Coumarin-Induced Hepatotoxicity: A Narrative Review.

Coumarin is an effective treatment for primary lymphoedema, as well as lymphoedema related to breast cancer radiotherapy or surgery. However, its clinical use is limited in several countries due to the possible occurrence of hepatotoxicity, mainly in the form of mild to moderate transaminase elevation. It is worth noting that only a few cases of severe hepatotoxicity have been described in the literature, with no reported cases of liver failure. Data available on coumarin absorption, distribution, metabolism, and excretion have been reviewed, focusing on hepatotoxicity studies carried out in vitro and in vivo. Finally, safety and tolerability data from clinical trials have been thoroughly discussed. Based on these data, coumarin-induced hepatotoxicity is restricted to a small subset of patients, probably due to the activation in these individuals of alternative metabolic pathways involving specific CYP450s isoforms. The aim of this work is to stimulate research to clearly identify patients at risk of developing hepatotoxicity following coumarin treatment. Early identification of this subset of patients could open the possibility of more safely exploiting the therapeutical properties of coumarin, allowing patients suffering from lymphoedema to benefit from the anti-oedematous activity of the treatment.

Noncontrast Magnetic Resonance Lymphangiography in a Rare Case of Everolimus-Related Lymphedema.

Everolimus is a mammalian target of rapamycin (mTOR) inhibitor, which is used in immunosuppressive treatment regimens in solid-organ transplant recipients. Although mTOR inhibitors are usually well tolerated, their adverse effects have been reported: sirolimus treatment in transplant patients has been rarely reported to be associated with lymphedema of the skin and subcutaneous tissues, whereas the use of everolimus seemed to be less burdened by this type of adverse effect. We report the case of a 58-year-old man with a history of end-stage renal disease of unknown etiology who had undergone right renal transplantation 11 years before. After the transplant, the patient soon developed bilateral progressive swelling involving feet and legs. The symptoms of the left limb improved markedly after discontinuing everolimus. This condition has been classified as everolimus-induced lymphedema. The patient was referred to our department for the execution of a noncontrast magnetic resonance lymphangiography, that is, a noninvasive magnetic resonance imaging technique that has recently proposed for the study of lymphedema. Noncontrast magnetic resonance lymphangiography showed asymmetry between the lower extremities with signs of advanced lymphedema located in the right lower limb and dilated peripheral lymphatic vessels.Drug withdrawal is currently the only effective solution for treating this type of secondary lymphedema; however, with the prolonged use of the drug, lymphedema tends to persist even after mTOR inhibitor suspension, with only partial clinical improvement, as in this case.This case report describes the imaging characteristics of such condition at noncontrast magnetic resonance lymphangiography and discusses the rare adverse effects of everolimus. Immediate suspension of the drug is the only effective strategy to avoid the persistence of this disorder.

Incidence of peripheral edema in patients receiving PI3K/mTOR/CDK4/6 inhibitors for metastatic breast cancer.

PURPOSE: This study evaluated development of edema in patients receiving PI3K/mTOR/CDK4/6 targeted therapy for metastatic breast cancer (MBC). METHODS: We reviewed medical records of 160 patients receiving targeted therapy with PI3K/mTOR/CDK4/6 inhibitors to treat MBC (n = 160; 185 treatment occurrences). Clinicopathologic data, treatment details, and edema incidence were recorded. RESULTS: Edema incidence was 43.1% (69/160) overall and 25.6% (41/160) in the upper extremity ipsilateral to the treated breast. In 185 therapy regimens administered, 6.8% of patients on a PI3K inhibitor, 8.8% of patients on an mTOR inhibitor, and 9.2% of patients on a CDK4/6 inhibitor experienced new onset or worsened preexisting upper extremity edema. Further, 9.1% of patients on a PI3K inhibitor, 18.8% of patients on an mTOR inhibitor, and 10.5% of patients on a CDK4/6 inhibitor experienced new onset or worsened preexisting edema elsewhere in the body. Multivariate logistic regression showed that, beyond the established breast cancer-related lymphedema (BCRL) risk factors [axillary lymph node dissection (Odds Ratio (OR) 2.69, p = 0.020), regional lymph node irradiation (OR 6.47, p < 0.001), and body-mass index ≥ 30 kg/m2 (OR 3.46, p = 0.006)], a relative decrease in serum albumin after 3 months of treatment increased risk of developing edema (OR 2.07, p = 0.062). Neither duration nor type of therapy were significant risk factors for edema. CONCLUSION: PI3K/mTOR/CDK4/6 inhibitors may influence the development of edema, which may cause or exacerbate progression of BCRL in patients with MBC. The varied incidence of edema between therapeutic regimens warrants vigilant monitoring of patients treated with these therapies, especially those at high risk of developing BCRL.

Survivorship, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Survivorship provide screening, evaluation, and treatment recommendations for common physical and psychosocial consequences of cancer and cancer treatment to help healthcare professionals who work with survivors of adult-onset cancer in the posttreatment period. This portion of the guidelines describes recommendations regarding the management of anthracycline-induced cardiotoxicity and lymphedema. In addition, recommendations regarding immunizations and the prevention of infections in cancer survivors are included.

Lymphedema, musculoskeletal events and arm function in older patients receiving adjuvant chemotherapy for breast cancer (Alliance A171302).

PURPOSE: Musculoskeletal events (MEs) resulting from breast cancer treatment can significantly interfere with the quality of life (QOL) of older adults. We evaluated the incidence of MEs in women 65 years and older who had surgery and adjuvant chemotherapy for breast cancer, and the impact of treatment on MEs and arm function. PATIENTS AND METHODS: Patient-reported data in Alliance/CALGB 49907 were collected using the EORTC QLQ-BR23 and physician-reported adverse events to characterize self-reported MEs and incidence of lymphedema. EORTC QLQ-BR23 items related to musculoskeletal events were analyzed in this study and data collected at study entry (post-operative) and 12 and 24 months post-entry. RESULTS: Lymphedema, arm function, and ME data were available for 321 patients. One or more MEs were reported by 87% (median number = 3) and 64% (median number = 1) of patients post-operatively and at 24 months. At 24 months 2% had persistence of six MEs. Seventy-four percent experienced at least ≥3/6 types of MEs over the 24-month period. Detection of lymphedema at any time during the study was noted in 7.5% of the patients and appeared to be associated with the type of chemotherapy given: CMF 16.4%, capecitabine 5.8%, and AC 4%. Mastectomy and axillary node dissection were associated with the most MEs. LROM correlated with poorer arm function at all time periods. CONCLUSION: Potentially debilitating MEs occur in three-fourths of elderly women undergoing standard therapy for breast cancer. Emphasis should be placed on prevention, identification, and treatment of these MEs to improve QOL.

Association between adjuvant docetaxel-based chemotherapy and breast cancer-related lymphedema.

Docetaxel-based chemotherapy can lead to fluid retention and secondary peripheral edema of the extremities, but its association with lymphedema remains unclear. In this study, we retrospectively investigated the relationship between adjuvant docetaxel-based chemotherapy and breast cancer-related lymphedema. Patients with stage II/III breast cancer who received adjuvant chemotherapy were evaluated for lymphedema on the basis of arm circumference measurements. The incidence and risk factors of lymphedema were determined by Kaplan-Meier and Cox proportional hazard analyses. A total of 320 patients were included. Specifically, 182 patients received docetaxel and 138 patients did not receive docetaxel. Compared with docetaxel-free chemotherapy, docetaxel-based chemotherapy significantly increased the 2.5-year cumulative incidence of all-grade lymphedema (19.91 vs. 32.09%; P=0.011), which was further verified in grade 1-2 (P=0.012), but not in grade 3 lymphedema (P=0.448). Similar results were found in a comparison between docetaxel and nontaxane, but not in a comparison between docetaxel and other taxanes. Multivariate analysis showed that docetaxel-based chemotherapy is an independent risk factor for both all-grade (hazard ratio=1.73; P=0.017) and grade 1-2 lymphedema (hazard ratio=1.87; P=0.022). In conclusion, adjuvant docetaxel-based chemotherapy significantly increased the risk of breast cancer-related lymphedema.

Neutrophilic Dermatosis Limited to Lipo-Lymphedematous Skin in a Morbidly Obese Woman on Dasatinib Therapy.

Neutrophilic dermatosis (ND) confined to postmastectomy lymphedema, localized Sweet syndrome, is a newly recognized disease. In this study, the authors describe a 44-year-old obese woman with chronic myelogenous leukemia in molecular remission on dasatinib therapy, who presented with a painful urticarial eruption limited to lipo-lymphedematous skin and accompanied by malaise, episodic fever, diarrhea, neutrophilia, and leukocytosis. Initially transient and migratory, the rash became fixed, papular, and vesicular and showed minimal response to corticosteroids. Biopsy demonstrated sparse perivascular and interstitial dermal neutrophilic infiltrates, without vasculitis or significant dermal edema. Aggregates of neutrophils were found within and surrounding lymphangiectases. Biopsy of a new onset papule 3 weeks later demonstrated papillary dermal edema, denser neutrophilic infiltrate, and vasculitis-like changes. These 2 histopathologic patterns of ND, early and late, resemble neutrophilic urticarial dermatitis (also known as neutrophilic dermatitis with systemic inflammation) and Sweet syndrome, respectively. Extensive workup did not reveal evidence of relapsed chronic myelogenous leukemia, infection, or a coexisting systemic inflammatory disease. Dasatinib was discontinued and the eruption gradually resolved over 2.5 months. Still in molecular remission (no detectable BCR-ABL gene fusion), dasatinib therapy was recommenced at 3-month follow-up. After 10 months, she complains of malaise and arthralgia, but no cutaneous symptoms. The evolution and slow resolution of this ND in lipo-lymphedematous skin implicate poor lymphatic clearance of factors, antigenic and/or toxic, involved in the pathogenesis of ND.

Adjuvant taxanes and the development of breast cancer-related arm lymphoedema.

BACKGROUND: Despite affecting approximately one-quarter of all patients undergoing axillary lymph node dissection, the pathophysiology of breast cancer-related lymphoedema (BCRL) remains poorly understood. More extensive locoregional treatment and higher body mass index have long been identified as major risk factors. This study aimed to identify risk factors for BCRL with a specific focus on the potential impact of chemotherapy on the risk of BCRL. METHODS: This was a retrospective analysis of a cohort of consecutive patients with breast cancer treated at a major London regional teaching hospital between 1 January 2010 and 31 December 2012. All patients had node-positive disease and underwent axillary lymph node dissection. Data regarding tumour-, patient- and treatment-related characteristics were collected prospectively. The diagnosis of BCRL was based on both subjective and objective criteria. Multivariable Cox proportional hazards regression was used to assess the association between treatment and risk of BCRL. RESULTS: Some 27.1 per cent of all patients (74 of 273) developed BCRL over the study period. Administration of taxanes showed a strong association with the development of BCRL, as 52 (33.5 per cent) of 155 patients who received taxanes developed BCRL. Multivariable Cox regression analysis demonstrated that patients who received taxanes were nearly three times more likely to develop BCRL than patients who had no chemotherapy (hazard ratio 2.82, 95 per cent c.i. 1.31 to 6.06). No such increase was observed when taxanes were administered in the neoadjuvant setting. CONCLUSION: The present findings suggest that adjuvant taxanes play a key role in the development of BCRL after surgery. This may support the use of taxanes in a neoadjuvant rather than adjuvant setting.

Sexual concerns of women diagnosed with breast cancer-related lymphedema.

PURPOSE: Lymphedema is a common side effect of breast cancer treatment that may negatively impact on a woman's physical and psychological well-being. This study aimed to understand the impact of breast cancer-related lymphedema on women's sexual functioning, and to identify key concerns of these women regarding sexual issues. METHODS: Purposive sampling recruited 17 women aged 38-67 years with mild to severe lymphedema. Telephone interviews concerning sexual issues were transcribed verbatim and thematic analysis undertaken. RESULTS: Women perceived sexual concerns arising from lymphedema to exacerbate concerns arising from breast cancer. Four interrelated factors determined the extent of lymphedema's sexual impact: (a) swelling severity and location, (b) needing to wear a compression garment, (c) body image concerns raised by lymphedema and breast cancer treatment, and (d) their sexual partner's acceptance and supportiveness. In particular, a supportive partner was instrumental in assisting women to overcome sexual issues caused by severe swelling and/or body image concerns. Few women reported being asked about sexual issues by any health professional, and most women indicated that they were unwilling to discuss sexual concerns with health professionals, friends, or family. CONCLUSIONS: Lymphedema had the potential to accentuate sexual issues caused by breast cancer, but most women were reluctant to discuss issues with anyone other than their partner. These findings are relevant to health professionals designing breast cancer psychosexual interventions and future research addressing lymphedema-specific sexual concerns.

Pemetrexed-Associated Eyelid Edema: Effective Treatment by Excision of Lymphedematous Eyelid Tissue.

Pemetrexed is an antimetabolite agent that inhibits multiple folate-requiring enzymes and is used in the treatment of mesothelioma and non-small-cell lung cancer. One of its toxicities is isolated cutaneous swelling affecting the eyelids and/or orbit. The pathologic assessment or its management has not been addressed to date. Herein, the authors report a case of a 77-year-old woman treated with pemetrexed for non-small-cell lung adenocarcinoma who developed persistent, severe bilateral lower eyelid swelling for several months, despite compresses and oral diphenhydramine. Elective excision was performed with good results and no recurrence after 6 months' follow up. Histopathologically, the excised tissue showed changes typical of dermatochalasis with dissolution of collagen and elastic bundles and marked dilation of lymphatic vessels. The combination of pre-existing, localized lymphatic failure and capillary leakage secondary to pemetrexed therapy can explain the onset and worsening swelling with successive rounds of chemotherapy.

[Sirolimus-induced lymphedema in a kidney-transplant recipient: Partial recovery after changeover to tacrolimus]. / Lymphœdème induit par le sirolimus chez une greffée rénale : amélioration après remplacement par le tacrolimus.

BACKGROUND: Lymphedema induced by mTOR inhibitors is a side-effect rarely reported to date. PATIENTS AND METHODS: Long-lasting bilateral lower-limb lymphedema with left predominance developed in a 71-year-old stable renal transplant recipient after 40 months of sirolimus treatment. Although no change in lymphedema was observed after 21 months despite dosage reduced, it improved markedly after changeover to tacrolimus. DISCUSSION: Regardless of the individual drug, mTOR inhibitors can cause lymphedema. This effect may be countered through substitution with tacrolimus. CONCLUSION: Physicians should be aware of lymphedema as a side-effect of mTOR inhibitors. It can be improved by substitution with tacrolimus. However, early withdrawal of mTOR inhibitors is recommended before irreversible lymphedema occurs.

Human lymphatic vessel contractile activity is inhibited in vitro but not in vivo by the calcium channel blocker nifedipine.

Calcium channel blockers (CCB) are widely prescribed anti-hypertensive agents. The commonest side-effect, peripheral oedema, is attributed to a larger arterial than venous dilatation causing increased fluid filtration. Whether CCB treatment is detrimental to human lymphatic vessel function and thereby exacerbates oedema formation is unknown. We observed that spontaneous lymphatic contractions in isolated human vessels (thoracic duct and mesenteric lymphatics) maintained under isometric conditions were inhibited by therapeutic concentrations (nanomolar) of the CCB nifedipine while higher than therapeutic concentrations of verapamil (micromolar) were necessary to inhibit activity. Nifedipine also inhibited spontaneous action potentials measured by sharp microelectrodes. Furthermore, noradrenaline did not elicit normal increases in lymphatic vessel tone when maximal constriction was reduced to 29.4 ± 4.9% of control in the presence of 20 nmol l(-1) nifedipine. Transcripts for the L-type calcium channel gene CACNA1C were consistently detected from human thoracic duct samples examined and the CaV1.2 protein was localized by immunoreactivity to lymphatic smooth muscle cells. While human lymphatics ex vivo were highly sensitive to nifedipine, this was not apparent in vivo when nifedipine was compared to placebo in a randomized, double-blinded clinical trial: conversely, lymphatic vessel contraction frequency was increased and refill time was faster despite all subjects achieving target nifedipine plasma concentrations. We conclude that human lymphatic vessels are highly sensitive to nifedipine in vitro but that care must be taken when extrapolating in vitro observations of lymphatic vessel function to the clinical situation, as similar changes in lymphatic function were not evident in our clinical trial comparing nifedipine treatment to placebo.

Vaccines and risk of lymphoedema--a case report of a breast cancer patient.

BACKGROUND: Vaccinations have been linked to lymphoedema but there is no quality scientific evidence to support or refute a causative relationship. OBJECTIVE: We report on a case of a breast cancer patient who developed lymphoedema following vaccination in her 'at risk' arm. She had previously undergone mastectomy and axillary clearance but did not have lymphoedema before the vaccinations. DISCUSSION: The risk of lymphoedema is still present for many years following breast surgery. Patients who are at risk of lymphoedema should be warned to report persistent swelling after vaccination so that they can be referred early for physiotherapy intervention if required.

Characteristics of Lymphedema in Patients Treated with Mammalian Target of Rapamycin Inhibitors.

Purpose: To investigate the characteristics of lymphedema in patients treated with mammalian target of rapamycin (mTOR) inhibitors and delineate complex decongestive therapy (CDT) outcomes. Methods and Results: We retrospectively analyzed 24 patients with mTOR inhibitor-induced lymphedema and 7 lymphedema patients (control) not treated with mTOR inhibitors, who visited the lymphedema clinic of the department of rehabilitation medicine from March 2016 to December 2019. We comprehensively reviewed clinical features, medication history, associated diseases, lymphoscintigraphy, lower extremity computed tomography venography (LE CTV), and the effect of CDT. By using ImageJ program, we measured the cross-sectional area (CSA) of muscle and subcutaneous fat of mid-thigh image in LE CTV and compared them to a control group not treated with mTOR inhibitors. Seventeen patients on sirolimus and seven patients on everolimus were included, with an approximately equal distribution of stages 2 and 3 lymphedema, and most with pitting edema. Ten patients had breast or gynecological cancer and underwent lymph node dissection. Lymphedema developed after mTOR inhibitor initiation, not postoperatively. Lymphoscintigraphy revealed decreased lymph node uptake and dermal backflow. LE CTV revealed subcutaneous honeycomb-shaped trabecular areas in the affected limbs of seven patients. Patients treated with mTOR inhibitors had a larger mean subcutaneous fat CSA and a smaller mean muscular CSA than controls. Lymphedema improved or remained unchanged after initial CDT. Daily CDT adequately controlled 11 cases, but exacerbation occurred in 5 of 7 poorly compliant patients, and cellulitis occurred in 6 patients. Conclusion: Physicians should identify mTOR inhibitor-related lymphedema early and discuss medication alternatives and CDT with patients.

Evaluation of lymphatic function by means of dynamic Gd-BOPTA-enhanced MRL in experimental rabbit limb lymphedema.

BACKGROUND: The aim of this study was to investigate the value and technical methods of 3D dynamic contrast-enhanced magnetic resonance lymphangiography (MRL) in the assessment of lymphatic anatomy and function in the presence of extremity lymphedema. MATERIAL/METHODS: An improved experimental model of obstructive lymphedema was established in 1 hind limb of 6 New Zealand White rabbits. 3D contrast-enhanced MRL was performed with a 3.0-T MR unit after the intracutaneous injection of Gd-BOPTA into the interdigital webs of the dorsal paws. Maximum-intensity projection (MIP) was used to reconstruct the images of the lymphatic system. The dynamic nodal enhancement in the popliteal fossa and time-signal intensity curves between lymphedematous and contralateral limbs were compared. Morphologic abnormalities of the lymphatic system were also evaluated and compared with lymphoscintigraphy (LSG). RESULTS: 3D dynamic contrast-enhanced MRL images were obtained after the administration of Gd-BOPTA. In the normal limb, the popliteal fossa lymph nodes and their afferent and efferent lymph-collecting vessels were clearly visualized as the Gd tracer was rapidly cleared from the interstitial compartment. In contrast, the Gd tracer accumulated slowly at the prior surgical site in the lymphedematous limb. The nodal enhancement of lymphedematous limbs was significantly less than that of the contralateral limbs (P<0.01). Types of time-signal intensity curves were also significantly different between the 2 groups (P<0.001). CONCLUSIONS: 3D dynamic contrast-enhanced MRL can visualize the precise anatomy of lymphatic vessels and lymph nodes in extremity lymphedema, as well as objectively evaluate the functional status of lymph flow transport.

Analysis of Unusual Adverse Effects After Radium-223 Dichloride Administration.

BACKGROUND: To our knowledge, no previous study or literature review has been performed about the effects of the extravasation of therapeutic radiopharmaceutical agents and its potential consequences, especially regarding alpha-particle emitting radiopharmaceuticals. METHODS: Even if Radium-223 dichloride is known to be a relatively safe drug to manage, despite the correctness of the procedures applied , unexpected delayed adverse effects can occur. In our vast experience, we rarely observed lymphedema, even after some time, at the site of administration. RESULTS: Management of lymphedema caused by radiopharmaceuticals administration has been addressed through clinical examples. The sudden intervention allowed a fast remission of the signs and symptoms complained by patients treated with Radium-223 dichloride. CONCLUSION: The management of adverse effects after radiopharmaceuticals administration as in case of lymphedema onset, is extremely simple. These data confirm the safety of Radium-223 treatment.

Everolimus-related unilateral abdominal lymphedema in a renal cancer patient: A case report.

RATIONALE: Unilateral manifestation of lymphedema during everolimus therapy has been described only rarely, mostly in transplant recipients. PATIENT CONCERNS: We report the first case of a patient who developed unilateral abdominal lymphedema, during a short period of everolimus treatment for renal cancer. DIAGNOSIS: The abdominal asymmetry occurred only on the right side of the abdomen, neither ultrasound nor CT scan detected ascites but showed enlargement of the abdominal wall. The Naranjo Adverse Drug Reaction Probability scale was evaluated, in this case, a score of 6 indicated a probable adverse reaction to everolimus. INTERVENTIONS: Discontinuation of everolimus therapy led to immediate alleviation and reduction of the lymphedema, with worsening once again after initiating retreatment with everolimus at a reduced dose. OUTCOMES: The patient's lymphedema recovered after discontinuation of everolimus. LESSONS: This rare case demonstrates the importance of the selection of mammalian target of rapamycin inhibitors using caution, especially for patients with a high risk of developing lymphedema.