Lymphatics, Volume 4, Issue 3 (September 2026) – 15 articles

Lymphedema is usually approached as a survivorship complication; yet, many of the injuries that produce lymphatic failure begin during cancer treatment planning. Regional nodal irradiation, chemoradiation, lymph-node surgery, systemic therapy, obesity, infection history, and baseline lymphatic reserve can converge to produce chronic swelling, fibrosis, cellulitis risk, functional limitation, and an impaired quality of life. Despite this, lymphatic drainage pathways are rarely contoured, constrained, or prospectively monitored as organs at risk in radiotherapy practice. This commentary argues that the lymphatic system should enter radiotherapy-planning discussions as a candidate toxicity structure, while cautioning against premature universal dose constraints. Evidence signals are clinically meaningful but not yet protocol-defining: in the MA.20 breast cancer trial, regional nodal irradiation increased lymphedema from 4.5% to 8.4%; in nasopharyngeal carcinoma, mean doses of approximately 58.7 Gy to level IV and 58.6 Gy to levels I–VII were proposed as thresholds associated with moderate/severe facial lymphedema; and gynecological cancer studies report wide lower-limb lymphedema incidence ranges, with radiotherapy, lymphadenectomy, number of nodes removed, and body mass index repeatedly implicated as risk factors. The immediate priority is not mandatory lymphatic sparing, but lymphatic-aware planning: a baseline risk assessment, reproducible candidate contours, dose–volume reporting, selective sparing where oncologically safe, and prospective toxicity monitoring. The author proposed a framework to reflect this argument. Making lymphatic toxicity visible, measurable, and modelled may help shift lymphedema from an accepted late effect to a potentially preventable planning endpoint. Full article

Cutaneous T-cell lymphoma (CTCL) is a chronic, generally incurable group of non-Hodgkin lymphomas associated with substantial symptom burden, yet receipt of palliative-intent treatment in this population remains uncharacterized. We conducted a cross-sectional retrospective study of 13,215 patients with CTCL using the National Cancer Database (2004–2023) to evaluate receipt of palliative-intent treatment by sociodemographic and disease characteristics using χ² tests, Wilcoxon rank sum tests, Fisher’s exact tests, and multivariable logistic regression. Only 355 patients (2.7%) received palliative-intent treatment. In multivariable analysis, the strongest factors associated with palliative-intent treatment receipt were regional stage (OR, 3.19; 95% CI, 2.43–4.17) and distant stage (OR, 2.49; 95% CI, 1.86–3.31). Treatment at academic facilities was associated with significantly lower odds of NCDB-defined palliative care receipt (OR, 0.59; 95% CI, 0.47–0.76). Medicare insurance, primary cutaneous CD30+ histology, higher comorbidity burden, head and neck primary site, and more recent diagnosis were also independently associated with receipt of palliative-intent treatment. Sex, race, income, and distance to the facility were not significant. Palliative-intent treatment receipt is markedly low in CTCL despite guideline recommendations supporting early integration. Systematic screening for palliative care needs is warranted, particularly for patients with advanced-stage disease or high symptom burden. Full article

Prostate cancer is the prototypical immunologically cold solid tumor, with objective response rates of only 3–5% to immune checkpoint inhibitors in unselected metastatic castration-resistant disease and an estimated 89.8% of tumors classified as immunologically ignorant. Three convergent features sustain this phenotype: low tumor mutational burden with defective Major Histocompatibility Complex class I antigen presentation; an immunosuppressive microenvironment dominated by regulatory T-cells, myeloid-derived suppressor cells, and M2 macrophages; and dense stromal and vascular barriers that exclude effector lymphocytes. Across these mechanisms, one compartment has received disproportionately little attention: the lymphatic system. Tumor-associated lymphatic remodeling driven by vascular endothelial growth factor C and D produces structurally abnormal vessels that impair antigen and dendritic cell trafficking to tumor-draining lymph nodes; the lymph nodes themselves are reprogrammed to a tolerogenic state by lymphatic endothelial cells expressing programmed death-ligand 1 and lacking costimulation and by regulatory T-cells that suppress effector egress. This review synthesizes evidence that in prostate cancer, immune coldness reflects not merely a problem of checkpoint engagement with the tumor but a failure of antigen trafficking at the lymphatic interface. We discuss therapeutic strategies that target this axis, such as lymphangiogenesis-inducing vaccines, lymph-node-directed checkpoint delivery, induction of intratumoral tertiary lymphoid structures and stromal reprogramming, as complements to existing immunotherapy. Targeting trafficking, not only checkpoints, may be the prerequisite for converting PCa from cold to hot. Full article

Lymphedema is a chronic, progressive disorder caused by impaired lymphatic drainage. It leads to swelling, inflammation, fibrosis, increased infection risk, and reduced quality of life. Diagnosis is primarily clinical and is supported by limb measurements, functional assessment, and imaging. Ultrasonography helps exclude mimicking conditions, lymphoscintigraphy assesses lymphatic transport, and magnetic resonance lymphangiography defines lymphatic anatomy to guide treatment planning. Management should be multidisciplinary and tailored to disease stage. Complex decongestive therapy remains the first-line treatment, while surgical options such as lymphaticovenular anastomosis, vascularized lymph node transfer, and liposuction are increasingly used in selected patients. Early recognition and individualized treatment are essential for durable disease control. This article reviews the current evidence on the diagnosis, imaging, and management of lymphedema and highlights recent developments in the field. Full article

The discovery of the glymphatic system and meningeal lymphatic vessels established that the brain possesses an organized lymphatic clearance network that drains to the deep cervical lymphatics. Disruption of this system has been suggested to contribute to the accumulation of pathogenic proteins implicated in neurodegeneration. Cervical lymphatic reconstruction has been associated with some neurological benefit in Alzheimer’s and Parkinson’s disease, and preclinical work has demonstrated that noninvasive manipulation of superficial cervical lymphatics can increase cerebrospinal fluid outflow. Whether noninvasive cervicofacial lymphedema therapy can produce comparable neurological effects remains unknown. We report two men with Parkinson’s disease (Hoehn and Yahr stages 2.5 and 3) treated with a standardized cervicofacial lymphedema therapy protocol targeting cervical and facial lymphatic pathways. Total MDS-UPDRS scores decreased by 19 points (34.5%) in Patient 1 and 5 points in Patient 2. The reduction in Patient 1 exceeded the published threshold for clinically meaningful total-score improvement. Benefits were reproducible and session-linked, and were accompanied by motor and non-motor gains in cognition, alertness, mood, energy, and sleep; interruption of therapy was associated with return toward baseline. Cervicofacial lymphedema therapy may represent a low-risk, noninvasive intervention hypothesized to influence brain lymphatic clearance in Parkinson’s disease. Full article

Lymphoid malignancies comprise a diverse group of hematologic cancers characterized by extensive genetic, epigenetic, and microenvironmental heterogeneity. Despite substantial advances in targeted therapies and immunotherapeutic approaches, disease relapse and therapeutic resistance remain major clinical challenges. Increasing evidence suggests that malignant lymphoid cells are highly dependent on protein homeostasis (proteostasis) networks to cope with the elevated proteotoxic stress imposed by oncogenic signaling, rapid proliferation, immunoglobulin synthesis, and microenvironmental stressors. This dependence, often referred to as proteostasis addiction, represents a critical vulnerability that can be therapeutically exploited. Proteostasis is maintained through an integrated network that regulates protein synthesis, folding, quality control, and degradation. In lymphoid malignancies, dysregulation of these pathways drives adaptive responses involving molecular chaperones, the unfolded protein response (UPR), the ubiquitin–proteasome system (UPS), and autophagy–lysosome pathways. These mechanisms collectively enable tumor cells to survive conditions that would otherwise induce proteotoxic collapse and cell death. Notably, the clinical success of proteasome inhibitors in plasma cell neoplasms has provided proof of concept that targeting proteostasis can yield meaningful therapeutic benefit. In this review, we discuss the major sources of proteotoxic stress in lymphoid malignancies and summarize the molecular mechanisms that sustain proteostasis addiction. We further examine current and emerging therapeutic strategies aimed at disrupting proteostasis networks, including proteasome inhibitors, UPR-targeted agents, chaperone-directed therapies, and novel targeted protein degradation technologies. Finally, we highlight the contribution of proteostasis remodeling to therapeutic resistance and discuss future opportunities for biomarker development and precision medicine. A deeper understanding of proteostasis dependencies may facilitate the identification of novel therapeutic vulnerabilities and improve outcomes for patients with lymphoid malignancies. Full article

The association between Down syndrome (DS) and Hodgkin lymphoma (HL) is rare, with only a few cases reported in the literature. Here, we report the case of a pediatric patient with DS diagnosed with HL. In addition, a literature review was conducted, identifying only seven pediatric cases. We highlight treatment-related toxicity in this group of patients. Given the high survival rates of patients with HL, current strategies focus on individualizing treatment intensity based on the initial disease characteristics and the patient’s response. This consideration becomes even more important in patients with DS. The patient described in this report achieved complete metabolic remission after chemotherapy, experienced manageable grade 3 treatment-related toxicities, and remains in complete remission after 27 months of follow-up. Full article

Background: Breast cancer-related lymphedema (BCRL) is a potentially debilitating outcome following breast cancer treatment. Much attention has been given to preventive and curative strategies for BCRL. Patients with inflammatory breast cancer (IBC) are at particularly increased risk, with approximately half of patients with IBC developing BCRL. We present preliminary outcome data for inflammatory breast cancer patients who undergo a multipronged preventative strategy with immediate lymphatic reconstruction at the time of axillary lymph node dissection, compressive arm sleeve wearing, and occupational therapy. We also present a literature review on IBC and BCRL. Methods: A retrospective review of patients with IBC undergoing immediate lymphatic reconstruction with lymphovenous bypass at the time of axillary lymph node dissection was performed. All patients were referred to occupational therapy for establishment of care and arm sleeve fitting and had at least 12 months of follow-up. The primary outcome of interest was the development of lymphedema. Additionally, a narrative review of the literature was performed. All English language studies pertaining to BCRL in patients with IBC were considered. Results: Eighteen patients with IBC underwent immediate lymphatic reconstruction with lymphovenous bypass between April 2022 and September 2023 by three reconstructive microsurgeons. Average follow-up time was 24.4 months (range 12.5–33.9 months). All patients underwent successful lymphovenous bypass of at least 1 channel. Of the 18 patients, 3 (16.6%) developed symptoms of lymphedema, such as heaviness of the posterior arm (2/3, 67%) or edema of the forearm (1/3, 33%). No patients developed >10% change in extremity volume. Conclusions: BCRL is a debilitating and common outcome following breast surgery in patients with IBC. Immediate reconstruction with lymphovenous bypass coupled with occupational therapy and compression sleeve management may reduce the risk for BCRL in this population. Full article

Venetoclax-based therapy is effective in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but tumor lysis syndrome (TLS) risk necessitates a resource-intensive five-week dose ramp-up with intravenous hydration, frequent laboratory monitoring, and clinic-based observation, creating logistical barriers particularly in community settings. We conducted a single-center, IRB-approved retrospective pilot study of 30 patients with CLL/SLL who underwent a cytoreduction-adapted, IV-free outpatient venetoclax ramp-up with reduced laboratory monitoring between 2023 and 2026. All patients received cytoreductive therapy—predominantly single-agent BTKi—and met protocol-defined low-tumor-burden criteria (ALC < 20 × 10⁹/L, lymph nodes < 5 cm, no splenomegaly, CrCl > 45 mL/min) before venetoclax initiation. Venetoclax was self-administered at home with laboratory monitoring reduced to a single approximately 12-h post-dose assessment per dose-escalation week. Median age was 71 years; 80% had received ≥2 prior therapy lines, and 37% had high-risk cytogenetics. Monitoring compliance was 100%. No laboratory or clinical TLS, IV hydration, hospitalizations, dose interruptions, treatment discontinuations, or deaths occurred during ramp-up. These pilot data support the feasibility and early safety of simplified outpatient venetoclax initiation in adequately cytoreduced patients and warrant prospective multicenter validation. Full article

Lymphedema and phlebolymphedema are increasingly recognized as prevalent chronic conditions that extend beyond traditional cancer-related populations. Although Complete Decongestive Therapy remains the foundation of management, real-world treatment success is often limited by challenges with long-term adherence, particularly when therapies disrupt patients’ daily activities. This commentary explores the physiologic relationship between mobility and fluid transport, emphasizing the complementary roles of movement and compression in supporting venous and lymphatic return. Emerging evidence from studies of wearable, non-pneumatic compression technologies suggest that allowing patients to remain active during treatment may improve limb-volume reduction, quality of life, and adherence compared with conventional pneumatic systems. These findings challenge longstanding assumptions regarding immobilization and trunk compression while reinforcing the importance of patient-centered treatment strategies. As the burden of chronic edema continues to grow, clinicians should increasingly consider mobility as an active therapeutic component and prioritize interventions that align with both human physiology and the realities of everyday life. Full article

Sentinel lymph node (SLN) mapping plays a pivotal role in oncological staging in veterinary medicine. However, conventional techniques often depend on radioactive tracers or specialized imaging equipment that is unavailable in many clinical settings. This brief report describes the use of indirect radiographic lymphography with the non-ionic iodinated contrast agent iohexol for SLN identification in a dog with auricular melanoma. A 12-year-old spayed female mixed-breed dog presented with an ulcerated cutaneous mass affecting the left auricle. Cytological evaluation was consistent with a melanocytic neoplasm. Immediately before surgery, iohexol was administered intradermally at four peritumoral sites (0.75 mL per cm²). Radiographic images acquired 3 and 4.5 min after injection demonstrated lymphatic drainage to the superficial ventral and superficial dorsal cervical lymph nodes, which were identified as sentinel lymph nodes. The patient underwent vertical ear canal ablation, conchectomy, partial auriculectomy, and excision of the mapped sentinel lymph nodes. Histopathological examination confirmed a mixed-type cutaneous melanoma with macrometastatic involvement of the superficial ventral cervical sentinel node and micrometastatic deposits in both the superficial dorsal cervical and left parotid lymph nodes. Although the parotid lymph node was not enlarged radiographically, afferent lymphatic channels indicated contrast uptake, and histopathology confirmed metastatic involvement. This finding supports considering elective regional lymphadenectomy alongside sentinel lymph node biopsy in similar cases. An incidental cutaneous hemangiosarcoma was identified at a distant abdominal site, excised with complete margins, and was unrelated to the primary tumor. No systemic adverse effects associated with iohexol administration were observed, and only transient mild-to-moderate localized edema developed at the injection site, resolving spontaneously without treatment. These findings suggest that iohexol-based indirect radiographic lymphography is a practical, safe, and accessible technique for sentinel lymph node identification and may represent a promising, though not yet validated, alternative for lymphatic staging in veterinary oncology, although further prospective studies are needed to establish its diagnostic accuracy. Full article

Multiple myeloma (MM) is a malignant plasma cell disorder and one of the most common tumors of lymphoid origin. In the process of oncogenesis, there is a significant change in the immune balance in the body, which leads to the suppression of the immune response to the tumor. This immune suppression is one of the reasons why the tumor can progress and cause serious health problems for the patient. One of the key factors that affect immune balance is innate lymphoid cells (ILCs). ILCs play an important role in regulating the immune response and can both promote and hinder the development of tumor processes, depending on their functional state and interaction with other cells of the immune system. Among ILCs, ILC1 mainly exert antitumour activity, but ILC2 and ILC3 are usually protumorigenic. One of the standard treatments for MM is autologous hematopoietic stem cell transplantation (auto-HSCT), and the aim of our study was to evaluate the effect of auto-HSCT on ILCs in MM. We assessed the number and subpopulation composition of ILCs in MM patients before and after auto-HSCT. In MM patients, an increase in the proportion of ILC2 and a decrease in ILC1 are observed before auto-HSCT compared to healthy controls. The subpopulation composition of ILCs changes in patients with multiple myeloma after auto-HSCT, with an increase in ILC1 and a decrease in ILC2 compared to pre-auto-HSCT values. No differences were observed in the relative number of different types of ILC in MM patients after auto-HSCT and in healthy controls. It has been shown that the number of immature CD5⁺ILC2s in the peripheral blood of patients with multiple myeloma is comparable to that of healthy individuals. However, in MM patients, HSCT leads to an increase in the relative number of CD5⁺ILC2s. Full article

Mismatch repair–deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancers exhibit high mutational burden and abundant neoantigen formation, generating a highly immunogenic tumour microenvironment characterised by dense lymphocytic infiltration and strong sensitivity to immune checkpoint inhibition. In metastatic colorectal cancer, PD-1 blockade produces durable responses almost exclusively in dMMR tumours, establishing mismatch repair status as a predictive biomarker for immunotherapy responsiveness. Recent studies extending immune checkpoint inhibitors (ICIs) into the neoadjuvant setting for localised dMMR colorectal cancer have produced major pathological response rates exceeding 90%, with pathological complete response (pCR) rates frequently surpassing 60%, challenging traditional oncologic staging frameworks, particularly with respect to lymph node assessment. Baseline clinical nodal staging in dMMR tumours is complicated by immune-mediated lymphadenopathy. Reactive lymphoid hyperplasia driven by tumour antigen exposure frequently produces enlarged lymph nodes that mimic metastatic disease on cross-sectional imaging. Following neoadjuvant immunotherapy, treatment-related immune activation may further increase nodal size or metabolic activity, while pathological examination often reveals sterilised nodes or immune infiltration without viable tumour. Consequently, conventional radiologic criteria for nodal metastasis demonstrate limited specificity in this context. The discordance between imaging findings and pathological outcomes raises important implications for staging accuracy, response assessment, and treatment planning. This review examines the biological basis of lymphatic involvement in dMMR colorectal cancer, evaluates the performance of current imaging modalities for nodal staging, and summarises emerging evidence from neoadjuvant immunotherapy trials. Particular emphasis is placed on the interpretation of lymph node findings in the era of immune checkpoint blockade and the implications for surgical decision-making, organ preservation, and future staging paradigms. Full article

The treatment of chronic lymphocytic leukemia (CLL) has shifted from chemoimmunotherapy to targeted therapy, resulting in improved outcomes and patient survival. The aim of this study was to evaluate the efficacy and safety of venetoclax-based regimens in patients with relapsed/refractory CLL, as well as their effectiveness in patients previously treated with ibrutinib. We retrospectively analyzed 98 patients with CLL who received venetoclax in the second or later lines of therapy in Slovakia between 2018 and 2024. The median age was 68 years, and treatment was administered either as monotherapy or in combination with rituximab. Response to treatment was assessed according to the iwCLL 2018 criteria and clinical practice. Patients who achieved complete hematologic and clinical remission but did not undergo confirmatory bone marrow examination were classified as having unconfirmed complete remission (uCR). An overall response was achieved in the majority of patients (in 99%), with 2% achieving complete remission, 65% incomplete complete remission and 32% partial remission. At a median follow-up of 34 months, median overall survival was not reached (mean 52.5 months), and median progression-free survival was 45 months. Survival outcomes were evaluated using Kaplan–Meier analysis. Patients previously treated with ibrutinib had significantly worse outcomes (p = 0.022). Adverse events were predominantly hematological (64%), with 19% being grade 3–4. In line with the conclusions of clinical trials and retrospective analysis from real-life practice, we can say that venetoclax-based treatment regimens are highly effective in patients with CLL in higher lines of treatment, with acceptable and well-manageable toxicity. Full article

Background: Chimeric antigen receptor T-cell (CAR-T) therapies have transformed the treatment of haematologic malignancies, yet their adverse event (AE) profiles across all approved agents have not been consolidated using a pharmacovigilance methodology in a single comparative analysis. Methods: Using the FDA Adverse Events Reporting System (FAERS) and OpenVigil 2.1, disproportionality analyses for all six FDA-approved CAR-T therapies were performed, stratified by target antigen: anti-CD19 agents (axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel, brexucabtagene autoleucel) and anti-BCMA agents (idecabtagene vicleucel, ciltacabtagene autoleucel). For each of the 25 most frequently reported AEs per agent, the report event counts, reporting odds ratio (ROR) with 95% confidence interval, proportional reporting ratio (PRR), and chi-squared statistic were calculated. Results: A total of 36,567 AEs were identified across all six agents. Cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome were the most frequent and most disproportionate AEs across all six therapies, with RORs exceeding 240 in every agent. Idecabtagene vicleucel had the highest ROR for cytokine release syndrome among all agents (ROR 1934.6), while brexucabtagene autoleucel had the highest ROR for immune effector cell-associated neurotoxicity syndrome (ROR 2089.6). Ciltacabtagene autoleucel exhibited a unique neurological toxicity profile, cranial nerve paralysis (ROR 3167.6, PRR 3055.0, chi² 199,190), parkinsonism (ROR 145.5, PRR 136.6, chi² 24,840), Bell’s palsy (ROR 380.4, PRR 370.3), and facial paralysis (ROR 72.7), consistent with the late neurotoxicity syndrome previously characterized, and absent from other agents’ top 25 AE lists. Brexucabtagene autoleucel demonstrated secondary malignancy signals including squamous cell carcinoma of skin (ROR 308.2) and myelodysplastic syndrome (ROR 97.9). Tisagenlecleucel showed the highest hypogammaglobulinemia signal among all agents (ROR 614.1, PRR 536.5, chi² 144,832) alongside a broad pancytopenia profile. Hemophagocytic lymphohistiocytosis was a significant finding with ciltacabtagene autoleucel (ROR 71.0) and brexucabtagene autoleucel (ROR 57.8). Conclusions: CAR-T therapies share class-wide toxicities in cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, but exhibit clinically important drug-specific and target-class-specific AE profiles. This consolidated FAERS-based analysis corroborates and extends prior pharmacovigilance work by providing direct cross-agent comparisons, and supports the use of agent-tailored monitoring strategies, particularly for the distinctive late neurological toxicity associated with ciltacabtagene autoleucel. Full article