Hereditary hemorrhagic telangiectasia (HHT): a practical guide to management

Hereditary hemorrhagic telangiectasia (HHT), the second most common inherited bleeding disorder, is associated with the development of malformed blood vessels. Abnormal blood vessels may be small and cutaneous or mucosal (telangiectasia), with frequent complications of bleeding, or large and visceral (arteriovenous malformations [AVMs]), with additional risks that can lead to significant morbidity and even mortality. HHT can present in many different ways and can be difficult to recognize, particularly in younger patients in the absence of a known family history of disease or epistaxis, its most common manifestation. HHT is commonly diagnosed using the established Curaçao clinical criteria, which include (1) family history, (2) recurrent epistaxis, (3) telangiectasia, and (4) visceral AVMs. Fulfillment of 3 or more criteria provides a definite diagnosis of HHT, whereas 2 criteria constitute a possible diagnosis of HHT. However, these criteria are insufficient in children to rule out disease due to the age-dependent development of some of these criteria. Genetic testing, when positive, can provide definitive diagnosis of HHT in all age groups. Clinical course is often complicated by significant epistaxis and/or gastrointestinal bleeding, leading to anemia in half of adult patients with HHT. The management paradigm has recently shifted from surgical approaches to medical treatments aimed at control of chronic bleeding, such as antifibrinolytic and antiangiogenic agents, combined with aggressive iron replacement with intravenous iron. Guidelines for management of HHT, including screening and treatment, were determined by expert consensus and originally published in 2009 with updates and new guidelines in 2020.

Long-Term Survival of PD-1 Inhibitor Combined with Antiangiogenic Agents in a Patient with Pulmonary Sarcomatoid Carcinoma Complicated with Esophageal Cancer: A Case Resport and Literature Review

Pulmonary sarcomatoid carcinoma (PSC) is a highly aggressive rare subtype of non-small cell lung cancer (NSCLC). PSC is known for its poor prognosis and low sensitivity to conventional treatments such as chemotherapy, radiation, and adjuvant therapies. In recent years, the application of targeted therapy and immunotherapy in this field has made progress. Although programmed cell death 1 (PD-1) inhibitors have been reported to show favorable antitumor effects in PSC patients with high programmed death-ligand 1 (PD-L1) expression, the efficacy of PD-1 inhibitors in combination with antiangiogenic drugs has not been investigated. Here, we report for the first time a case of dual-source cancer with low expression of PD-L1 and microsatellite stability (MSS) which showed continuous response to sintilimab combined with anlotinib as first-line treatment and achieved a long progression free survival (PFS) of 24 months with no serious adverse reactions. This case presents a new therapeutic prospect for PSC and a potential to enhance its prognosis and treatment strategies.

Combination of anti-angiogenic therapy Apatinib and immune therapy potentiate tumor microenvironment

Tumor immune therapy, especially anti-programmed cell death ligand-1/programmed cell death-1 (PD-L1/PD-1) treatment, is currently the focus of substantial attention. However, despite its enormous successes, the overall response rate of cancer immunotherapy remains suboptimal. There is an increased interest in combining PD-L1/PD-1 treatment with anti-angiogenic drug Apatinib to enhance antitumor effect. Presently available data seem to suggest that Apatinib may exert immune suppressive effects to make the PD-L1/PD-1 treatment works. Here, we review the extensive tumor microenvironment immune modulatory effects from antiangiogenic agents Apatinib in order to supporting VEGFR2 targettherapies in clinical trials are existing.

355 Pembrolizumab and bevacizumab in platinum resistant epithelial ovarian cancer patients

BackgroundThere is a medical need in platinum resistant ovarian cancer patients. Median progression-free survival (PFS) is 3.4 months with chemotherapy and 6.7 months with chemotherapy-bevacizumab combination regimens.1 RECIST overall response rate (ORR) is 11.8% and 27.3%, respectively. The ORR is 15.9% for bevacizumab as a monotherapy with a median PFS of 4.4 months.2MethodsNCT03596281 An open-label phase 1b trial with a modified toxicity probability interval design to evaluate the combination of a flat dose of 400mg bevacizumab for 6 cycles and 200mg pembrolizumab until disease progression, unacceptable toxicity or completed 24 months of treatment in patients with platinum resistant ovarian cancer. The primary evaluation criteria is safety, the secondary endpoint is the efficacy.Results19 patients have been enrolled between January 2019 and February 2021 in 6 French centers. Patients‘ characteristics are reported (table 1). No dose limiting toxicities were observed. Grade 3 treatment related adverse events occurred in 3 patients (i.e. arterial thromboembolism, bowel perforation, proteinuria and sepsis). No grade 4/5 toxicities were induced. A median of 7 cycles (range 3–14) were administered. Median follow-up of patients was 4.1 months (1.8–23). The RECIST ORR was 26.3% (1 complete response and 4 partial responses) (table 2). The disease control rate was 78.9%. The time to progression was not yet reached in 6 patients. The ORR was equivalent whether patients have been pretreated or not with bevacizumab (27.3 and 25% respectively) (table 3). The ORR according to the combined positive score (CPS) for the evaluation of PD-L1 was 50.0% for CPS≥10% (n=4), 30.0% for a CPS≥1% (n=10) and 25.0% for CPS<1 (n=8) (table 4).ConclusionsA chemotherapy-free regimen combining pembrolizumab and bevacizumab was well tolerated and showed encouraging results in heavily pretreated platinum resistant ovarian cancer patients independent of their previous challenge with antiangiogenic agents.AcknowledgementsFunding for this research was provided by Fondation Cancer du Luxembourg and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationNCT03596281ReferencesPujade-Lauraine E, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Onco Off J Am Soc Clin Oncol 32,1302–1308 (2014).Cannistra SA, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol Off J Am Soc Clin Oncol 33,5180–5186 (2007).Ethics ApprovalThis study was approved by CPP Sud Méditerranée V institution’s Ethics Board; approval number 18.020 (EudraCT number 2017-004197-34).ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Medication-Related Osteonecrosis of the Jaw in Patients Treated Concurrently with Antiresorptive and Antiangiogenic Agents: Systematic Review and Meta-Analysis

ABSTRACT Introduction Medication-related osteonecrosis of the jaws (MRONJ) is a known adverse event related to the use of antiresorptive (AR) drugs. More recently, an association between antiangiogenic (AA) drugs and MRONJ has been suggested. This review aimed to investigate the overall prevalence and relative risk of MRONJ in patients treated concurrently with AA and AR agents in comparison with a single AA or AR drug. Methods A review protocol was registered with PROSPERO (ID: CRD42020214244). A systematic literature search, study selection, quality assessment, and data extraction were carried out following PRISMA guidelines. Random-effects meta-analysis models were used to summarize relative estimates for the outcomes, namely prevalence and relative risk of MRONJ. Exposure variable included type of drug, specifically AA and AR agents administered either concurrently or individually. Results Eleven studies were included in the final qualitative and quantitative syntheses. The overall pooled weighted prevalence of MRONJ with concurrent AA-AR drugs was 6% (95% CI: 3–8%), compared with 0% (95% CI: 0–0%) for AA only and 5% (95% CI: 0–10%) for AR only. However, high heterogeneity was noted among included studies. Retrospective cohort studies showed a higher pooled prevalence of 13% (95% CI: 10–17%) for concurrent AA-AR therapy. The pooled risk ratio for MRONJ revealed a risk with concurrent AA-AR drugs 2.57 times as high as with AR only (95% CI: 0.84–7.87); however, this difference was not statistically significant. Concurrent AA-AR drugs had a risk for MRONJ 23.74 times as high as with AA only (95% CI: 3.71–151.92). Conclusions High-quality, representative studies are needed for accurate estimation of relative risk of MRONJ with concurrent AA and AR therapy.

Investigation of the Effectiveness of Surgical Treatment on Maxillary Medication-Related Osteonecrosis of the Jaw: A Literature Review

Aim: Medication-related osteonecrosis of the jaw (MRONJ) occurs after exposure to medication (antiresorptive or antiangiogenic agents) for bone-related complications. It is more common in the mandible than in the maxilla. The present study investigated maxillary MRONJ in elderly patients through a meta-analysis. Methods: Keywords, including “MRONJ”, “maxilla”, and “surgery”, were entered into databases, including Embase, PubMed/MEDLINE, Cochrane Library, and ProQuest, which were searched systematically. Results: Investigating 77 studies, we found that 18 (2 case reports and 16 case series) papers conformed to the standards. The results revealed a 2.6:1 female-to-male ratio of disease occurrence. The average age of patients was 70.6 ± 5.5 years, and most patients were in the third stage (43.6%). The average time of medication usage was 50.0 ± 20.1 months. The pooled proportion of clinical efficacy of surgery was 86%. Conclusion: To prevent and manage MRONJ, all elderly patients should maintain proper oral hygiene and receive dental examinations regularly. Risk assessment and safety management of MRONJ should be performed by medical teams.

Poly (ADP-ribose) polymerase-1 (PARP1) as a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome.

Poly (ADP-ribose) polymerase-1 (PARP1) is a key mediator of various forms of DNA damage repair and plays an important role in the progression of several cancer types. The enzyme is activated by binding to DNA single-strand and double-strand breaks. Its contribution to chromatin remodeling makes PARP1 crucial for gene expression regulation. Inhibition of its activity with small molecules, leads to the synthetic lethal effect by impeding DNA repair in the treatment of cancer cells. At first PARP1 inhibitors (PARPi) were developed to target BRCA mutated cancer cells. Currently, PARPi are being studied to be used in a broader variety of patients either as single agents or in combination with chemotherapy, antiangiogenic agents, ionizing radiation, and immune checkpoint inhibitors. Ongoing clinical trials on olaparib, rucaparib, niraparib, veliparib and the most recent talazoparib show the advantage of these agents in overcoming PARPi resistance and underline their efficacy in targeted treatment of several hematologic malignancies. In this review, focusing on the crucial role of PARP1 in physiological and pathological effects in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), we give an outline of the enzyme's mechanisms of action and its role in the pathophysiology and prognosis of MDS/AML and we analyze the available data on the use of PARPi, highlighting their promising advances in clinical application.

Unexpected Favorable Outcome to PD-1 Antibody Plus Lenvatinib in a Patient With Recurrent Intestinal Follicular Dendritic Cell Sarcoma: A Case Report and Literature Review

BackgroundFollicular dendritic cell sarcoma (FDCS) is an uncommon malignant cancer, and there is no standard treatment to date. Resection followed by adjuvant chemotherapy or radiation is considered the most commonly used strategy for treatment. However, the treatment for patients who have progressed after systemic treatment is more controversial.Case summaryIn this case report, we describe a 57-year-old man with primary small intestine FDCS where surgery and second-line systemic chemotherapy failed. After disease progression (PD), the patient received sintilimab plus lenvatinib as third-line treatment and achieved a progression-free survival (PFS) with 7 months.ConclusionThis is the first report of a FDCS patient treated with immune checkpoint inhibitors (ICIs) and antiangiogenic agents, sintilimab and lenvatinib, as third-line therapy. Our case provides a potential therapeutic option for patients with FDCS who progressed after multiline therapy.

Simulations on the efficacy of radiotherapy with different time schemes of antiangiogenic therapy

The combination of radiotherapy and antiangiogenic agents has been suggested to be potent in tumor growth control compared to the application of antiangiogenic therapy or radiotherapy alone. Since radiotherapy is highly dependent on the oxygen level of the tumor area, antiangiogenic agents are utilized for the reoxygenation of tumor vasculature. We present a mathematical framework to investigate the efficacy of radiotherapy combined with antiangiogenic treatment. The framework consists of tumor cells, vasculature, and oxygenation levels evolving with time to mimic a tumor microenvironment. Non-linear partial differential equations (PDEs) are employed to simulate each component of the framework. Different treatment schemes are investigated to see the changes in tumor growth and oxygenation. To test combination schedules, radiation monotherapy, neoadjuvant, adjuvant, and concurrent cases are simulated. The efficiency of each therapy scheme on tumor growth control, the changes in tumor cell density, and oxygen levels shared by tumor cells are represented. The simulation results indicate that the application of radiotherapy after antiangiogenic treatment is more efficient in tumor growth control compared to other therapy schemes. The present study gives an insight into the possible interaction and timing of the combination of radiotherapy and antiangiogenic drug treatment.