Cancer and heart disease are the leading causes of mortality in the USA. Advances in cancer therapies, namely, the development and use of chemotherapeutic agents alone or in combination, are becoming increasingly prevalent.

Many chemotherapeutic agents have been associated with adverse cardiovascular manifestations. The mechanisms of these sequelae remain incompletely understood. In particular, microtubule inhibitor (MTI) agents have been related to the development of heart failure, myocardial ischemia, and conduction abnormalities. At present, there are no guidelines for patients undergoing MTI therapy as it pertains to both preventative and mitigatory strategies for cardiovascular complications. We conducted a literature review focusing on content related to the use of MTIs and their effect on the cardiovascular system. MTIs have been associated with various forms of cardiotoxicity, and fatal cardiotoxicities are rare. The most well-described cardiotoxicities are brady- and tachyarrhythmias. The co-administration of anthracycline-based agents with MTIs can increase the risk of cardiotoxicity.

Pulmonary veno-occlusive disease (PVOD) is a rare disease characterized by the obstruction of small pulmonary veins leading to pulmonary hypertension. However, the mechanisms underlying pulmonary vessel occlusion remain largely unclear.

A mitomycin C (MMC)-induced PVOD rat model was used as in vivo animal model, and primarily cultured rat pulmonary microvascular endothelial cells (PMVECs) were used as in vitro cell model.

Our data suggested an endothelial-to-mesenchymal transition (EndoMT) may be present in the pulmonary microvessels isolated from either PVOD patients or MMC-induced PVOD rats. In comparison to the control vessels, vessels from both PVOD patients and PVOD rats had co-localized staining of specific endothelial marker von Willebrand factor (vWF) and mesenchymal marker α-smooth muscle actin (α-SMA), suggesting the presence of cells that co-express endothelial and mesenchymal markers. In both the lung tissues of MMC-induced PVOD rats and MMC-treated rat PMVECs there were decreased levels of endothelial markers (e.g. VE-cadherin and CD31) and increased mesenchymal markers (e.g. vimentin, fibronectin and α-SMA) were detected indicating EndoMT. Moreover, MMC-induced activation of the TGFβ/Smad3/Snail axis, while blocking this pathway with either selective Smad3 inhibitor (SIS3) or small interfering RNA (siRNA) against Smad3, dramatically abolished the MMC-induced EndoMT. Notably, treatment with SIS3 remarkably prevented the pathogenesis of MMC-induced PVOD in rats.

Our data indicated that targeted inhibition of Smad3 leads to a potential, novel strategy for PVOD therapy, likely by inhibiting the EndoMT in pulmonary microvasculature.

Pulmonary venoocclusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) predominantly characterized by pulmonary vein and capillary involvement. An association between chemotherapy, in particular mitomycin C (MMC), and PVOD has been reported.

What are the characteristics of MMC-induced PVOD, and what is the prognosis for patients with MMC-induced PVOD?

We report the clinical, functional, radiologic, and hemodynamic characteristics at diagnosis and outcomes of patients with PVOD from the French PH Registry after exposure to MMC. The results are expressed as the median (minimum-maximum).

From June 2011 to December 2018, 17 incident cases of MMC-induced PVOD were identified. At diagnosis, these patients had severe clinical and functional impairment, with 12 patients having a New York Heart Association (NYHA) functional class of III or IV and a 6-min walk distance of 220 (0-465) m. Right heart catheterization confirmed severe precapillary PH with a mean pulmonary artery pressure of 38 (30-52) mm Hg, a cardiac index of 2.2 (1.5-4) L/(min × m²), and pulmonary vascular resistance of 8.3 (5.1-14.5) Wood units. The diffusing capacity of the lungs for carbon monoxide was markedly decreased at 31% (20%-51%) of the theoretical values associated with severe hypoxemia. MMC was withdrawn for all patients, and 14 patients received specific pulmonary arterial hypertension (PAH) therapies. Among these patients, mild but statistically insignificant improvements were observed in NYHA functional class (P = .10), 6-min walk distance (P = .09), and pulmonary vascular resistance (-4.7 Wood units; P = .052) at reassessment (median delay of 4.8 months). Three patients experienced pulmonary edema requiring the cessation or reduction of PAH treatment. The median overall survival was 20 months, and the 6-, 12-, and 24-month survival rates were 76%, 58%, and 18%, respectively.

PVOD after MMC treatment is a rare but life-threatening complication associated with a poor prognosis despite MMC withdrawal and PAH-specific therapy.

Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension characterized by the obstruction of small pulmonary veins and a dismal prognosis. PVOD may be sporadic or heritable because of biallelic mutations of the EIF2AK4 gene coding for GCN2. Isolated case reports suggest that chemotherapy may be a risk factor for PVOD.

We reported on the clinical, functional, and hemodynamic characteristics and outcomes of 7 cases of PVOD induced by mitomycin-C (MMC) therapy from the French Pulmonary Hypertension Registry. All patients displayed squamous anal cancer and were treated with MMC alone or MMC plus 5-fluoruracil. The estimated annual incidence of PVOD in the French population that have anal cancer is 3.9 of 1000 patients, which is much higher than the incidence of PVOD in the general population (0.5/million per year). In rats, intraperitoneal administration of MMC induced PVOD, as demonstrated by pulmonary hypertension at right-heart catheterization at days 21 to 35 and major remodeling of small pulmonary veins associated with foci of intense microvascular endothelial-cell proliferation of the capillary bed. In rats, MMC administration was associated with dose-dependent depletion of pulmonary GCN2 content and decreased smad1/5/8 signaling. Amifostine prevented the development of MMC-induced PVOD in rats.

MMC therapy is a potent inducer of PVOD in humans and rats. Amifostine prevents MMC-induced PVOD in rats and should be tested as a preventive therapy for MMC-induced PVOD in humans. MMC-induced PVOD in rats represents a unique model to test novel therapies in this devastating orphan disease.

Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy-induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal models (mouse, rat, and rabbit). Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (43.2%). In three different animal models, cyclophosphamide was able to induce PH on the basis of hemodynamic, morphological, and biological parameters. In these models, histopathological assessment confirmed significant pulmonary venous involvement highly suggestive of PVOD. Together, clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon, but severe, pulmonary vascular complication of alkylating agents.

Pulmonary venoocclusive disease (PVOD) is a rare lung disease, diagnosed in 5% to 10% of patients with pulmonary hypertension (PH). The incidence, prevalence, and etiology of PVOD in children are not well defined. The mortality remains high, related, at least partly, to the limited treatment options.

This retrospective analysis (1985-2011) summarizes symptoms, associated factors, treatment, and outcomes of nine pediatric patients (five girls, four boys) with histologic confirmation of PVOD.

PH was diagnosed at a mean age of 13.5 years (range, 8-16 years), followed by the definitive diagnosis of PVOD at a mean age of 14.3 years (range, 10-16 years). Symptoms such as decreased exercise tolerance (n = 6) and/or shortness of breath (n = 9) preceded the diagnosis by 21 months on average; the mean survival time after diagnosis was 14 months (range, 0-47 months). CT scans of the lungs showed typical radiologic features. Treatment included supplemental home oxygen (n = 5), diuretics (n = 9), warfarin (n = 4), and pulmonary vasodilators (n = 4). Four children were listed for lung transplantation, and three have undergone transplantation. Eight patients died, including two after lung transplantation. One patient with lung transplant survived with good quality of life.

PVOD is an important differential diagnosis for pediatric patients with PH. CT scanning is a valuable tool to image lung abnormalities; the definitive diagnosis can only be made by examination of lung biopsy specimens, which subjects the patient to additional risk. Early listing for lung transplantation is essential, as the mean survival time is only 14 months.

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension which occurs in 0.1-0.2 people per million. Its etiology is still poorly understood but is related to several risk factors. The histopathology of PVOD is characterized by intimal fibrosis narrowing or the occlusion of small pulmonary veins or venules. A definitive diagnosis requires a surgical biopsy, which is a risky procedure. Thus, the diagnosis must be based on high clinical suspicion and the results of various diagnostic tests, mainly high-resolution computed tomography, pulmonary function tests, bronchoalveolar lavage, and right heart catheterization. The definitive treatment is limited to lung transplantation. Several pulmonary arterial hypertension-specific agents may cause pulmonary edema in PVOD. However, the cautious use of such medications in selected patients, and surgical or mechanical supports, may successfully bridge patients to transplantation. Given the scant knowledge regarding this entity, future studies with a focus on elucidating the etiology and establishing the optimal treatment are required, as is further development in diagnosis.

Progress in understanding the basic biology and the development of new therapies for pulmonary arterial hypertension have led to improvements in survival. This article reviews clinically important changes in the classification of the pulmonary hypertensive diseases, as well as the epidemiology of various forms of pulmonary hypertension. The risk factors for the development of pulmonary arterial hypertension, prognostic markers, and the effects of current therapies on survival are discussed.

This report describes two cases of segmental pulmonary vein occlusion secondary to lung malignancy in which lung biopsies showed histological features of veno-occlusive disease. These are the first cases to be reported in the literature in which such lung parenchymal histological changes are described in association with lung malignancy.

Pulmonary veno-occlusive disease (PVOD) is a rare, almost universally fatal complication of chemotherapy and bone marrow transplantation with few treatment options. A 19-month-old boy with stage 4 neuroblastoma with fatal PVOD following high-dose chemotherapy with autologous peripheral blood stem cell rescue is described here. A comprehensive literature review revealed 40 case reports of PVOD in oncology patients. Various therapeutic modalities were attempted, with four survivors. PVOD should be considered in patients with dyspnea and cardiomegaly. Less invasive diagnostic methods and more effective therapies are needed.

Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension that mainly affects children and young adults. Its cause is unknown, although viral infections and drugs have been implicated. Patients with PVOD present with symptoms of right-sided heart failure. Radiologic examination shows prominent pulmonary arteries with Kerley B lines, pleural effusion, and mediastinal adenopathy. The definite diagnosis is made by histologic examination. Eccentric intimal fibrosis and recanalized thrombi in pulmonary veins and venules, arterialized veins, alveolar edema, and medial hypertrophy of arteries are seen on lung biopsy. No effective treatment is available; lung transplantation has been tried. The prognosis associated with PVOD is poor.

Pulmonary veno-occlusive disease (PVOD) was diagnosed in an adult following chemotherapy and bone marrow transplantation (BMT) for acute lymphoblastic leukemia. A medical literature review showed only three previous reports of PVOD following BMT occurring in children but no prior cases in adults.

Capillary microscopy is an easy, noninvasive procedure to examine in vivo the dermis capillaries of the nailfold. It has demonstrated clinical use in the etiologic study of Raynaud's phenomenon. We consider a "vascular activity pattern" to be present at capillary microscopy when one of the following associations is observed: tortuous capillary vessels plus ramifications with or without loss of a moderate amount of capillaries. Capillary tortuousity alone is not considered pathologic. It is well known that bleomycin (BLEO) can occasionally induce vascular-associated diseases. To examine the vascular damage produced by BLEO, we performed capillary microscopic studies on 40 patients with neoplasia, 21 of whom had received BLEO during the previous year. The maximum accumulated doses ranged from 15 to 379 U. The other 19 patients had advanced neoplasia, and 10 of them had received antitumoral combinations that did not contain BLEO. No one had clinical signs attributable to vascular toxicity. Twenty-six patients had no pathologic patterns (11 received BLEO and 15 did not). In the group of 14 patients with activity patterns, 10 had received BLEO and 4 had not (P = 0.035). Ten of 11 patients treated with BLEO who had normal capillary microscopic studies received total doses of less than 100 U. We conclude that capillary microscopy may demonstrate the vascular damage induced by BLEO even in asymptomatic patients.

We report three cases of pulmonary veno-occlusive disease which developed following treatment for malignant neoplasms. Two patients received single agent BCNU chemotherapy for malignant gliomas. The third patient underwent combination radiation and chemotherapy for Hodgkin's disease. Isolated case reports of pulmonary veno-occlusive disease following therapy for malignant disease are reviewed and clinical features summarized. Pulmonary veno-occlusive disease in this setting is thought to be rare. However, the diagnosis is rarely suspected clinically and is difficult to diagnose pathologically. Therefore, the true incidence of this complication is unknown and may be higher than believed. It is important that both clinician and pathologist be aware of this entity; otherwise, elastic tissue stains may not be performed and the diagnosis missed.