interval [CI]: 2.84-10.33, p=0.0006) and IVC maximum AP diameter at the level of the renal vein ostium (MD = 5.69 mm, 95% CI: 4.35-7.03, p<0.0001). Renal vein maximum AP dimension was not associated with IVC wall invasion (MD = 2.56 mm, 95% CI: -0.46-5.58, p=0.10). CONCLUSION: Multi-technique work-up, specifically CT and MRI and reporting of vascular radiographic parameters, of RCC patients with IVC tumour thrombus may be useful in predicting IVC wall invasion, thereby allowing appropriate surgical planning and patient education.

Induction therapy with hepatic arterial infusion chemotherapy enhances the efficacy of lenvatinib and pd1 inhibitors in treating hepatocellular carcinoma patients with portal vein tumor thrombosis.

BACKGROUND: Hepatic arterial infusion chemotherapy (HAIC) with fluorouracil, leucovorin, and oxaliplatin (FOLFOX), lenvatinib and programmed death receptor-1 signaling inhibitors (PD1s) all alone have been proven effective in treating advanced hepatocellular carcinoma (HCC), yet the efficacy and safety of the tri-combination therapy in treating HCC patients with portal vein tumor thrombosis (PVTT) remains unknown. METHODS: In this retrospective study, HCC patients with PVTT received either induction therapy of HAIC and lenvatinib plus PD1s in the initial period of treatment and then dual maintenance therapy of lenvatinib and PD1s (HAIC-Len-PD1) or continuous lenvatinib combined with PD1s (Len-PD1). RESULTS: In total, 53 and 89 patients were enrolled into the Len-PD1 group and HAIC-Len-PD1 group, respectively. The median overall survival times were 13.8 months in the Len-PD1 group and 26.3 months in the HAIC-Len-PD1 group (hazard ratio (HR) = 0.43, P < 0.001). The median progression-free survival (PFS) time was significantly longer in the HAIC-Len-PD1 group than in the Len-PD1 group (11.5 months versus 5.5 months, HR = 0.43, P < 0.001). Induction therapy showed an objective response rate (ORR) 3 times higher than lenvatinib combined with PD1s therapy (61.8% versus 20.8%, P < 0.001), and exhibited inspiring intra- and extra-hepatic tumor control ability. Induction therapy led to more adverse events than lenvatinib combined with PD1s therapy, most of which were tolerable and controllable. CONCLUSION: The induction therapy of FOLFOX-HAIC and lenvatinib plus PD1s is an effective and safe treatment for HCC patients with PVTT. The concept of induction therapy could be applied to other local-regional treatments and drugs combinations in HCC management.

Comparison of survival benefit between salvage surgery after conversion therapy versus surgery alone for hepatocellular carcinoma with portal vein tumor thrombosis: a propensity score analysis.

BACKGROUND: Salvage surgery after conversion therapy with a combination of tyrosine kinase inhibitor and anti-programmed death-1 antibody has shown improved survival benefits in patients with hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). We aimed to compare the survival benefits in a retrospective cohort of patients with HCC with PVTT who underwent salvage surgery after conversion therapy and surgery alone. METHODS: From January 2015 to October 2021, we selected patients diagnosed with HCC with PVTT who underwent liver resection at Chinese PLA General Hospital. The primary endpoint in the comparison of survival benefits between conversion therapy and surgery-alone groups was recurrence-free survival. Propensity score matching was applied to reduce any potential bias in the study. RESULTS: The 6-, 12-, and 24-month recurrence-free survival rates in the conversion and surgery alone groups were 80.3% vs 36.5%, 65.4% vs 29.4%, and 56% vs 21%, respectively. On multivariable Cox regression analyses, conversion therapy significantly reduced HCC-related mortality and HCC recurrence rates compared with surgery alone. CONCLUSIONS: For patients with HCC with PVTT, surgery after conversion therapy is in relationship with increased survival in comparison with surgery alone.

Surgical Management of Renal Cell Carcinoma with Inferior Vena Cava Tumor Thrombus.

Most kidney cancers are primary renal cell carcinomas (RCC) of clear cell histology. RCC is unique in its ability to invade into contiguous veins - a phenomenon terms venous tumor thrombus. Surgical resection is indicated for most patients with RCC and an inferior vena cava (IVC) thrombus in the absence of metastatic disease. Resection also has an important role in selected patients with metastatic disease. In this review, we discuss the comprehensive management of the patient with RCC with IVC tumor thrombus, emphasizing a multidisciplinary approach to the surgical techniques and perioperative management.

Portal Vein Resection in Pancreatic Cancer Surgery: Risk of Thrombosis and Radicality Determine Survival.

OBJECTIVE: To evaluate the outcomes of pancreatic cancer [pancreatic ductal adenocarcinoma (PDAC)] surgery with concomitant portal vein resection (PVR), focusing on the PVR type according to the International Study Group of Pancreatic Surgery (ISGPS). BACKGROUND: Surgery offers the only chance for cure in PDAC. PVR is often performed for borderline or locally advanced tumors. METHODS: Consecutive patients with PDAC operated between January 2006 and January 2018 were included. Clinicopathologic characteristics and outcomes were analyzed and tested for survival prediction. RESULTS: Of 2265 PDAC resections, 1571 (69.4%) were standard resections and 694 (30.6%) were resections with PVR, including 149 (21.5%) tangential resections with venorrhaphy (ISGPS type 1), 21 (3.0%) resections with patch reconstruction (type 2), 491 (70.7%) end-to-end anastomoses (type 3), and 33 (4.8%) resections with graft interposition (type 4). The 90-day mortality rate was 2.6% after standard resection and 6.3% after resection with PVR ( P <0.0001). Postoperative portal vein thrombosis and pancreas-specific surgical complications most frequently occurred after PVR with graft interposition (21.2% and 48.5%, respectively). In multivariable analysis, age 70 years and above, ASA stages 3/4, increased preoperative serum carbohydrate antigen 19-9, neoadjuvant treatment, total pancreatectomy, PVR, higher UICC stage, and R+ resections were significant negative prognostic factors for overall survival. Radical R0 (>1 mm) resection resulted in 23.3 months of median survival. CONCLUSIONS: This is the largest single-center, comparative cohort study of PVR in PDAC surgery, showing that postoperative morbidity correlates with the reconstruction type. When radical resection is achieved, thrombosis risk is outweighed by beneficial overall survival times of nearly 2 years.

Histopathological Features of Cancer-Associated Venous Thromboembolism: Presence of Intrathrombus Cancer Cells and Prothrombotic Factors.

BACKGROUND: Cancer-associated venous thromboembolism (VTE) is a critical complication in patients with cancer. However, the pathological findings of VTE are limited. Here, we investigated the histopathological features of cancer-associated VTE in human autopsy cases. METHODS: We clinically examined the autopsy cases of VTE with (n=114) and without cancer (n=66) and immunohistochemically analyzed the expression of prothrombotic factors in intrathrombus cancer cells, the thrombus contents of erythrocytes, fibrin, platelets, citrullinated histone H3, and degree of organization. RESULTS: Vascular wall invasion or small cell clusters of cancer cells was observed in thrombi in 27.5% of deep vein thrombosis and 25.9% of pulmonary embolism cases. The majority of the cancer cells in deep vein thrombi appeared to be invading the vessel wall, whereas the majority of pulmonary thrombi had cancer cell clusters, consistent with embolization via blood flow. These cancer cells were immunohistochemically positive for TF (tissue factors) or podoplanin in up to 88% of VTE cases. The frequency of TF-positive monocyte/macrophages in thrombi was higher in cancer-associated VTE than that in VTE without cancer. Citrullinated histone H3 was predominantly observed in the early stages of organizing thrombi. There was no significant difference in thrombus components between VTE with cancer and without cancer groups. CONCLUSIONS: Vascular wall invasion or cancer cell clusters in thrombi might influence thrombogenesis of cancer-associated VTE. TF and podoplanin in cancer cells and in monocyte/macrophages may induce coagulation reactions and platelet aggregation. Neutrophil extracellular traps may play a role in the early stages of VTE, regardless of cancer status.