Vascular endothelial growth factor (VEGF) targeting therapy for persistent, recurrent, or metastatic cervical cancer.

BACKGROUND: Cervical cancer ranks as the fourth leading cause of death from cancer in women. Historically, women with metastatic or recurrent cervical cancer have had limited treatment options. New anti-angiogenesis therapies, such as vascular endothelial growth factor (VEGF) targeting agents, offer an alternative strategy to conventional chemotherapy; they act by inhibiting the growth of new blood vessels, thereby restricting tumour growth by blocking the blood supply. OBJECTIVES: To assess the benefits and harms of VEGF targeting agents in the management of persistent, recurrent, or metastatic cervical cancer. SEARCH METHODS: We performed searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, online registers of clinical trials, and abstracts of scientific meetings up until 27 May 2020. SELECTION CRITERIA: We examined randomised controlled trials (RCTs) that evaluated the use of VEGF targeting agents alone or in combination with conventional chemotherapy or other VEGF targeting agents. DATA COLLECTION AND ANALYSIS: Three review authors independently screened the results of search strategies, extracted data, assessed risk of bias, and analysed data according to the standard methods expected by Cochrane. The certainty of evidence was assessed via the GRADE approach. MAIN RESULTS: A total of 1634 records were identified. From these, we identified four studies with a total of 808 participants for inclusion. We also identified two studies that were awaiting classification and nine ongoing studies. Bevacizumab plus chemotherapy versus chemotherapy Treatment with bevacizumab plus chemotherapy may result in lower risk of death compared to chemotherapy alone (hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.62 to 0.95; 1 study, 452 participants; low-certainty evidence). However, there are probably more specific adverse events when compared to chemotherapy alone, including gastrointestinal perforations or fistulae (risk ratio (RR) 18.00, 95% CI 2.42 to 133.67; 1 study, 440 participants; moderate-certainty evidence); serious thromboembolic events (RR 4.5, 95% CI 1.55 to 13.08; 1 study, 440 participants; moderate-certainty evidence); and hypertension (RR 13.75, 95% CI 5.07 to 37.29; 1 study, 440 participants; moderate-certainty evidence). There may also be a higher incidence of serious haemorrhage (RR 5.00, 95% CI 1.11 to 22.56; 1 study, 440 participants; low-certainty evidence). In addition, the incidence of serious adverse events is probably higher (RR 1.44, 95% CI 1.16 to 1.79; 1 study, 439 participants; moderate-certainty evidence). The incremental cost-effectiveness ratio was USD 295,164 per quality-adjusted life-year (1 study, 452 participants; low-certainty evidence). Cediranib plus chemotherapy versus chemotherapy Treatment with cediranib plus chemotherapy may or may not result in similar risk of death when compared to chemotherapy alone (HR 0.94, 95% CI 0.53 to 1.65; 1 study, 69 participants; low-certainty evidence). We found very uncertain results for the incidences of specific adverse events, including gastrointestinal perforations or fistulae (RR 3.27, 95% CI 0.14 to 77.57; 1 study, 67 participants; very low-certainty evidence); serious haemorrhage (RR 5.45, 95% CI 0.27 to 109.49; 1 study, 67 participants; very low-certainty evidence); serious thromboembolic events (RR 3.41, 95% CI 0.14 to 80.59; 1 study, 60 participants; very low-certainty evidence); and serious hypertension (RR 0.36, 95% CI 0.02 to 8.62; 1 study, 67 participants; very low-certainty evidence). In addition, there may or may not be a similar incidence of serious adverse events compared to chemotherapy alone (RR 1.15, 95% CI 0.75 to 1.78; 1 study, 67 participants; low-certainty evidence). Apatinib plus chemotherapy or chemotherapy/brachytherapy versus chemotherapy or chemotherapy/brachytherapy Treatment with apatinib plus chemotherapy or chemotherapy/brachytherapy may or may not result in similar risk of death compared to chemotherapy alone or chemotherapy/brachytherapy alone (HR 0.90, 95% CI 0.51 to 1.60; 1 study, 52 participants; low-certainty evidence). However, hypertension events may occur at a higher incidence as compared to chemotherapy alone or chemotherapy/brachytherapy alone (RR 5.14, 95% CI 1.28 to 20.73; 1 study, 52 participants; low-certainty evidence). Pazopanib plus lapatinib versus lapatinib Treatment with pazopanib plus lapatinib may result in higher risk of death compared to lapatinib alone (HR 2.71, 95% CI 1.16 to 6.31; 1 study, 117 participants; low-certainty evidence). We found very uncertain results for the incidences of specific adverse events, including gastrointestinal perforations or fistulae (RR 2.00, 95% CI 0.19 to 21.59; 1 study, 152 participants; very low-certainty evidence); haemorrhage (RR 2.00, 95% CI 0.72 to 5.58; 1 study, 152 participants; very low-certainty evidence); and thromboembolic events (RR 3.00, 95% CI 0.12 to 72.50; 1 study, 152 participants; very low-certainty evidence). In addition, the incidence of hypertension events is probably higher (RR 12.00, 95% CI 2.94 to 49.01; 1 study, 152 participants; moderate-certainty evidence). There may or may not be a similar incidence of serious adverse events as compared to lapatinib alone (RR 1.45, 95% CI 0.94 to 2.26; 1 study, 152 participants; low-certainty evidence). Pazopanib versus lapatinib Treatment with pazopanib may or may not result in similar risk of death as compared to lapatinib (HR 0.96, 95% CI 0.67 to 1.38; 1 study, 152 participants; low-certainty evidence). We found very uncertain results for the incidences of specific adverse events, including gastrointestinal perforations or fistulae (RR 1.03, 95% CI 0.07 to 16.12; 1 study, 150 participants; very low-certainty evidence); haemorrhage (RR 1.03, 95% CI 0.31 to 3.40; 1 study, 150 participants; very low-certainty evidence); and thromboembolic events (RR 3.08, 95% CI 0.13 to 74.42; 1 study, 150 participants; very low-certainty evidence). In addition, the incidence of hypertension events is probably higher (RR 11.81, 95% CI 2.89 to 48.33; 1 study, 150 participants; moderate-certainty evidence). The risk of serious adverse events may or may not be similar as compared to lapatinib (RR 1.31, 95% CI 0.83 to 2.07; 1 study, 150 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: We found low-certainty evidence in favour of the use of bevacizumab plus chemotherapy. However, bevacizumab probably increases specific adverse events (gastrointestinal perforations or fistulae, thromboembolic events, hypertension) and serious adverse events. We found low-certainty evidence that does not support the use of cediranib plus chemotherapy, apatinib plus chemotherapy, apatinib plus chemotherapy/brachytherapy, or pazopanib monotherapy. We found low-certainty evidence suggesting that pazopanib plus lapatinib worsens outcomes. The VEGF inhibitors apatinib and pazopanib may increase the probability of hypertension events.

Preoperative transarterial embolization of a recurrent orbital solitary fibrous tumor with significant hypervascularity: a case report.

BACKGROUND: Orbital solitary fibrous tumors (SFTs) are rare neoplasms. Recurrent, hypervascular, malignant variations of orbital SFTs have recently been noted and can present a surgical challenge. CASE PRESENTATION: We describe a case of a 53-year-old Chinese woman with a history of a resected orbital SFT. She presented with proptosis, limited eyeball movement, and visual loss in the right eye, suggestive of a recurrent SFT. Ocular examination with multimodal imaging revealed a large, nonpulsatile, noncompressible, hypervascular mass behind the eyeball. The patient underwent preoperative transarterial embolization of the main blood supply to the tumor in order to control intraoperative blood loss, followed by ocular enucleation to optimize exposure and enable complete resection of the tumor. Embolization of the right ophthalmic artery and the distal branch of the right internal maxillary artery caused an immediate, substantial reduction of vascular flow, which allowed us to enucleate the eyeball and resect the tumor with minimal blood loss and no complications. CONCLUSIONS: Our case is so far the first Chinese case of successful preoperative embolization of the main blood supply to a large, recurrent, hypervascular orbital SFT. This case also described a different surgical approach to achieve total removal of an orbital SFT without osteotomy.

Targeting vasculogenic mimicry by phytochemicals: A potential opportunity for cancer therapy.

Vasculogenic mimicry (VM) is regarded as a process where very aggressive cancer cells generate vascular-like patterns without the presence of endothelial cells. It is considered as the main mark of malignant cancer and has pivotal role in cancer metastasis and progression in various types of cancers. On the other hand, resistance to the antiangiogenesis therapies leads to the cancer recurrence. Therefore, development of novel chemotherapies and their combinations is urgently needed for abolition of VM structures and also for better tumor therapy. Hence, identifying compounds that target VM structures might be superior therapeutic factors for cancers treatment and controlling the recurrence and metastasis. In recent times, naturally occurring compounds, especially phytochemicals have obtained great attention due to their safe properties. Phytochemicals are also capable of targeting VM structure and also their main signaling pathways. Consequently, in this review article, we illustrated key signaling pathways in VM, and the phytochemicals that affect these structures including curcumin, genistein, lycorine, luteolin, columbamine, triptolide, Paris polyphylla, dehydroeffusol, jatrorrhizine hydrochloride, grape seed proanthocyanidins, resveratrol, isoxanthohumol, dehydrocurvularine, galiellalactone, oxacyclododecindione, brucine, honokiol, ginsenoside Rg3, and norcantharidin. The recognition of these phytochemicals and their safety profile may lead to new therapeutic agents' development for VM elimination in different types of tumors.

Serum metabolites may be useful markers to assess vascular invasion and identify normal alpha-fetoprotein in hepatocellular carcinoma undergoing liver resection: a pilot study.

PURPOSE: Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver with a dismal prognosis. Vascular invasion, among others, is the most robust indicator of postoperative recurrence and overall survival after liver resection for HCC. Few studies to date have attempted to search for effective markers to predict vascular invasion before the operation. The current study would examine the plasma metabolic profiling via 1H-NMR of HCC patients undergoing liver resection and aim to search for potential biomarkers in the early detection of HCC with normal alpha-fetoprotein (AFP) and the diagnosis of vascular invasion preoperatively. MATERIALS AND METHODS: HCC patients scheduled to receive liver resections for their HCC were recruited and divided into two separate groups, investigation cohort and validation cohort. Their preoperative blood samples were collected and subjected to a comprehensive metabolomic profiling using 1H-nuclear magnetic resonance spectroscopy (NMR). RESULTS: There were 35 HCC patients in the investigation group and 22 patients in the validation group. Chronic hepatitis B remained the most common etiology of HCC, followed by chronic HCV infection. The two study cohorts were essentially comparable in terms of major clinicopathological variables. After 1H-nuclear NMR analysis, we found in the investigation cohort that HCC with normal alpha-fetoprotein (AFP < 15 ng/mL) had significantly higher serum level of O-acetylcarnitine than those with higher AFP (AFP ≥ 15 ng/mL, P = 0.025). In addition, HCC with microscopic vascular invasion (VI) had significantly higher preoperative serum level of formate than HCC without microscopic VI (P = 0.023). These findings were similar in the validation cohort. CONCLUSION: A comprehensive metabolomic profiling of HCC demonstrated that serum metabolites may be utilized to assist the early diagnosis of AFP-negative HCC patients and recognition of microvascular invasion in order to facilitate preoperative surgical planning and postoperative follow-up. Further, larger scale prospective studies are warranted to consolidate our findings.

Microvascular Invasion as a Predictor of Response to Treatment with Sorafenib and Transarterial Chemoembolization for Recurrent Intermediate-Stage Hepatocellular Carcinoma.

Background The evidence of combining sorafenib with transarterial chemoembolization (TACE) for intermediate-stage recurrent hepatocellular carcinoma (HCC) is limited. Patient responses to this treatment varied because of the heterogeneous nature of intermediate-stage recurrent HCC, making it important to identify patients who are most likely to benefit from this combination therapy. Purpose To compare sorafenib administered in combination with TACE versus TACE alone in the treatment of recurrent intermediate-stage HCC after initial hepatectomy and to determine the relationship of microvascular invasion (MVI) to survival. Materials and Methods In this retrospective multicenter study, 3652 consecutive patients were found to have intrahepatic recurrences after initial hepatectomy of primary HCC from January 2010 to December 2016. Of these, 260 patients with intermediate-stage recurrent HCC underwent combination treatment with sorafenib and TACE or TACE alone. Overall survival (OS) and progression-free survival (PFS) were compared between these two treatments according to MVI status by using log-rank tests. Results A total of 128 patients were administered combination therapy (mean age, 55 years ± 7.6 [standard deviation]; 107 men) and 132 patients were administered TACE alone (mean age, 56 years ± 8.3; 110 men). The 5-year OS and PFS were higher in the combination group than in the TACE group (OS: 38.9% vs 20.5%, respectively, P = .01; PFS, 37.5% vs 18.7%, respectively, P = .003). For patients with MVI-positive lesions, the median OS and PFS after combination treatment (n = 55) were longer than those after TACE alone (n = 72; OS: 17.2 months vs 12.1 months, respectively, P = .02; PFS: 17.0 months vs 11.0 months, respectively, P = .02). Multivariable analysis showed that tumor number, MVI status, and treatment allocation were significant predictors of OS and PFS, whereas tumor size was a prognostic factor for PFS. Conclusion Patients with recurrent intermediate-stage hepatocellular carcinoma and lesions positive for microvascular invasion (MVI) had longer survival times by using a combined treatment of sorafenib with transarterial chemoembolization (TACE) compared with TACE alone; patients with MVI-negative lesions did not show survival benefit from combined therapy. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Malloy in this issue.

Association of Preoperative Hypercoagulability with Poor Prognosis in Hepatocellular Carcinoma Patients with Microvascular Invasion After Liver Resection: A Multicenter Study.

BACKGROUND: Microvascular invasion (MVI) predicts poor prognosis in patients with hepatocellular carcinoma (HCC). HCC patients with hypercoagulability are prone to develop thrombosis; however, the relationship between preoperative coagulability state, as reflected by the international normalized ratio (INR) level, and MVI remains unclear. METHODS: From January 2009 to December 2012, HCC patients who underwent R0 liver resection (LR) from four cancer centers entered into this study. The overall survival (OS) and recurrence-free survival (RFS) rates were compared using the Kaplan-Meier method and Cox regression analysis. RESULTS: Of the 2509 HCC patients who were included into this study, 1104 were found to have MVI in the resected specimens. These patients were divided into the low (n = 151), normal (n = 796), and high (n = 157) INR subgroups based on the preoperative INR levels. The low INR subgroup had a significantly higher incidence of MVI than the normal or high INR subgroups (61.6% vs. 41.6% vs. 44.6%; p < 0.001). HCC patients with MVI were significantly more likely to have a low preoperative INR level (p < 0.001); the INR level (p < 0.001) was an independent risk factor of OS and RFS. HCC patients with MVI in the low INR subgroup had significantly worse RFS and OS than the normal or high INR subgroups (median RFS 13.5 vs. 20.2 vs. 21.6 months, p < 0.001; median OS 35.5 vs. 59.5 vs. 57.0 months, p < 0.001). CONCLUSIONS: Preoperative hypercoagulability was associated with poor long-term prognosis in HCC patients with MVI after R0 LR.

Angiotropism in recurrent cutaneous squamous cell carcinoma: Implications for regional tumor recurrence and extravascular migratory spread.

Extravascular migratory metastasis is a form of cancer metastasis in which tumor cells spread by tracking along the abluminal aspect of vessel walls without breaking the vascular endothelial lining or intraluminal invasion. This phenomenon has been extensively described in melanoma and is being increasingly recognized in other neoplasms. Various modalities of treatment, including radiation-, chemo-, targeted-, and immune- therapies may potentially induce angiotropic behavior in neoplastic cells. Although there is a risk for tumor recurrence and metastasis, angiotropism may be under-recognized and is rarely reported. Here, we report a case of recurrent poorly-differentiated acantholytic squamous cell carcinoma of the scalp with extensive perineural invasion, previously treated with multiple therapies. There was multifocal extravascular cuffing of neoplastic cells around and focally involving the walls of small to medium-caliber blood vessels within and surrounding the tumor, without obvious tumor intravasation. In addition, small subtle nests of neoplastic keratinocytes were noted along the abluminal aspect of a large-caliber deep dermal blood vessel in an en-face margin, away from the main tumor mass. Such involvement can be difficult to identify; and thus, may be missed particularly during intra-operative frozen section evaluation, leading to false-negative margins and is therefore, a diagnostic pitfall.

Vascular architecture mapping for early detection of glioblastoma recurrence.

OBJECTIVE: Treatment failure and inevitable tumor recurrence are the main reasons for the poor prognosis of glioblastoma (GB). Gross-total resection at repeat craniotomy for GB recurrence improves patient overall survival but requires early and reliable detection. It is known, however, that even advanced MRI approaches have limited diagnostic performance for distinguishing tumor progression from pseudoprogression. The novel MRI technique of vascular architectural mapping (VAM) provides deeper insight into tumor microvascularity and neovascularization. In this study the authors evaluated the usefulness of VAM for the monitoring of GB patients and quantitatively analyzed the features of neovascularization of early- and progressed-stage GB recurrence. METHODS: In total, a group of 115 GB patients who received overall 374 follow-up MRI examinations after standard treatment were retrospectively evaluated in this study. The clinical routine MRI (cMRI) protocol at 3 Tesla was extended with the authors' experimental VAM approach, requiring 2 minutes of extra time for data acquisition. Custom-made MATLAB software was used for calculation of imaging biomarker maps of macrovascular perfusion from perfusion cMRI as well as of microvascular perfusion and architecture from VAM data. Additionally, cMRI data were analyzed by two board-certified radiologists in consensus. Statistical procedures included receiver operating characteristic (ROC) analysis to determine diagnostic performances for GB recurrence detection. RESULTS: Overall, cMRI showed GB recurrence in 89 patients, and in 28 of these patients recurrence was detected earlier with VAM data, by 1 (20 patients) or 2 (8 patients) follow-up examinations, than with cMRI data. The mean time difference between recurrence detection with VAM and cMRI data was 147 days. During this time period the mean tumor volume increased significantly (p < 0.001) from 9.7 to 26.8 cm3. Quantitative analysis of imaging biomarkers demonstrated microvascular but no macrovascular hyperperfusion in early GB recurrence. Therefore, ROC analysis revealed superior diagnostic performance for VAM compared with cMRI. CONCLUSIONS: This study demonstrated that the targeted assessment of microvascular features using the VAM technique provided valuable information about early neovascularization activity in recurrent GB that is complementary to perfusion cMRI and may be helpful for earlier and more precise monitoring of patients suffering from GB. This VAM approach is compatible with existing cMRI protocols. Prospective clinical trials are necessary to investigate the clinical usefulness and potential benefit of increased overall survival with the use of VAM in patients with recurrent GB.

A phase II evaluation of sunitinib in the treatment of persistent or recurrent clear cell ovarian carcinoma: An NRG Oncology/Gynecologic Oncology Group Study (GOG-254).

OBJECTIVES: To determine the efficacy and tolerability of sunitinib in recurrent or persistent clear cell ovarian cancer patients. METHODS: All patients had one or two prior regimens with measurable disease. Tumors were at least 50% clear cell histomorphology and negative for WT-1 antigen and estrogen receptor expression by immunohistochemistry. Sunitinib 50 mg per day for 4 weeks was administered in repeated 6-week cycles until disease progression or prohibitive toxicity. Primary end points were progression-free survival (PFS) at 6 months and clinical response. The study was designed to determine if the drug had a response rate of at least 20% or 6-month PFS of at least 25%. RESULTS: Of 35 patients enrolled, 30 were treated and eligible (median age: 51, range: 27-73). Twenty-five (83%) were White, 4 (13%) Asian, and 1 (3%) unknown. The majority 28 (83%) patients, underwent ≤3 but 2 (7%) had 16 courses of study therapy. Five (16.7%) patients had PFS ≥6 months (90% CI: 6.8%-31.9%). Two (6.7%) patients had a partial or complete response (90% CI: 1.2%-19.5%). The median PFS was 2.7 months. The median overall survival was 12.8 months. The most common grade 3 adverse events were fatigue (4), hypertension (4), neutropenia (4), anemia (3), abdominal pain (3), and leukopenia (3). Grade 4-5 adverse events included: thrombocytopenia (5), anemia (2), acute kidney Injury (1), stroke (1), and allergic reaction (1). CONCLUSION: Sunitinib demonstrated minimal activity in the second- and third-line treatment of persistent or recurrent clear cell ovarian carcinoma. ClinicalTrials.gov number, NCT00979992.

[A Resected Case of Adenosquamous Carcinoma of Pancreas That Relapsed in Remnant Pancreas].

A 70's man underwent subtotal stomach preserving pancreatoduodenectomy(SSPPD)for pancreatic head cancer. The pathological diagnosis was adenosquamous carcinoma(ASC)of the pancreas. Two months after surgery, a recurrent tumor in the remnant pancreas was confirmed with a CT scan and suspected to be ASC by endoscopic ultrasound-guided fine needle aspiration(EUS-FNA). As the recurrent lesion was limited in the pancreas, total remnant pancreatectomy(TP)was performed 4 months after SSPPD. The final pathological diagnosis was ASC. Two months after TP, liver and para-aortic lymph node metastases were revealed. The patient has been alive for 14 months after SSPPD with chemotherapy. Because of its rarity, it is difficult to implement treatment plans for recurrent ASC in the remnant pancreas.

The influences of peritumoral lymphatic invasion and vascular invasion on the survival and recurrence according to the molecular subtypes of breast cancer.

PURPOSE: We aimed to compare the influences of lymphatic invasion (LI) and vascular invasion (VI) on survival and recurrence according to the molecular subtypes of breast cancer. METHODS: We retrospectively analyzed data on 820 breast cancer patients and assessed overall survival (OS) and disease-free survival (DFS) according to LI and VI using the Kaplan-Meier estimator and the Cox proportional hazards model. RESULTS: Both positive LI and positive VI showed inferior OS and DFS compared with negative LI and negative VI (all p < 0.001). Both positive LI and positive VI showed higher local, regional, and distant recurrence rates (p = 0.002 for regional recurrence of VI, p < 0.001 for all the others). Although LI was a significant independent predictor of OS (hazard ratio [HR] 1.927; 95% confidence interval [CI] 1.046-3.553) and DFS (HR 1.815; 95% CI 1.063-3.096), VI was not in the multivariate analyses. Regarding OS, both positive LI and positive VI showed worse survival rates in the luminal A (p = 0.016 and p = 0.024, respectively) and triple negative subtypes (both p < 0.001). Regarding DFS, LI was a significant prognosticator in the luminal A and triple negative (both p < 0.001) subtypes. VI was a significant prognosticator across all molecular subtypes, although the prognostic impact was most prominent in the luminal A subtype (p < 0.001). CONCLUSIONS: Both LI and VI were significant, unfavorable prognostic factors of OS and DFS, especially in the luminal A and triple negative breast cancer subtypes. Although LI was a significant independent predictor of OS and DFS, VI was not after the multivariate analyses.

Isolated Limb Perfusion for Melanoma is Safe and Effective in Elderly Patients.

BACKGROUND: Data on isolated limb perfusion (ILP) in elderly melanoma patients are scarce. We aimed to evaluate the efficacy and safety of ILP in our institutional cohort of melanoma patients. METHODS: We performed retrospective analysis of stage IIIB/C melanoma patients who underwent ILP for melanoma in-transit metastases (ITMs) in our institution between 2000 and 2016. Normothermic ILP was performed with either melphalan or melphalan and tumor necrosis factor. Baseline and treatment characteristics, locoregional progression-free survival (LPFS) and melanoma-specific survival (MSS) were assessed and prognostic factors for response, recurrence, and survival were analyzed using univariable and multivariable analysis. RESULTS: Overall, 91 patients were included in this study. Based on the median age of 70 years, we split patients into younger and elderly groups. No differences in response rates were observed between age groups, with an overall response rate of 81% and complete response (CR) rate of 47%. LPFS did not differ between age groups, and median LPFS was 16 months for patients with a CR. Median MSS was 38 months and differed between younger (45 months) and elderly patients (18 months). Toxicity was generally mild and did not differ between age groups. Two patients (2.2%) suffered Wieberdink IV toxicity, while no patients required amputation because of severe toxicity. CR was prognostic for improved LPFS and MSS, while patients >70 years of age and patients with stage IIIC disease had a higher risk of melanoma-specific death. CONCLUSIONS: Because of its safety profile and high CR rates, ILP is a viable option for patients with bulky or multiple melanoma ITMs, including elderly (>70 years of age) patients.

Radiofrequency Ablation of Hepatic Tumor: Subjective Assessment of the Perilesional Vascular Network on Contrast-Enhanced Computed Tomography Before and After Ablation Can Reliably Predict the Risk of Local Recurrence.

OBJECTIVE: To determine whether simple, subjective analysis of the perilesional vascular network can predict the risk of local recurrence after radiofrequency ablation (RFA) of liver malignancies on contrast-enhanced computed tomography (CECT). METHODS: Contrast-enhanced computed tomography's 103 patients (59 men and 44 women; mean age, 63 years (range, 31-84 years) with 134 lesions who underwent RFA between 2000 and 2010 were retrospectively analyzed. The primary tumors include colorectal carcinoma (58 patients), hepatocellular carcinoma (n = 13), breast carcinoma (n = 8), neuroendocrine tumor (n = 5), and others (n = 19). Three blinded radiologists independently reviewed the CECT (a triple phase liver protocol for hypervascular tumors and a single phase for the hypovascular tumors) before and 6 weeks after RFA and subjectively estimated the width of the ablative margin on a 3-point scale (optimal, 1; suboptimal, 2; and residual tumor, 3). Local recurrence was determined on follow-up CECT. RESULTS: The consensus score was 1 in 94, 2 in 28, and 3 in 12 lesions. κ among readers was 0.75. Local recurrence occurred in 3 lesions with a score of 1 and 12 lesions with a score of 2. The consensus score was a significant univariate predictor of local recurrence. CONCLUSIONS: Subjective estimation of the width of ablative margin can reliably predict the risk of local recurrence.

Platelet to lymphocyte ratio and red cell distribution width as prognostic factors for survival and recurrence in patients with oral cancer.

Although platelet to lymphocyte ratio (PLR) and red cell distribution width (RDW) have been reported as good predictors for survival outcomes in various cancers, there is limited data supporting these as reliable predictors in oral cancer. This study thus aimed to assess the prognostic value of PLR and RDW markers in predicting survival and recurrence rates in patients with oral cancer. The records of 374 oral cancer patients treated with curative intent over a 7-year period (2009-2015) were reviewed. Survival and recurrence outcomes were compared between those with low and high PLR (≤135 vs. >135) and those with low and high RDW (≤14.05 vs. >14.05) using hazard ratios (HR). The 5-year disease-specific survival was significantly higher and recurrence rate significantly lower among the low PLR group compared to the high PLR group (65.7 vs. 37.6%; p < 0.001 and 34.4 and 57.5%; p < 0.001), respectively. There were no significant differences between the low and high RDW groups for disease-specific survival (53.6 vs. 54.7%, p = 0.408) and recurrence (40.0% vs. 53.8%, p = 0.079). Multivariate analysis showed that PLR was associated with disease-specific survival (HR = 2.05, p < 0.001) and recurrence (HR = 1.69, p < 0.005) after adjusting for other factors, but not RDW. High PLR shows promise as a prognostic predictor for poor survival and recurrence in patients with oral cancer, but further studies are required. RDW has no prognostic value on any outcome.

[PET/CT and biochemical recurrence of prostate adenocarcinoma: Added value of 68Ga-PSMA-11 when 18F-fluorocholine is non-contributive]. / TEP/TDM et récidive biologique d'adénocarcinome prostatique : apport du 68Ga-PSMA-11 lorsque la 18F-fluorocholine n'est pas contributive.

INTRODUCTION: Since April 201, we have introduced PET/CT using a ligand of prostate-specific membrane antigen labeled with gallium-68 (PSMA-11). We aimed to evaluate its positivity rate and impact in patients presenting biochemical recurrence of prostate cancer whose 18F-fluorocholine (FCH) PET/CT was non-contributive. PATIENTS AND METHOD: Patients were prospectively included between April and December 2016. PET/CT was performed 60min after injection of 2MBq/kg of body mass of 68Ga-PSMA-11. Three anatomical areas were considered: prostatic lodge, pelvic lymph nodes and distant locations. The impact of PSMA-11 PET/CT was assessed by comparing changes in therapeutic strategy decided during multidisciplinary meeting. RESULTS: Thirty-three patients were included. The mean PSA serum level measured on the month of the PSMA-11 PET/CT was 2,8ng/mL. Twenty-five (76%) PSMA-11 PET/CT were positive, 7 (21%) negative and 1 (3%) equivocal. Of 11 patients whose FCH PET/CT showed equivocal foci, PSMA-11 PET/CT confirmed those foci in 5 cases. Follow-up was available for 18 patients (55%). PSMA-11 PET/CT results led to a change in management in 12 patients (67%). CONCLUSION: 68Ga-PSMA-11 PET/CT is useful in detecting recurrence of prostate cancer, by identifying residual disease which was not detected on other imaging modalities and by changing management of 2 patients out of 3. LEVEL OF EVIDENCE: 5.

Damage effect of high-intensity focused ultrasound on breast cancer tissues and their vascularities.

BACKGROUND: High-intensity focused ultrasound (HIFU) is a noninvasive therapy that makes entire coagulative necrosis of a tumor in deep tissue through the intact skin. There are many reports about the HIFU's efficacy in the treatment of patients with breast cancer, but randomized clinical trials are rare which emphasize on the systematic assessment of histological changes in the ablated tumor vascularities, while clinical trials utilizing bevacizumab and other anti-angiogenic drugs in breast cancer have not demonstrated overall survival benefit. The purpose of this study is to evaluate the damage effect of HIFU on breast cancer tissues and their vascularities. METHODS: Randomized clinical trials and the modality of treat-and-resect protocols were adopted. The treated outcome of all patients was followed up in this study. The target lesions of 25 breast cancer patients treated by HIFU were observed after autopsy. One slide was used for hematoxylin-eosin (HE) staining, one slide was used for elastic fiber staining by Victoria blue and Ponceau's histochemical staining, and one slide was used for vascular endothelial cell immunohistochemical staining with biotinylated-ulex europaeus agglutinin I (UEAI); all three slides were observed under an optical microscopic. One additional slide was systematically observed by electron microscopy. RESULTS: The average follow-up time was 12 months; no local recurrence or a distant metastatic lesion was detected among treated patients. Histological examination of the HE slides indicated that HIFU caused coagulative necrosis in the tumor tissues and their vascularities: all feeder vessels less than 2 mm in diameter in the insonated tumor were occluded, the vascular elasticity provided by fibrin was lost, the cells were disordered and delaminated, and UEAI staining of the target lesions was negative. Immediately after HIFU irradiation, the tumor capillary ultrastructure was destroyed, the capillary endothelium was disintegrated, the peritubular cells were cavitated, and the plasma membrane was incomplete. CONCLUSIONS: HIFU ablation can destroy all proliferating tumor cells and their growing vascularities simultaneously; this may break interdependent vicious cycle of tumor angiogenesis and neoplastic cell growth that results in infinite proliferation. While it cannot cause tumor resistance to HIFU ablation, it may be a new anti-angiogenic strategy that needs further clinical observation and exploration. Furthermore, the treatment indications of HIFU ablation were reviewed and discussed in this manuscript.

Recurrences in stage II rectal carcinoma after curative resection alone: from the viewpoint of angiogenesis.

BACKGROUND: Angiogenesis plays a pivotal role in malignant tumor progression. The count of blood microvessels of the tumor has been recognized as an indicator of malignant potential of the tumors and provides the ability to predict tumors recurrence. The role endoglin in the Dukes B rectal cancer is still unexplored. The aims of this study were to examine immunohistochemical expression of endoglin in resected rectal cancer and investigate the relationship of tumor recurrence and other clinicopathological variables to the endoglin-assessed microvessel density of the tumor tissue and distal resection margins. METHODS: The study included 95 primary rectal adenocarcinomas, corresponding to 95 distal and 95 proximal resection margin specimens from surgical resection samples. Tumor specimens were paraffin embedded, and immunohistochemical staining for the CD105 endothelial antigen was performed to count CD105-MVD. For exact measurement of the CD105-MVD used, a computer-integrated system Alphelys Spot Browser 2 was used. RESULTS: The MVD was significantly higher in the tumor samples compared with the distal resection margins (p < 0.0001) and the proximal resection margins (p < 0.0001). There was no significant difference in the MVD between distal and proximal resection margins (p = 0.147). The type of surgical resection was a significant factor for determining the recurrence of tumors (p = 0.0104). There was no significant effect of patients' age, gender, tumor location, grade of differentiation, histological tumor type, and the size and depth of tumor invasion on the recurrence of the tumor. The recurrence rate was significantly higher in the low CD105-MVD group of patients than in the high CD105-MVD group of patients (log rank test, p = 0.0406). Result of the multivariate analysis showed that the type of surgery (p = 0.0086), MVD tumors (p = 0.0385), and MVD of proximal resection margin (p = 0.0218) were the independent prognostic factors for the recurrent tumors. CONCLUSIONS: CD105-assessed MVD could help to identify patients with more aggressive disease and increased risk of developing tumor recurrence after surgical treatment in stage II rectal cancer (RC).

Phase II evaluation of dalantercept, a soluble recombinant activin receptor-like kinase 1 (ALK1) receptor fusion protein, for the treatment of recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group Study 0229N.

OBJECTIVE: This two-stage phase II study assessed activity of single agent dalantercept in patients with recurrent/persistent endometrial carcinoma (EMC). METHODS: Eligible patients had persistent/recurrent EMC after 1-2 prior cytotoxic regimens, measurable disease (RECIST 1.1), and GOG performance≤2. Dalantercept 1.2mg/kg subcutaneous was administered once every 3weeks until disease progression (PD)/development of prohibitory toxicity. Primary objectives were to estimate the proportion of patients with persistent/recurrent EMC, who survive progression-free without receiving non-protocol therapy (TPFS) for at least 6months and to estimate the proportion having objective tumor response. RESULTS: All 28 enrolled patients were eligible and evaluable. Median age: 62years. Most common histologies: 32% Grade 1/2 endometrioid and 54% serous tumors. Prior treatment: 1 or 2 regimens in 82% and 18% of patients, respectively. Eighteen patients received prior radiation therapy. Patients received 1-12 cycles of dalantercept, and 46% of patients received ≤2cycles. The most common adverse events (AE) were fatigue, anemia, constipation and peripheral edema. Grade 3/4 AEs occurred in 39% and 4% of patients. One grade 5 gastric hemorrhage in a patient with a history of radiation fibrosis/small bowel obstruction was deemed possibly dalantercept-related. All patients are off study: 86% for PD. No ORs were observed; 57% had stable disease and 11% had TPFS>6 mos. Median progression-free and overall survival: 2.1months (90% CI: 1.4-3.2) and 14.5months (90% CI: 7.0-17.5), respectively. CONCLUSIONS: Dalantercept has insufficient single agent activity in recurrent EMC to warrant further investigation at this dose level and schedule.

p-CREB expression in human meningiomas: correlation with angiogenesis and recurrence risk.

Despite total surgical resection, a percentage of meningiomas do unexpectedly recur. At present the prediction of recurrence risk and the management of recurrent tumours represent major issues in the patients affected by meningiomas. The present study aims at investigating the prognostic value of the expression of the phosphorylated transcription factor cyclic AMP responsive element binding protein (p-CREB) in a series of meningiomas of different histotype and grade. While no p-CREB expression was found in specimens of normal leptomeninges, 71 % of meningiomas in our cohort expressed p-CREB. In addition, nuclear expression of p-CREB was present in the endothelia of tumor vessels in all of the meningiomas, but not in the vessels of the non-neoplastic meninges. High expression of p-CREB was significantly more frequent in meningiomas showing atypical, chordoid or microcystic histotype (P = 0.0003), high histological grade (P < 0.0001), high Ki-67 labeling index (P = 0.0001), high microvessel density counts (P < 0.0001) and high vascular endothelial growth factor expression (P = 0.0113). In addition, high p-CREB expression was significantly associated with the development of recurrences (P = 0.0031) and it was a significant negative, albeit not independent, prognostic factor for disease free survival in patients with meningiomas submitted to complete surgical removal (P = 0.0019). In conclusion, we showed that p-CREB is expressed in human meningiomas and that it represents a significant predictor of recurrence risk in these tumors. Due to its high expression in more aggressive tumors and in the tumor vessels, it may represent a novel therapeutic target in meningiomas.

Angiogenesis-related prognosis in patients with oral squamous cell carcinoma-role of the VEGF +936 C/T polymorphism.

BACKGROUND: The aim of the study was the immunohistological assessment of VEGF-single nucleotide polymorphism (SNP)-related angiogenic activity in oral squamous cell carcinoma (OSCC) in correlation with prognosis. METHODS: Fifty OSCC samples were immunostained with CD31-antibodies. Mean microvessel density (MVD) and staining intensity were determined and associated with clinicopathological/prognostic features as well as with the VEGF +936C/T SNP. RESULTS: A significant higher MVD could be seen for T3 and T4 compared with T1 and T2, N > 0 vs. N0 as well as G3-G4 vs. G1-G2 OSCCs (all: P < 0.05). A higher MVD was also associated with increased and earlier rates of local relapses, more metastases, and a significant decreased overall as well as disease-free survival (all: P < 0.05). When comparing T1 and T2 samples with +936-T-allele with T 1&2 samples without this allele, staining intensity was significantly increased (P = 0.002). CONCLUSIONS: Angiogenesis influences local as well as distant growth of OSCCs with a significant correlation between prognostic parameters. The correlation between VEGF +936-T-allele and increased CD31 immunostain needs further confirmation.