Lymphatic vessels in cancer.

The lymphatic system, composed of initial and collecting lymphatic vessels as well as lymph nodes that are present in almost every tissue of the human body, acts as an essential transport system for fluids, biomolecules, and cells between peripheral tissues and the central circulation. Consequently, it is required for normal body physiology but is also involved in the pathogenesis of various diseases, most notably cancer. The important role of tumor-associated lymphatic vessels and lymphangiogenesis in the formation of lymph node metastasis has been elucidated during the last two decades, whereas the underlying mechanisms and the relation between lymphatic and peripheral organ dissemination of cancer cells are incompletely understood. Lymphatic vessels are also important for tumor-host communication, relaying molecular information from a primary or metastatic tumor to regional lymph nodes and the circulatory system. Beyond antigen transport, lymphatic endothelial cells, particularly those residing in lymph node sinuses, have recently been recognized as direct regulators of tumor immunity and immunotherapy responsiveness, presenting tumor antigens and expressing several immune-modulatory signals including PD-L1. In this review, we summarize recent discoveries in this rapidly evolving field and highlight strategies and challenges of therapeutic targeting of lymphatic vessels or specific lymphatic functions in cancer patients.

Development and physiological functions of the lymphatic system: insights from human genetic studies of primary lymphedema.

Primary lymphedema is a long-term (chronic) condition characterized by tissue lymph retention and swelling that can affect any part of the body, although it usually develops in the arms or legs. Due to the relevant contribution of the lymphatic system to human physiology, while this review mainly focuses on the clinical and physiological aspects related to the regulation of fluid homeostasis and edema, clinicians need to know that the impact of lymphatic dysfunction with a genetic origin can be wide ranging. Lymphatic dysfunction can affect immune function so leading to infection; it can influence cancer development and spread, and it can determine fat transport so impacting on nutrition and obesity. Genetic studies and the development of imaging techniques for the assessment of lymphatic function have enabled the recognition of primary lymphedema as a heterogenic condition in terms of genetic causes and disease mechanisms. In this review, the known biological functions of several genes crucial to the development and function of the lymphatic system are used as a basis for understanding normal lymphatic biology. The disease conditions originating from mutations in these genes are discussed together with a detailed clinical description of the phenotype and the up-to-date knowledge in terms of disease mechanisms acquired from in vitro and in vivo research models.

Pathogenic variants in HGF give rise to childhood-to-late onset primary lymphoedema by loss of function.

Developmental and functional defects in the lymphatic system are responsible for primary lymphoedema (PL). PL is a chronic debilitating disease caused by increased accumulation of interstitial fluid, predisposing to inflammation, infections and fibrosis. There is no cure, only symptomatic treatment is available. Thirty-two genes or loci have been linked to PL, and another 22 are suggested, including Hepatocyte Growth Factor (HGF). We searched for HGF variants in 770 index patients from the Brussels PL cohort. We identified ten variants predicted to cause HGF loss-of-function (six nonsense, two frameshifts, and two splice-site changes; 1.3% of our cohort), and 14 missense variants predicted to be pathogenic in 17 families (2.21%). We studied co-segregation within families, mRNA stability for non-sense variants, and in vitro functional effects of the missense variants. Analyses of the mRNA of patient cells revealed degradation of the nonsense mutant allele. Reduced protein secretion was detected for nine of the 14 missense variants expressed in COS-7 cells. Stimulation of lymphatic endothelial cells with these 14 HGF variant proteins resulted in decreased activation of the downstream targets AKT and ERK1/2 for three of them. Clinically, HGF-associated PL was diverse, but predominantly bilateral in the lower limbs with onset varying from early childhood to adulthood. Finally, aggregation study in a second independent cohort underscored that rare likely pathogenic variants in HGF explain about 2% of PL. Therefore, HGF signalling seems crucial for lymphatic development and/or maintenance in human beings and HGF should be included in diagnostic genetic screens for PL.

Congenital Vascular and Lymphatic Diseases.

Over the past several centuries, the integration of contemporary medical techniques and innovative technologies, like genetic sequencing, have played a pivotal role in enhancing our comprehension of congenital vascular and lymphatic disorders. Nonetheless, the uncommon and complex characteristics of these disorders, especially considering their formation during the intrauterine stage, present significant obstacles in diagnosis and treatment. Here, we review the intricacies of these congenital abnormalities, offering an in-depth examination of key diagnostic approaches, genetic factors, and therapeutic methods.

Lessons of Vascular Specialization From Secondary Lymphoid Organ Lymphatic Endothelial Cells.

Secondary lymphoid organs, such as lymph nodes, harbor highly specialized and compartmentalized niches. These niches are optimized to facilitate the encounter of naive lymphocytes with antigens and antigen-presenting cells, enabling optimal generation of adaptive immune responses. Lymphatic vessels of lymphoid organs are uniquely specialized to perform a staggering variety of tasks. These include antigen presentation, directing the trafficking of immune cells but also modulating immune cell activation and providing factors for their survival. Recent studies have provided insights into the molecular basis of such specialization, opening avenues for better understanding the mechanisms of immune-vascular interactions and their applications. Such knowledge is essential for designing better treatments for human diseases given the central role of the immune system in infection, aging, tissue regeneration and repair. In addition, principles established in studies of lymphoid organ lymphatic vessel functions and organization may be applied to guide our understanding of specialization of vascular beds in other organs.

Role of the Lymphatics in Cardiac Disease.

Cardiovascular diseases remain the largest cause of death worldwide with recent evidence increasingly attributing the development and progression of these diseases to an exacerbated inflammatory response. As a result, significant research is now focused on modifying the immune environment to prevent the disease progression. This in turn has highlighted the lymphatic system in the pathophysiology of cardiovascular diseases owing, in part, to its established function in immune cell surveillance and trafficking. In this review, we highlight the role of the cardiac lymphatic system and its potential as an immunomodulatory therapeutic target in selected cardiovascular diseases.

Rictor, an mTORC2 Protein, Regulates Murine Lymphatic Valve Formation Through the AKT-FOXO1 Signaling.

BACKGROUND: Lymphatic valves are specialized structures in collecting lymphatic vessels and are crucial for preventing retrograde lymph flow. Mutations in valve-forming genes have been clinically implicated in the pathology of congenital lymphedema. Lymphatic valves form when oscillatory shear stress from lymph flow signals through the PI3K/AKT pathway to promote the transcription of valve-forming genes that trigger the growth and maintenance of lymphatic valves. Conventionally, in many cell types, AKT is phosphorylated at Ser473 by the mTORC2 (mammalian target of rapamycin complex 2). However, mTORC2 has not yet been implicated in lymphatic valve formation. METHODS: In vivo and in vitro techniques were used to investigate the role of Rictor, a critical component of mTORC2, in lymphatic endothelium. RESULTS: Here, we showed that embryonic and postnatal lymphatic deletion of Rictor, a critical component of mTORC2, led to a significant decrease in lymphatic valves and prevented the maturation of collecting lymphatic vessels. RICTOR knockdown in human dermal lymphatic endothelial cells not only reduced the level of activated AKT and the expression of valve-forming genes under no-flow conditions but also abolished the upregulation of AKT activity and valve-forming genes in response to oscillatory shear stress. We further showed that the AKT target, FOXO1 (forkhead box protein O1), a repressor of lymphatic valve formation, had increased nuclear activity in Rictor knockout mesenteric lymphatic endothelial cells in vivo. Deletion of Foxo1 in Rictor knockout mice restored the number of valves to control levels in lymphatic vessels of the ear and mesentery. CONCLUSIONS: Our work identifies a novel role for RICTOR in the mechanotransduction signaling pathway, wherein it activates AKT and prevents the nuclear accumulation of the valve repressor, FOXO1, which ultimately enables the formation and maintenance of lymphatic valves.

Understanding central nervous system fluid networks: Historical perspectives and a revised model for clinical neurofluid imaging.

The central nervous system (CNS) lacks traditionally defined lymphatic vasculature. However, CNS tissues and barriers compartmentalize the brain, spinal cord, and adjacent spaces, facilitating the transmittal of fluids, metabolic wastes, immune cells, and vital signals, while more conventional lymphatic pathways in the meninges, cervicofacial and paraspinal regions transmit efflux fluid and molecules to peripheral lymph and lymph nodes. Thus, a unique and highly organized fluid circulation network encompassing intraparenchymal, subarachnoid, dural, and extradural segments functions in unison to maintain CNS homeostasis. Pathways involved in this system have been under investigation for centuries and continue to be the source of considerable interest and debate. Modern imaging and microscopy technologies have led to important breakthroughs pertaining to various elements of CNS fluid circuitry and exchange over the past decade, thus enhancing knowledge on mechanisms of mammalian CNS maintenance and disease. Yet, to better understand precise anatomical routes, the physiology and clinical significance of these CNS pathways, and potential therapeutic targets in humans, fluid conduits, flow-regulating factors, and tissue effects must be analyzed systematically and in a global manner in persons across age, demographical factors, and disease states. Here, we illustrate the system-wide nature of intermixing CNS fluid networks, summarize historical and clinical studies, and discuss anatomical and physiological similarities and differences that are relevant for translation of evidence from mice to humans. We also review Cushing's classical model of cerebrospinal fluid flow and present a new framework of this "third circulation" that emphasizes previously unexplained complexities of CNS fluid circulation in humans. Finally, we review future directions in the field, including emerging theranostic techniques and MRI studies required in humans.

Surgical options for lymphedema after gynecological cancer treatment: current trends and advances.

Lower leg lymphedema is an important complication after gynecological treatment that can severely affect the quality of life of long-term survivors of these malignancies. As a chronic and progressive disease, affected patients will require life-long therapy centered on compression. Although conventional compressive treatments can be effective, they are extremely burdensome and time-consuming for most patients and adherence is challenging. With advances in the field of reconstructive microsurgery, new procedures have been developed in the past decades to help these patients in their continuous care and have been offered at many oncological centers around the world as a first line of treatment. We performed a PubMed search using the Mesh terms 'Lymphedema/surgery' and 'Lower extremity' yielding a total of 508 articles. Of these, 35 articles were included for analysis. Articles that failed to provide a comprehensive analysis of outcomes following surgical treatment, studies examining treatment for upper limb lymphedema, primary lymphedema, or lower extremity lymphedema resulting from non-gynecologic etiologies, and studies that failed to have a minimum of 6 months follow-up were excluded. A comprehensive review of these 35 articles including over 1200 patients demonstrated large variability on the outcomes reported; however, an overall benefit from these procedures was found. Surgical options including lymphovenous anastomosis, vascularized lymph node transfers, and excisional procedures can be performed in patients with lower leg lymphedema, depending on staging and findings in indocyanine green lymphography. Surgical treatment of lymphedema is an effective option that can improve symptoms and quality of life of patients suffering from lymphedema following gynecologic cancers.

Evaluation of the Effect of Botulinum Toxin A on the Lymphatic Endothelial Cells.

INTRODUCTION: Botulinum toxin A (BoTA) is a neurotoxin formed by Clostridium botulinum, with a broad medical application spectrum. While the primary effect of BoTA is on the muscles, the effects of BoTA in other systems including the blood vasculature have already been examined, revealing unexpected actions. However, no studies exist to the best of our knowledge regarding the potential effects of BoTA on the lymphatic vascular system, possessing a critical role in health and disease. Isolated human lymphatic endothelial cells (LECs) were cultured in dedicated in vitro culture systems. The analysis including imaging and cell culture approaches as well as molecular biology techniques is performed to examine the LEC alterations occurring upon exposure to different concentrations of BoTA. MATERIALS AND METHODS: Human LECs were cultured and expanded on collagen-coated petri dishes using endothelial basal medium and the commercial product Botox from Allergan as used for all our experiments. Harvested cells were used in various in vitro functional tests to assess the morphologic and functional properties of the BoTA-treated LECs. Gene expression analysis was performed to assess the most important lymphatic system-related genes and pathways. RESULTS: Concentrations of 1, 5 or 10 U of BoTA did not demonstrate a significant effect regarding the proliferation and migration capacity of the LECs versus untreated controls. Interestingly, even the smallest BoTA dose was found to significantly decrease the cord-like-structure formation capacity of the seeded LECs. Gene expression analysis was used to underpin possible molecular alterations, suggesting no significant effect of BoTA in the modification of gene expression versus the starvation medium control. CONCLUSION: LECs appear largely unaffected to BoTA treatment, with an isolated effect on the cord-like-structure formation capacity. Further work needs to assess the effect of BoTA on the smooth-muscle-cell-covered collecting lymphatic vessels and the possible aesthetic implications of such an effect, due to edema formation. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Lymphatic System and the Kidney: From Lymphangiogenesis to Renal Inflammation and Fibrosis Development.

The lymphatic kidney system plays a crucial role in managing interstitial fluid removal, regulating fluid balance, and tuning immune response. It also assists in the reabsorption of proteins, electrolytes, cytokines, growth factors, and immune cells. Pathological conditions, including tissue damage, excessive interstitial fluid, high blood glucose levels, and inflammation, can initiate lymphangiogenesis-the formation of new lymphatic vessels. This process is associated with various kidney diseases, including polycystic kidney disease, hypertension, ultrafiltration challenges, and complications post-organ transplantation. Although lymphangiogenesis has beneficial effects in removing excess fluid and immune cells, it may also contribute to inflammation and fibrosis within the kidneys. In this review, we aim to discuss the biology of the lymphatic system, from its development and function to its response to disease stimuli, with an emphasis on renal pathophysiology. Furthermore, we explore how innovative treatments targeting the lymphatic system could potentially enhance the management of kidney diseases.

The Role of NRF2 in Cerebrovascular Protection: Implications for Vascular Cognitive Impairment and Dementia (VCID).

Vascular cognitive impairment and dementia (VCID) represents a broad spectrum of cognitive decline secondary to cerebral vascular aging and injury. It is the second most common type of dementia, and the prevalence continues to increase. Nuclear factor erythroid 2-related factor 2 (NRF2) is enriched in the cerebral vasculature and has diverse roles in metabolic balance, mitochondrial stabilization, redox balance, and anti-inflammation. In this review, we first briefly introduce cerebrovascular aging in VCID and the NRF2 pathway. We then extensively discuss the effects of NRF2 activation in cerebrovascular components such as endothelial cells, vascular smooth muscle cells, pericytes, and perivascular macrophages. Finally, we summarize the clinical potential of NRF2 activators in VCID.

The Role of Inflammation in Lymphedema: A Narrative Review of Pathogenesis and Opportunities for Therapeutic Intervention.

Lymphedema is a chronic and progressive disease of the lymphatic system characterized by inflammation, increased adipose deposition, and tissue fibrosis. Despite early hypotheses identifying lymphedema as a disease of mechanical lymphatic disruption alone, the progressive inflammatory nature underlying this condition is now well-established. In this review, we provide an overview of the various inflammatory mechanisms that characterize lymphedema development and progression. These mechanisms contribute to the acute and chronic phases of lymphedema, which manifest clinically as inflammation, fibrosis, and adiposity. Furthermore, we highlight the interplay between current therapeutic modalities and the underlying inflammatory microenvironment, as well as opportunities for future therapeutic development.

Lymphatic vessels and the renin-angiotensin-system.

The lymphatic system is an integral part of the circulatory system and plays an important role in the fluid homeostasis of the human body. Accumulating evidence has recently suggested the involvement of lymphatic dysfunction in the pathogenesis of cardio-reno-vascular (CRV) disease. However, how the sophisticated contractile machinery of lymphatic vessels is modulated and, possibly impaired in CRV disease, remains largely unknown. In particular, little attention has been paid to the effect of the renin-angiotensin-system (RAS) on lymphatics, despite the high concentration of RAS mediators that these tissue-draining vessels are exposed to and the established role of the RAS in the development of classic microvascular dysfunction and overt CRV disease. We herein review recent studies linking RAS to lymphatic function and/or plasticity and further highlight RAS-specific signaling pathways, previously shown to drive adverse arterial remodeling and CRV organ damage that have potential for direct modulation of the lymphatic system.

Evaluation of the Superficial Collecting Lymph Vessels' Vasa Vasorum in Lymphoedematous Limbs Using Video Capillaroscopy.

OBJECTIVE: The pre-collecting and collecting lymph vessels have smooth muscle cells, and sufficient perfusion is vital to maintain their function. Although the vasa vasorum of the collecting lymph vessels (VVCL) have been histologically investigated, little is known about their physiology. This study aimed to investigate the relationship between morphology and blood flow of the VVCL in lymphoedematous limbs. METHODS: Medical records of lower extremity lymphoedema patients who underwent video capillaroscopy observation during supermicrosurgical lymphaticovenous anastomosis (LVA) surgery were reviewed. The collecting lymph vessels, dissected for LVA, were examined under video capillaroscopy (GOKO Bscan-ZD, GOKO Imaging Devices Co., Japan) with a magnification of 175x and 620x. Blood flow velocity of the VVCL was calculated by measuring the red blood cell movement using software (GOKO-VIP ver. 1.0.0.4, GOKO Imaging Devices Co., Japan). Based on the video capillaroscopy findings, the VVCL were grouped according to their morphology; the VVCL morphology types and blood flow velocity were then compared according to the lymphosclerosis severity grade. RESULTS: Sixty-seven lymph vessels in 20 lower extremity lymphoedema patients were evaluated, including s0 in 19 (28.4%), s1 in 34 (50.7%), s2 in 10 (14.9%), and s3 in four (6.0%) lymph vessels. The VVCLs were grouped into four types: type 1 (n = 4), type 2 (n = 37), type 3 (n = 19), and type 4 (n = 7). Blood flow velocity of the VVCL ranged 0 - 189.3 µm/sec (average 26.40 µm/sec). There were statistically significant differences in VVCL morphology (p < .001) and blood flow velocity (p < .001) according to lymphosclerotic severity. CONCLUSION: Vasa vasorum of the collecting lymph vessels could be grouped into four types with different characteristics. Morphological and physiological changes of the VVCL were related to sclerotic changes of the collecting lymph vessels.

Effectiveness of physical therapy in axillary web syndrome after breast cancer: a systematic review and meta-analysis.

BACKGROUND: The axillary web syndrome (AWS) is a surgical breast cancer sequel that limits the functionality of the patient and delays the protocol times of application of cancer treatments. This implies a long period of discomfort and limitations for the user. OBJECTIVE: To investigate the different physiotherapy treatments for the AWS and how effective they are. METHODS: A systematic review based on PRISMA protocol and registered in PROSPERO (CRD42021281354) was conducted. The research was performed using PubMed, Scopus, CINAHL, PEDro, and Web of Science databases during January 2022 and March 2022. All randomized controlled trials and controlled clinical trials were included in this review. RESULTS: A total of 188 articles were identified, with 9 studies selected for the systematic review. These studies basically propose treatments based on exercises and stretching, manual therapy, and the combination of manual therapy and exercises. CONCLUSIONS: Exercise and stretching are the most effective therapies within the field of physiotherapy for the rehabilitation of axillary web syndrome. They restore range of motion faster, reduce pain, improve quality of life, and reduce disabilities. Manual therapy, scar massage, and myofascial release could help improve outcomes but with worse results. The meta-analysis conclusion is that pain is the only outcome with a significant reduction after the application of physiotherapy treatments - 0.82 [- 1.67; 0.03]. This conclusion is drawn from the only three studies with small sample sizes.

Prophylactic complex physiotherapy in gynecologic cancer survivors: patient-reported outcomes based on a lymphedema questionnaire.

OBJECTIVE: Lower extremity lymphedema secondary to cancer treatment impacts quality of life for gynecological cancer survivors. Complex decongestive physiotherapy is applied when lymphedema is diagnosed, but prophylactic physiotherapy is not yet a standard of care. The aim of this study is to evaluate prophylactic complex physiotherapy in patients with gynecological cancer and its effects on patient-reported symptoms based on the Gynecologic Cancer Lymphedema Questionnaire. METHODS: The data of patients diagnosed with gynecological cancers who underwent lymphadenectomy from July 2021 to June 2022 was evaluated. All patients were referred to the physiotherapy unit before adjuvant treatment. Patients who accepted prophylactic physiotherapy were informed and massage and exercise training were implemented, whereas patients who declined were solely informed. Bilateral lower extremity circumferences were measured at 1, 3, 6, and 12 months at the levels of 10 cm, 30 cm, and 50 cm above the heels. A translated form of the Gynecologic Cancer Lymphedema Questionnaire was administered to all patients at the last visit. RESULTS: A total of 100 patients were included in the study. Patients were diagnosed with endometrial (50%), ovarian (32%), cervical (16%), and vulvar (2%) cancer. Overall, 70% underwent systematic pelvic±para-aortic lymphadenectomy whereas sentinel lymph node mapping was performed in 30%. Lymphedema was seen in 5% (n=3) of the prophylactic physiotherapy positive group and in 60% (n=24) of the physiotherapy negative group. The median score was 3 (range 1-5) in the physiotherapy positive group and 16 (range 9-20) in the physiotherapy negative group. In patients diagnosed with lymphedema in the physiotherapy negative group, systematic lymphadenectomy was performed in 91.7% (n=22) and a higher number of lymph nodes was extracted (median 45.5; p=0.002). CONCLUSION: Prophylactic complex physiotherapy is associated with lower rates of lymphedema and better patient-reported symptom scores according to the Gynecologic Cancer Lymphedema Questionnaire.

Translation and cross-cultural adaptation of the Gynecologic Cancer Lymphedema Questionnaire and the Lower Extremity Lymphedema Screening Questionnaire.

OBJECTIVE: There is a paucity of international data regarding self-reported lower extremity lymphedema and quality of life after surgery for gynecological cancer. Validated questionnaires are emerging, but translated versions are lacking. Cross-cultural adaptation is important to reduce the risk of introducing bias into a study. OBJECTIVE: To translate and culturally adapt the Gynecologic Cancer Lymphedema Questionnaire and the Lower Extremity Lymphedema Screening Questionnaire for a Norwegian population. METHODS: Permission to use the original English versions of the Gynecologic Cancer Lymphedema Questionnaire and the Lower Extremity Lymphedema Screening Questionnaire for translation was obtained. The questionnaires were translated using a procedure based on standard guidelines, including forward translation by native speakers of the target language, synthesis, back translation, and review. Seventeen patients from the Norwegian Radium Hospital gynecological cancer outpatient clinic, all expected to have stable disease, were invited for questionnaire test-retest by completing the same questionnaires twice at 3-4-week intervals. Internal consistency was assessed by calculating Cronbach's alpha. Test-retest reliability was assessed using an intra-class correlation coefficient. RESULTS: Twelve patients completed the questionnaires twice. Cronbach's alpha was 0.75 for the Gynecologic Cancer Lymphedema Questionnaire and 0.89 for the Lower Extremity Lymphedema Screening Questionnaire. The intra-class correlation coefficient was 0.86 for the Gynecologic Cancer Lymphedema Questionnaire and 0.91 for the Lower Extremity Lymphedema Screening Questionnaire. CONCLUSIONS: Translation and cross-cultural adaptation of these internationally validated patient-reported outcomes questionnaires for survivors of lower extremity lymphedema in gynecological cancer was feasible. The Norwegian translation of the Gynecologic Cancer Lymphedema Questionnaire and the Lower Extremity Lymphedema Screening Questionnaire showed acceptable internal consistency and the test-retest reliability was excellent.

Does sentinel node mapping impact morbidity and quality of life in endometrial cancer?

OBJECTIVES: To evaluate the prevalence of post-operative complications and quality of life (QoL) related to sentinel lymph node (SLN) biopsy vs systematic lymphadenectomy in endometrial cancer. METHODS: A prospective cohort included women with early-stage endometrial carcinoma who underwent lymph node staging, grouped as follows: SLN group (sentinel lymph node only) and SLN+LND group (sentinel lymph node biopsy with addition of systematic lymphadenectomy). The patients had at least 12 months of follow-up, and QoL was assessed by European Organization for Research and Treatment of Cervical Cancer Quality of Life Questionnaire 30 (EORTC-QLQ-C30) and EORTC-QLQ-Cx24. Lymphedema was also assessed by clinical evaluation and perimetry. RESULTS: 152 patients were included: 113 (74.3%) in the SLN group and 39 (25.7%) in the SLN+LND group. Intra-operative surgical complications occurred in 2 (1.3%) cases, and all belonged to SLN+LND group. Patients undergoing SLN+LND had higher overall complication rates than those undergoing SLN alone (33.3% vs 14.2%; p=0.011), even after adjusting for confound factors (OR=3.45, 95% CI 1.40 to 8.47; p=0.007). The SLN+LND group had longer surgical time (p=0.001) and need for admission to the intensive care unit (p=0.001). Moreover, the incidence of lymphocele was found in eight cases in the SLN+LND group (0 vs 20.5%; p<0.001). There were no differences in lymphedema rate after clinical evaluation and perimetry. However, the lymphedema score was highest when lymphedema was reported by clinical examination at 6 months (30.1 vs 7.8; p<0.001) and at 12 months (36.3 vs 6.0; p<0.001). Regarding the overall assessment of QoL, there was no difference between groups at 12 months of follow-up. CONCLUSIONS: There was a higher overall rate of complications for the group undergoing systematic lymphadenectomy, as well as higher rates of lymphocele and lymphedema according to the symptom score. No difference was found in overall QoL between SLN and SLN+LND groups.

Advances in photoacoustic imaging aided by nano contrast agents: special focus on role of lymphatic system imaging for cancer theranostics.

Photoacoustic imaging (PAI) is a successful clinical imaging platform for management of cancer and other health conditions that has seen significant progress in the past decade. However, clinical translation of PAI based methods are still under scrutiny as the imaging quality and clinical information derived from PA images are not on par with other imaging methods. Hence, to improve PAI, exogenous contrast agents, in the form of nanomaterials, are being used to achieve better image with less side effects, lower accumulation, and improved target specificity. Nanomedicine has become inevitable in cancer management, as it contributes at every stage from diagnosis to therapy, surgery, and even in the postoperative care and surveillance for recurrence. Nanocontrast agents for PAI have been developed and are being explored for early and improved cancer diagnosis. The systemic stability and target specificity of the nanomaterials to render its theranostic property depends on various influencing factors such as the administration route and physico-chemical responsiveness. The recent focus in PAI is on targeting the lymphatic system and nodes for cancer diagnosis, as they play a vital role in cancer progression and metastasis. This review aims to discuss the clinical advancements of PAI using nanoparticles as exogenous contrast agents for cancer theranostics with emphasis on PAI of lymphatic system for diagnosis, cancer progression, metastasis, PAI guided tumor resection, and finally PAI guided drug delivery.