Introduction

Human immunodeficiency virus (HIV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) surface glycoproteins, including shared epitope motifs, show similarities. This may lead to false-positive HIV results due to cross-reactivity between the two viruses. This study presents a systematic review of the published studies on their cross-reactivity.

Methods

A systematic review of the published studies of HIV and SARS-CoV2 cross-reactivity was conducted, the studies that met the following criteria were included: 1) Studies in the English language. 2) Studies in which the title included the required keywords. 3) Studies in which false positive results were achieved and confirmed. 4) Studies investigating the possibility of cross-reactivity between HIV and SARS-CoV2.

Results

A total of 11 studies and 466,140 patients were analyzed. Of the specified sexes, 363,786 (82.1%) of the participants were males. A total of 707 false-positive HIV results were recorded, of which 122 (17.3%) had detectable Coronavirus disease 2019 (COVID-19) antibodies. The remaining 585 (82.7%) false positives were either healthy patients or patients recovered from COVID-19 with no detectable COVID-19 antibodies. Twenty-five distinct tests were used as initial and confirmatory tests for both COVID-19 and HIV. Six (24%) unique fourth-generation HIV antigen/antibody combination tests, six (24%) HIV-specific molecular tests, and four (16%) HIV immunoassays were used.

Conclusion

COVID-19 should be considered a potential cause of false-positive results in HIV tests, due to the cross-reactivity between the antibodies or antigens from both viruses.

Thoracic outlet syndrome (TOS) is a complex and often overlooked condition caused by the compression of neurovascular structures as they pass through the thoracic outlet. This compression can result in pain, numbness, tingling, muscle weakness, and vascular complications, with severe cases leading to thrombosis or embolism.

TOS is classified into three types based on the affected structure: neurogenic, venous, and arterial. Neurogenic TOS is the most prevalent, accounting for over 90% of cases, and is more commonly seen in females. Venous TOS represents 3–5% of cases, while arterial TOS is the rarest, comprising only 1%. Diagnosing TOS is challenging due to its symptom overlap with various musculoskeletal and neurological disorders, often leading to misdiagnosis. The absence of universally accepted diagnostic criteria further complicates identification, relying primarily on clinical evaluations and inconsistent diagnostic methods.

Neurogenic TOS, in particular, is difficult to distinguish from other conditions with similar presentations. This study provides a comprehensive review of the differential diagnosis of neurogenic TOS, comparing it with musculoskeletal and neurological disorders that share overlapping clinical features.

Abstract

Introduction
Desmoid-type fibromatosis (DTF), also called aggressive fibromatosis, is a rare, benign, locally aggressive condition. Mammary DTF originates from fibroblasts and myofibroblasts within the breast tissue, representing 0.2% of all breast tumors. This study aims to present and discuss the clinical presentation and management of seven cases of breast DTF.

Methods

This single-center case series was conducted at the breast clinic of Smart Health Tower in Sulaymaniyah, Iraq. It included all patients diagnosed as breast DTF by histopathological examination, with those lacking complete data excluded. The patients were treated and managed between January 2021 and August 2024.

Results

This study involved seven female patients with a mean age of 35.29 ± 14.29 years. Clinically, six of them (85.71%) presented with a non-tender palpable breast mass, while one patient (14.28%) reported breast pain. Ultrasound revealed hypoechoic lesions in all cases. The average size of the masses was 29.43 ± 17.26 mm. All patients underwent wide local excision of the breast mass. Histopathological examination confirmed the diagnosis of DTF in all cases.

Conclusion

Diagnosing a desmoid tumor of the breast can be difficult, as it can mimic breast carcinoma. The Wide local excision is often the preferred treatment to prevent future recurrences.

Introduction

Desmoid-type fibromatosis (DTF), also known as aggressive fibromatosis, is a rare benign condition that can develop in various body parts, the most common being the extremities, abdominal wall, and intra-abdominal cavity [1]. Mammary DTF arises from fibroblasts and myofibroblasts within the breast tissue. It accounts for 0.2% of all breast tumors [1,2]. Although it does not metastasize, it is known for its local aggressiveness and high recurrence rate [2].

The term "desmoid" was introduced by Mueller in 1838, deriving from the Greek word "desmos," which refers to its tendon-like consistency. However, MacFarlane first described the disease in 1832 [3].

The DTF may occur sporadically or develop following surgical trauma, the implantation of silicone breast implants, or in association with Gardner's syndrome. While most cases of breast fibromatosis are reported in females, it can also occur in males [1]. It commonly affects individuals between 15 and 60 years of age, with the highest incidence occurring in the third and fourth decades of life [4].

Unpredictable and invasive growth patterns characterize the DTF. The tumor often proliferates during the early stages and may also accelerate due to pregnancy or hormonal changes. After this initial growth phase, many patients experience an extended period where the tumor remains stable [5].

Due to their rarity, desmoid tumors present a diagnostic and therapeutic challenge, as they often initially resemble breast carcinoma and have a high tendency for recurrence [6]. This study aims to describe and discuss the presentation and management of seven cases of breast DTF. All the references cited in this study were evaluated for eligibility [7].

Methods

Study design and setting

This single-center case series was conducted at the breast clinic of Smart Health Tower (Sulaymaniyah, Iraq). The patients were treated and managed between January 2021 and August 2024.

Participants

The study included all patients with confirmed breast DTF based on histopathological examination, while those with incomplete data were excluded.

Data collection

Data were collected from the hospital’s registry, including demographic details, clinical presentation, physical examination, medical history, breast ultrasound and mammography findings, core needle biopsy (CNB) and fine needle aspiration cytology (FNAC) results, histopathological examination (HPE), tumor size, magnetic resonance imaging (MRI) and computed tomography (CT) scan findings, types of surgeries performed, postoperative complications, follow-up duration, and recurrence.

Intervention

All patients underwent surgery under general anesthesia with the supine position following skin preparation and disinfection. The procedures involved making elliptical, radial, and semicircular incisions over the breast where the mass was suspected. After the skin was incised, a wide local excision (WLE) of the mass was performed. In one case, the mass extended into the chest wall muscles and involved two ribs, which were also excised. The long thoracic and thoracodorsal nerves were preserved in all cases. Lymph nodes from levels I, II, and III were removed. Hemostasis was achieved, a Redivac drain was inserted for each patient, and a chest tube drain was placed for one patient. The surgical site was then closed in layers.

Histopathological examination and preparation

Regarding pathologic examination, the specimens were fixed in 10% neutral buffered formalin for 24 hours prior to grossing. After that, the specimens were examined systemically, with appropriate sections taken from the tumors and the margins. The resultant blocks were then processed with the Sakura Histo-Tek VP1 automated processor using a standard 11-hour processing protocol through alcohol, xylene, and paraffin. Following embedding in paraffin and trimming, the blocks were sectioned onto regular glass slides, kept in an oven overnight, and then stained manually for hematoxylin and eosin (H&E) using Gill II hematoxylin. The slides were then dried, and coverslips were applied.

For immunohistochemistry, the paraffin blocks were sectioned onto charged glass slides and kept in an oven overnight. Antigen retrieval was achieved through boiling using the Dako PT Link with a solution of pH 6 or 9, depending on the target antibody. The slides were then washed with buffer solution and welled using the Dako Pen, followed by blocking endogenous peroxidase using hydrogen peroxide. The primary antibodies were then applied, followed by the secondary antibody (horseradish peroxidase) and the chromogen (diaminobenzidine). Counterstaining was achieved using hematoxylin Gill II, followed by drying and applying coverslips.

Data analysis

The data were collected using an Excel spreadsheet (Microsoft Excel 2021). They were analyzed qualitatively with Statistical Package for the Social Sciences (SPSS) software (version 27.0) and presented as mean, range, frequencies, and percentages.

Results

This study included seven female patients with an average age of 35.29 ± 14.29 years, ranging from 18 to 61 years. All of the patients were unemployed, and five of them were married (71.43%). Five patients' medical histories were unremarkable (71.43%), while two patients (28.57%) had hypothyroidism. Three patients (42.86%) had previously undergone different types of breast surgeries. None of the patients had a family history of breast cancer.

Among the clinical presentations, six patients (85.71%) had a non-tender palpable breast mass, while one patient (14.28%) experienced breast pain. Ultrasound showed hypoechoic lesions in all patients with BI-RADS 4 or 5 in four patients (57.14%). The average mass size was 29.43 ± 17.26 mm, ranging from 15 mm to 70 mm. In three cases (28.57%), MRI was used, revealing either heterogeneous or homogeneous masses. In one case (14.28%), a CT scan detected a mass in the chest wall with muscle invasion. A CNB was performed in 5 patients (71.43%), and FNAC of the axillary lymph node, which indicated benign lymphoid tissue, was performed in one patient (14.28%).

Mammography was performed in only one case (14.28%), showing scattered fibro-glandular density and benign calcification. All patients underwent WLE of the breast mass. In one case (14.28%), surgery required rib excision due to chest wall invasion in a recurrent desmoid tumor. The HPE in all cases, along with immunohistochemistry in 5 cases, confirmed the diagnosis of DTF, with no evidence of lymph node metastasis (Fig. 1). The mean follow-up period was 1.51 ± 0.98 years, ranging from 0.7 to 3 years, with no reported recurrences (Table 1).

Discussion

DTF is an intermediate soft tissue tumor marked by clonal fibroblastic proliferation originating in the deep soft tissues. This tumor tends to infiltrate surrounding tissues and has a high local recurrence rate but cannot metastasize [8,9]. They can originate primarily from breast tissue or secondarily from the pectoralis major muscle [1]. This condition typically impacts individuals aged 15 to 60 years, with the highest prevalence observed in the third and fourth decades of life [4]. It is approximately twice as common in women as in men [10]. In this study, the average age of the patients was 35.29 ± 14.29 years, ranging from 18 to 61 years, and all were female.

The exact cause of DTF remains unclear. However, associations with Gardner syndrome, prior trauma, and surgery have been documented [6]. Additionally, while silicone implants are mentioned in the literature as a potential cause, intraoperative trauma is considered more likely to be the primary factor [6].

Clinically, DTF of the breast presents with a wide range of manifestations. It is commonly described as a suspicious, mobile, firm, and painless nodule. However, cases of skin retraction and nipple retraction have also been reported in the literature [6]. Lorenzen et al. described 14 cases of breast DTF in their case series, with all patients presenting with a palpable breast mass [6]. Similarly, in the current study, 85.71% of the patients exhibited a painless breast mass, while only one patient reported breast pain instead of a breast mass.

Relying solely on imaging for diagnosing breast DTF is often inadequate due to its invasive characteristics, which can frequently lead to misdiagnosis as BI-RADS 4 or 5 [10]. On ultrasound, desmoid tumors typically appear as hypoechogenic, ill-defined masses [1]. Mammographically, they present as spiculated masses and, in rare cases, may show calcified deposits [1]. MRI is the most effective imaging technique for assessing the extent of the tumor, particularly when the chest wall is involved [11]. On MRI, desmoid tumors may appear as ill-defined hypointense or isointense masses on T1-weighted images and hyperintense masses on T2-weighted images [12]. In the present study, ultrasound showed hypoechoic lesions in each patient, and ultrasound showed BI-RADS 4 or 5 in 57.14%. Mammography was performed for one patient, showing scattered fibro-glandular density with benign calcifications. MRI was done for three patients, revealing either homogeneous or heterogeneous enhancing masses and varying sizes of fibro-glandular tissue. Additionally, CT scans of one case showed a chest wall mass with invasion of the pectoralis muscle.

Diagnosing a desmoid tumor of the breast can be challenging both clinically and radiologically, as it may resemble breast carcinoma [1]. A definitive diagnosis is only possible through HPE of the lesion. The tumor appears macroscopically as a grayish-white, firm, irregular nodular mass [1]. Microscopically, it is characterized by spindle cells with varying amounts of collagen fiber deposition [12]. Histopathologically, desmoid tumors must be distinguished from scar tissue, fibrosarcoma, or fibromatosis-like metaplastic spindle cell tumors [12].

Immunohistochemical analysis, particularly of preoperative biopsies, can aid in diagnosing desmoid fibromatosis. β-Catenin is a key immunohistochemical marker, showing nuclear expression in sporadic and familial cases in up to 80% of patients [6]. Mutations in the β-catenin gene (CTNNB1) are found in most cases of sporadic DTF, leading to the accumulation of this oncoprotein in the nucleus [6]. Elevated β-catenin levels activate the WnT signaling pathway, contributing to tumor development [6]. However, nuclear β-catenin staining is not specific to breast desmoid fibromatosis; it is also occasionally observed in spindle cell carcinomas, 23% of metaplastic breast carcinomas, and up to 93% of benign phyllodes tumors [13].

The treatment of breast desmoid tumors remains controversial due to the limited data available, given the low incidence of the disease [14]. Various approaches may be employed, including surgery, radiotherapy, chemotherapy, and hormonal therapy. Radical surgical excision is generally considered the treatment of choice [1]. However, complete excision may be avoided in carefully selected patients, especially when the surgery could result in poor functional or cosmetic outcomes, such as in cases where the lesion is superficial or subareolar and may require the removal of the nipple-areolar complex [14]. For some women, mastectomy may be recommended if they experience multiple recurrences, have a large tumor, or face difficulties in obtaining a histological diagnosis [15]. This study chose a comprehensive WLE as a preventive measure to avoid any potential future recurrences.

Breast DTF recurrence is common, with a prevalence of 18-29% over 3-6 years. There is also a risk of involvement with thoracic muscles and ribs [15]. WLE can help prevent or reduce the risk of recurrence [1]. For tumors that are unresectable or require extensive surgical procedures, such as major chest wall resection, radiotherapy may be considered as an alternative treatment option [16]. In this study, no recurrences were observed during the follow-up period. The mean follow-up duration was 1.51 ± 0.98 years, ranging from 0.7 to 3 years.

Systemic therapy can be employed for unresectable or recurrent desmoid tumors, as well as for patients who cannot tolerate surgical treatment or when the tumor involves the chest wall [1]. This therapy includes non-cytotoxic approaches, such as hormonal therapy with Tamoxifen alone or in combination with nonsteroidal anti-inflammatory drugs, as well as cytotoxic approaches like chemotherapy [1]. In the current study, one patient underwent a WLE and the removal of two ribs due to an irregular mass on the right chest wall that invaded the pectoralis muscle and contacted the intercostal muscle. A limitation of this study is the short follow-up duration, which may not be long enough to identify potential recurrences.

Conclusion

Diagnosing a desmoid tumor of the breast can be difficult, as it can mimic breast carcinoma. The WLE is often the preferred treatment to prevent future recurrences.

Declarations

Conflicts of interest: The author(s) have no conflicts of interest to disclose.

Ethical approval: The study's ethical approval was obtained from the scientific committee of the Kscien Organization for Scientific Research.

Patient consent (participation and publication): Verbal informed consent was obtained from patients for publication.

Source of Funding: Smart Health Tower

Role of Funder: The funder remained independent, refraining from involvement in data collection, analysis, or result formulation, ensuring unbiased research free from external influence.

Acknowledgements: None to be declared.

Authors' contributions: AMS and AMA were major contributors to the conception of the study, as well as to the literature search for related studies. HAN, MKA and AAQ were involved in the literature review, study design, and writing the manuscript. ZDH, HAY, SHH, SOK, FHK and HAS were involved in the literature review, the design of the study, the critical revision of the manuscript and the processing of the figures. FHK and AMS confirm the authenticity of all the raw data. RMA was the pathologist who performed the histopathological diagnosis. LRAP was the radiologist who performed the assessment of the case.  All authors have read and approved the final manuscript.

Use of AI: AI was not used in the drafting of the manuscript, the production of graphical elements, or the collection and analysis of data.

Data availability statement: Note applicable.

Introduction

Osteonecrosis, also known as avascular necrosis, aseptic necrosis, or ischemic necrosis, results from a temporary or permanent halt in blood flow to a portion of bone. This lack of blood supply can eventually cause the affected bone to collapse. Osteonecrosis around the elbow is not frequently observed. However, its occurrence in the trochlea known as Hegemann's disease is even rarer. Incidence rates of trochlear osteonecrosis have been reported to vary from 0.27% to less than 0.001% across different studies.

Case presentation

A 14-year-old male presented with severe right shoulder pain and swelling, along with mild right lateral-sided elbow pain due to a fall to the ground. The radiograph of the right shoulder revealed a proximal humeral metaphyseal greenstick fracture. Additionally, the radiograph of the right elbow incidentally revealed osteonecrosis of the distal humeral trochlea. The affected shoulder was immobilized and Conservative management was selected for treating the trochlear osteonecrosis.

Conclusion

Trochlear avascular necrosis is a rare condition that might cause mild discomfort or even be asymptomatic, potentially being diagnosed incidentally through radiographs. Typically, it can be managed with conservative treatment methods.

In the face of mounting healthcare challenges, developing countries grapple with resource constraints, underfunded health systems, and a growing burden of infectious and non-communicable diseases. The question is no longer whether healthcare systems can sustain themselves under these pressures—the evidence says they cannot—but how they can adapt and evolve to meet these needs. One promising approach lies in establishing and strengthening public-private partnerships (PPPs) [1].

PPPs are collaborations in which governments and private entities collaborate to achieve common health goals, leveraging the strengths of both sectors. The public sector offers reach, regulatory frameworks, and an understanding of population health needs, while the private sector contributes innovation, efficiency, and financial resources. Together, they can address healthcare access, quality, and affordability gaps [1].

In many developing countries, healthcare access remains unequal. Rural and underserved populations often lack essential services, while urban areas face overcrowded and overburdened public hospitals. By pooling resources and expertise, PPPs can deliver sustainable solutions, such as building health facilities in remote areas, funding community health programs, or providing cutting-edge technology and training to public hospitals.  Initiatives like the African Access Initiative have brought affordable medicines and diagnostic tools to low-income countries by fostering collaborations between governments and pharmaceutical companies. These partnerships ensure the availability of life-saving medications for conditions like cancer and diabetes [2].  In countries like India, PPPs have been instrumental in building state-of-the-art hospitals in rural areas, combining public funding with private expertise. For example, the Karnataka state government’s partnership with private hospitals expanded tertiary healthcare access to previously underserved populations [3]. Partnerships with multinational corporations and NGOs have facilitated training for healthcare professionals, enabling them to provide higher-quality care. In Kenya, PPPs have focused on improving maternal and child health outcomes through community-based education programs [4], in 2010, the Kurdistan Regional Government (KRI) asked for assistance from the RAND Corporation, a U.S.-based nonprofit policy think tank specializing in research and development across various fields, to support the reform of the healthcare system in the Kurdistan Region of Iraq. The primary goal of the reform was to establish a health system that could efficiently provide high-quality services to all individuals, with the support of Public-Private Partnerships (PPPs) [5].

Despite their promise, PPPs are not without challenges. Critics argue that these arrangements can lead to the privatization of public health assets or create inequities in service delivery. For instance, poorly regulated PPPs may prioritize profitability over the needs of vulnerable populations, leaving rural or low-income communities underserved.  Transparency, accountability, and robust legal frameworks are essential to mitigate these risks. Governments must ensure that PPP agreements prioritize public health outcomes with clear success metrics and oversight mechanisms.

As the global health landscape evolves, developing countries have an opportunity to harness PPPs as a tool for resilience and equity. By fostering inclusive partnerships that align public and private incentives, countries can mobilize resources, improve service delivery, and ensure sustainable healthcare financing.

The need for innovation and collaboration in healthcare has never been more urgent. Governments, private entities, and civil society must work together to create partnerships that prioritize the well-being of all citizens, particularly the most vulnerable. With the right frameworks, public-private partnerships can move beyond being a stopgap solution and become a cornerstone of sustainable health systems.

Let us embrace the potential of PPPs and work toward a future where healthcare is a right, not a privilege, for everyone, everywhere.

Introduction

Thoracic outlet syndrome is a group of disorders arising from compressive forces on the neurovascular bundle in that region due to different etiologies. This study aims to present a case with an intractable cough as a complication of the surgery and its management.

Case presentation

A 41-year-old woman had a 15-year history of bilateral upper limb pain and numbness. The pain worsened over the last two months. Tests and imaging confirmed thoracic outlet syndrome. Physiotherapy had no effect. She underwent thoracic outlet decompression (TOD) under general anesthesia via a supraclavicular incision. Post-surgery, she developed uncontrollable cough that didn't respond to medication. Two days after the operation, a bupivacaine (5%) injection near the phrenic nerve resolved the cough.

Literature review

The literature review identified several cases of TOD complications, including right phrenic nerve paralysis resolving in 3-6 months, unilateral right diaphragm dysfunction, and lung herniation successfully treated with thoracoscopic reduction. These cases underscore the diverse presentations and outcomes of TOD complications, highlighting the importance of early diagnosis and tailored management strategies.

Conclusion

A possible complication of surgical decompression for thoracic outlet syndrome is an intractable cough that can be relieved by the injection of local anesthesia into the area of the phrenic nerve.

Introduction

Sacrococcygeal teratoma (SCT) is a rare embryonal tumor that occurs in the sacrococcygeal region, with an incidence of about 1 in 35,000 to 40,000 live births. This study presents a systematic review of giant SCT greater than 10 cm.

Methods

A systematic review of published studies regarding giant SCT in infants was conducted. The studies included met the following criteria: 1) the teratoma was situated in the sacrococcygeal region; 2) all case reports involved infants with a teratoma larger than 10 cm, and 3) the size of the teratoma was verified to exceed 10 cm through diagnostic methods.

Results

The current study included 31 studies that met the inclusion criteria. The studies included patients aged 6.1 to 9.3 months, with a median age of 7.6 months, predominantly female (72.7%). Diagnoses were primarily made in the first and second trimesters (39%) or after birth (33.3%), with cesarean delivery being the most common method (66.7%). Tumors weighed between 1.5 and 5 kg, with an average diameter of 15.6 cm. Surgical resection was performed in 93.9% of cases. The most common complication was respiratory failure (30.3%), and histopathology revealed that 39.4% of tumors were immature teratomas, while 33.3% were mature teratomas. The overall survival rate was 66.7%, with 18.2% of survivors experiencing tumor recurrence. Most complications occurred in the second trimester; however, no significant associations were found concerning the timing of diagnosis. Additionally, tumor size did not significantly impact outcomes.

Conclusion

Routine ultrasound and MRI are essential for the antenatal diagnosis of SCT. Due to the high risk of morbidity with larger tumors, cesarean delivery is advised for tumors over 10 cm. Coccygectomy is the most effective approach to prevent recurrence, highlighting the importance of timely surgical intervention and ongoing follow-up.

Introduction

 Microwave ablation (MWA) has emerged as a minimally invasive treatment for patients with inoperable non-small cell lung cancer (NSCLC). However, whether it is more effective as a standalone treatment or in combination with chemotherapy warrants further investigation. This systematic review assesses the efficacy and safety of MWA as a standalone treatment and in combination with chemotherapy in managing NSCLC.

Methods

Studies were included if MWA was used either as a standalone treatment or combined with chemotherapy for managing NSCLC, regardless of whether chemotherapy was administered before or after MWA.

Results

The patient cohort included 928 patients. In 63.8% of the cases, MWA was used alone, and in 36.2% with chemotherapy. Complications from MWA alone were higher (59.29% vs. 32.74%). The tumor stage in 52.36% of the cases who underwent MWA alone was stage I; however, it was the IV stage in 82.44% of the cases who underwent MWA combined with chemotherapy. Patients with available data and treated with MWA alone experienced higher local progression (26% vs. 18.5%), distant recurrence (51.5% vs. 38.5%), and both local and distant recurrence (10.8% vs. 2.6%). Reported complete response was 88.6% among cases that underwent MWA alone. While it was 78.0% in those who underwent combined MWA and chemotherapy. The median overall survival was higher in the MWA alone group (24.9 to 69.6 months vs. 21.3 to 23.90 months).

Conclusion

MWA combined with chemotherapy may represent a more effective option, with a slightly similar treatment response, reducing the risk of recurrence and minimizing complications.

Abstract

Introduction

Cancer patients face a venous thromboembolism (VTE) risk that is up to 50 times higher compared to individuals without cancer. In 2010, direct oral anticoagulants (DOACs) such as apixaban, rivaroxaban, and edoxaban were introduced, consequently becoming the controversial oral anticoagulants for VTE therapy. This study is a meta-analysis of randomized clinical trials (RCTs) evaluating the use of edoxaban for treating VTE in cancer patients over different treatment durations.

Methods

Using Google Scholar, a systematic search for RCTs on edoxaban for cancer-associated VTE was performed. The data extracted covered patient numbers, age, gender, BMI, cancer type, edoxaban dosage, treatment duration, comorbidities, major bleeding, recurrent VTE incidence, and deaths. Statistical significance was set at 0.05.

Results

Out of 52 studies, nine with 3,190 cases met the inclusion criteria. The mean age was 66.68 years, with 1,604 females (50.28%). Major bleeding occurred in 192 patients (7.66%) in the 6- or 12-month group and 57 (8.35%) in the 3-month group (p=0.573). Recurrent VTE was observed in 145 patients (5.78%) in the 6- or 12-month group and 95 (13.91%) in the 3-month group (p<0.001). Deaths from any cause totaled 548 (21.86%) in the 6- or 12-month group and 165 (24.16%) in the 3-month group (p=0.110).

Conclusion

Cancer patients receiving edoxaban for six or 12 months experience a lower recurrence rate of VTE compared to those on a 3-month treatment. The incidence of major bleeding appears to be similar between the two treatment durations.

Introduction

Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), frequently occurs in cancer patients. Cancer is a condition characterized by abnormal cells' uncontrolled proliferation and persistence. Those with VTE who have cancer are at a higher risk of experiencing recurrent thromboembolism [1, 2].

Patients with cancer face a risk of VTE that is up to 50 times greater compared to those without cancer. The annual incidence of VTE in cancer patients varies between 3% and 15% [3]. Risk factors for developing cancer-associated thrombosis (CAT) extend beyond large pelvic masses that compress the iliac veins. They also include comorbidities, immobilization, chemotherapy, targeted therapies (such as bevacizumab), surgeries like lymphadenectomy, and the presence of intravenous catheters. These factors can contribute to a prothrombotic or hypercoagulable state [4].

The VTE is linked with considerable morbidity and mortality. Therefore, it is crucial to start anticoagulant therapy promptly and to maintain it for as long as the patient remains at elevated risk for recurrent events [5]. Anticoagulant therapy poses challenges in cancer patients due to their increased risk of both recurrent VTE and major bleeding compared to those without cancer. These complications can interfere with cancer treatments [5].

Low-molecular-weight heparin (LMWH), unfractionated heparin (UFH), and vitamin K antagonists (VKA) have been utilized in the treatment of CAT. Major guidelines, including those from the American Society of Clinical Oncology, the National Comprehensive Cancer Network, and the American Thoracic Society, recommend LMWH for treating CAT [4]. Nonetheless, the effectiveness of LMWH beyond six months is not well established, and its use can be challenging due to the need for daily subcutaneous injections [4].

In 2010, direct oral anticoagulants (DOACs) like apixaban, rivaroxaban, and edoxaban were introduced. These DOACs, which include factor Xa and thrombin inhibitors, have minimal interactions with food or other medications, like LMWH. This property enables fixed dosing without the need for regular coagulation monitoring [1, 4].

Recent large randomized controlled trials (RCTs) have demonstrated the benefits of DOACs over conventional VKAs for treating VTE. Consequently, DOACs have become the preferred oral anticoagulant for VTE therapy [6,7]. Moreover, DOACs have been shown to be non-inferior to LMWH when treating CAT. As a result, the use of DOACs in CAT patients is on the rise [8,9].

The optimal duration of anticoagulation therapy is determined by weighing the risk of recurrent VTE if the treatment is discontinued against the risk of bleeding if it is continued. Factors such as patient preference, life expectancy, and cost should also be considered [5].

This study is a meta-analysis of RCTs assessing the use of edoxaban for VTE in cancer patients across various treatment durations.

Methods

Study design

This meta-analysis was conducted strictly following the guidelines set by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Data sources and search strategy

A meta-analysis was conducted using Google Scholar to identify all published randomized studies on edoxaban treatment for cancer-associated VTE. The search used the following keywords: (Edoxaban OR Lixiana OR cancer OR tumor OR malignancy OR malignant OR cancerous OR tumorous AND thromboembolism OR embolism OR thrombosis).

Eligibility criteria

In this meta-analysis, only RCT studies were included. Studies were excluded if they were 1) non-English, 2) only abstracts, or 3) did not meet the inclusion criteria. All references included in this study were assessed for eligibility [10].

Study selection and data extraction

The titles and abstracts of the identified studies were first screened, followed by a thorough full-text screening to determine eligibility. Various data were extracted from the included studies, including number of patients, age, gender, BMI, type of cancer, edoxaban dosage, treatment duration, comorbidities, history of major bleeding and VTE, incidence of major bleeding and recurrent VTE during Edoxaban treatment, and the number of deaths.

Statistical analyses

The data were first used in a qualitative synthesis and then quantitatively re-analyzed using the Chi-square test and Fisher's exact test with the Statistical Package for Social Sciences (SPSS) version 27.0. The level of statistical significance was set at 0.05.

Results

A total of 52 studies were found in the search. Sixteen were directly excluded due to duplication, non-English language, or being pre-prints. The remaining 36 studies were screened by reviewing their titles and abstracts, with none removed after screening. All 36 studies underwent full-text screening, where 27 were excluded for various reasons. The remaining studies were evaluated for eligibility (Fig. 1); ultimately, nine studies [3-5, 8, 11-15], comprising 3,190 cases, met the inclusion criteria (Table 1). The mean age of the patients was 66.68 ± 10.70 years, with a predominance of females, accounting for 1,604 (50.28%) of the total population. Among the comorbidities, hypertension was the most common, affecting 535 patients (16.77%), followed by diabetes in 208 patients (6.52%). A history of major bleeding or recurrent VTE was reported in 210 patients (6.58%). Gastrointestinal tract cancer was the most frequently mentioned type of cancer in the included studies, affecting 273 patients (8.56%).

Regarding Edoxaban dosage, the standard dose of 60 mg/day was administered to 1,812 patients (56.80%), while a reduced dose of 30 mg/day was given to 1,377 patients (43.17%). Only one patient received a 15 mg/day dose. The studies included in the review used three different treatment durations: 3 months, 6 months, or 12 months.  A total of 2,507 patients, 78.59%, received edoxaban for either a 6-month or 12-month period, and 683 patients (21.41 %) received edoxaban for three months (Fig. 2). Major bleeding occurred in 192 patients (7.66 %) in the 6 or 12-month group and 57 patients (8.35%) in the 3-month group (p-value=0.573) (Table 2).

Recurrent VTE was observed in 145 patients (5.78%) in the 6-month or 12-month group and 95 patients (13.91%) in the 3-month group (p-value<0.001). The number of deaths from any causes was 548 deaths (21.86%) in the 6-month or 12-month, followed by 165 deaths (24.16%) in the 3-month group (p-value=0.110) (Table 3).

Discussion

Thrombogenesis can be triggered by several factors, including age, a sedentary lifestyle, and advances in imaging technologies that have led to increased diagnosis rates. Other contributing factors include using hematopoietic agents, blood transfusions, invasive intravascular catheters, and the effects of new antineoplastic drugs [16].

The high incidence and recurrence of VTE in cancer patients is well-documented. The pathogenesis of cancer-associated coagulopathy is complex and involves several mechanisms [17]. Tumor cells can trigger blood coagulation through various processes, including producing procoagulant factors, fibrinolytic activities, and pro-aggregating effects [17]. The hemostatic side effects of oncological treatments, such as cytotoxic drugs, hormone therapy, anti-angiogenic therapy, radiotherapy, and surgery, also contribute to blood coagulopathies [18].

Treating VTE associated with active malignancy involves not only managing the thrombosis but also addressing the cancer itself. This approach is complicated by issues such as bleeding risks and the potential for recurrent VTE [19].

The LMWH has been the preferred anticoagulant for CAT following evidence from major RCTs that demonstrated its superiority over traditional vitamin K antagonists (VKAs) (20-23). Recently, several large RCTs have compared DOACs and LMWH, demonstrating that DOACs are non-inferior to LMWH for treating venous VTE in patients with CAT, and they have emerged as an alternative to LMWH [6,8,9].

Based on the results from several clinical trials, including Hokusai VTE Cancer (edoxaban vs. dalteparin, n=522 vs. 524), Caravaggio (apixaban vs. dalteparin, n=576 vs. 579), and SELECT-D (rivaroxaban vs. dalteparin, n=203 vs. 203), as well as meta-analyses incorporating these studies, DOACs are deemed effective, safe, and useful for treating CAT [6,8,9]. These trials indicated that the VTE recurrence rates with DOACs range from 4% to 8%, and the major bleeding rates range from 3% to 7%, which are comparable to those observed with LMWH (3). In line with the studies referenced, the present review found that the overall recurrence rate and major bleeding were 7.52% and 7.80%, respectively.

In a sub-analysis of the HOKUSAI trial, which included 771 cancer patients with VTE, edoxaban was associated with a trend toward lower VTE recurrence and significantly reduced clinically relevant bleeding compared to warfarin [14]. Similarly, other Xa inhibitors, such as rivaroxaban and apixaban, demonstrated comparable benefits in sub-analyses of the EINSTEIN-DVT and PE trials [24] and the AMPLIFY trial [6]. These findings suggest that Xa inhibitors may be as effective as, and potentially safer than, warfarin for treating VTE in cancer patients [17].

A recent RCT, the ONCO DVT study, demonstrated the potential benefits of extended anticoagulation therapy with edoxaban for patients with cancer-associated isolated distal DVT, particularly in reducing thrombotic risk [15]. However, concerns have been raised about the increased risk of bleeding associated with prolonged anticoagulation in patients with cancer-associated VTE. Therefore, individual risk assessment and tailored treatment strategies are crucial for optimizing management in these patients [11]. In their RCT, Chatani et al. found that the 12-month cumulative incidence of major bleeding was higher in the 12-month treatment group compared to the 3-month group for patients receiving 60 mg of edoxaban (14.3% vs. 4.4%, p-value = 0.046). However, for the 30 mg edoxaban subgroup, the incidence of major bleeding did not differ significantly between the two treatment durations (8.7% vs. 8.6%, p-value = 0.89). However, the cumulative 12-month incidence of symptomatic recurrent VTE was lower in the 12-month group compared to the 3-month group for both the 60 mg and 30 mg doses (1.1% vs. 7.6%, p-value = 0.002) [11]. In the current review, major bleeding occurred in 7.66% of patients in the 6 or 12-month treatment group and 8.35% of those in the 3-month group for both the 60 mg and 30 mg doses, with no statistically significant difference found (p-value = 0.573). Consistent with Chatani et al.’s findings, the recurrence rate of VTE was higher in the 3-month group for both doses.

In a RCT conducted by Raskob and colleagues, edoxaban was used for 522 cases of cancer-associated VTEs; the number of deaths from any cause in their study was 39.5% [8]. In the present review, the mortality rate from any cause was 22.35%. The comparison between the two groups for both the 60 mg and 30 mg doses showed no significant difference (p-value = 0.110).

Conclusion

Cancer patients receiving edoxaban for six or 12 months experience a lower recurrence rate of VTE compared to those on a 3-month treatment. The incidence of major bleeding appears to be similar between the two treatment durations.

Declarations

Conflicts of interest: The author(s) have no conflicts of interest to disclose.

Ethical approval: Not applicable, as systematic reviews do not require ethical approval.

Patient consent (participation and publication): Not applicable.

Funding: The present study received no financial support.

Acknowledgements: None to be declared.

Authors' contributions: FHK, SSO and RMA were significant contributors to the conception of the study and the literature search for related studies. FJA, DHMS, MNH and KFH were involved in the literature review, the study's design, and the critical revision of the manuscript, and they participated in data collection. HAN, NSS and MQM were involved in the literature review, study design, and manuscript writing. DAO, SHT, RJR, SHM and TNM Literature review, final approval of the manuscript, and processing of the tables. FHK and HAN confirm the authenticity of all the raw data. All authors approved the final version of the manuscript.

Use of AI: AI was not used in the drafting of the manuscript, the production of graphical elements, or the collection and analysis of data.

Data availability statement: Note applicable.