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Patients with a solid tumor or hematologic malignancy are often addressed to emergency units for an acute respiratory complication associated with the underlying cancer or secondary to treatments. The current article is part of a thematic series: "Intensive care and emergencies in solid tumours and blood cancer patients" and will develop the following points: (1) malignant proximal airway obstruction and, more specifically, the role of therapeutic bronchoscopy; (2) superior vena cava syndrome by tumor compression and/or secondary to thrombosis (diagnosis, local and systemic treatments); (3) cancer-related pulmonary embolism (incidence, indications for low-molecular weight heparins and direct oral anticoagulants). Other respiratory emergencies will be dealt in the other articles of this series., (Copyright © 2023. Published by Elsevier Masson SAS.)

Literature regarding etiology and trends of incidence of major thoracic vein thrombosis in the United States is limited. To study the causes, complications, in-hospital mortality rate, and trend in the incidence of major thoracic vein thrombosis which could have led to superior vena cava syndrome (SVCS) between 2010 and 2018. Data from the nationwide emergency department sample (NEDS) that constitutes 20% sample of hospital-owned emergency departments (ED) and in-patient sample in the United States were analyzed using diagnostic codes. A linear p-trend was used to assess the trends. Of the total 1082 million ED visits, 37,807 (3.5/100,000) (mean age 53.81 ± 18.07 years, 55% females) patients were recorded with major thoracic vein thrombosis in the ED encounters. Among these patients, 4070 (10.6%) patients had one or more cancers associated with thrombosis. Pacemaker/defibrillator-related thrombosis was recorded in 2820 (7.5%) patients, while intravascular catheter-induced thrombosis was recorded in 1755 (4.55%) patients. Half of the patients had associated complication of pulmonary embolism. A total of 59 (0.15%) patients died during these hospital encounters. The yearly trend for the thrombosis for every 100,000 ED encounters in the United States increased from 2.17/100,000 in 2010 to 5.98/100,000 in 2018 (liner p-trend < 0.001). Yearly trend for catheter/lead associated thrombosis was also up-trending (p-trend 0.015). SVCS is an uncommon medical emergency related to malignancy and indwelling venous devices. The increasing trend in SVCS incidence, predominantly catheter/lead induced, and the high rate of associated pulmonary embolism should prompt physicians to remain vigilant for appropriate evaluation., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Our objective was to evaluate whether IV immunoglobulin (IVIg) increases the risk of thromboembolic events in neurology outpatients with inflammatory neuropathies, as there is conflicting evidence supporting this hypothesis, mainly from non-neurologic cohorts. We investigated this question over 30 months in our cohort of patients with inflammatory neuropathies receiving regular IVIg and found a greater incidence of arterial and venous thromboembolic events than population-based rates determined by hospital admissions data. Vascular risk factors were more common in the event group but there were no IVIg administration factors that contributed to the risk. This study suggests that IVIg may have a small but contributory role in determining thromboembolic risk in the inflammatory neuropathy cohort and more evidence is required before it is clear whether the current primary prevention guidelines are appropriate in this group of patients., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objectives: Superior vena cava syndrome (SVCS) is a medical emergency which can also be seen in Behçet's syndrome (BS). Having noted that BS patients with SVCS frequently complained of sleep disturbances, snoring and sleep apnea, suggesting obstructive sleep apnea (OSA), we formally surveyed the risk for OSA among BS patients., Methods: We studied 28 patients, all male, with SVCS (Group 1), 129 with vascular involvement without a SVCS (Group 2) and 151 with no vascular involvement (Group 3). In addition, 100 apparently healthy individuals (Group 4) were studied. The Berlin questionnaire (BQ), a validated screening tool with a high sensitivity and modest specificity that identifies individuals with high-risk for OSA, was administered to all study participants., Results: The study groups were similar with regard to age (Group 1, mean age: 44.3±9.7; Group 2, mean age: 41.5±8.7, Group 3, mean age: 40.4±9.4 and Group 4, mean age: 42.1±9.4) mean body mass index and the frequency of hypertension and other comorbidities. The frequency of those patients at high-risk for OSA according to the BQ was 57%, 17%, 17% and 11% in Groups 1, 2, 3 and 4, respectively (p<0.05). Age-adjusted ORs of OSA compared to healthy controls (Group 4) was 11.00 (95%CI: 4.01-30.07) for Group 1, 1.78 (95%CI: 0.81-3.94) for Group 2, 1.92 (95%CI: 0.90-4.14) for Group 3., Conclusions: BS patients with SVCS are at high risk for OSA. This is probably due to the external pressure of the significant presence of venous collaterals that surround the upper airways. Our results should be further confirmed by polysomnography, and future research should be carried out to clarify the causes of this association.

Superior vena cava syndrome (SVCS) results in vascular, respiratory, and neurologic compromise. A systematic search was conducted to determine the prevalence of pediatric SVCS subtypes and identify clinical characteristics/treatment strategies that may influence overall outcomes. Data from 101 case reports/case series (142 patients) were analyzed. Morbidity (30%), mortality (18%), and acute complications (55%) were assessed as outcomes. Thrombosis was present in 36%, with multi-modal anticoagulation showing improved outcome by >50% (P = 0.004). Infant age (P = 0.04), lack of collaterals (P = 0.007), acute complications (P = 0.005), and clinical presentation may have prognostic utility that could influence clinical decisions and surveillance practices in pediatric SVCS., (© 2018 Wiley Periodicals, Inc.)

Background: Establishing vascular access is a common neonatal intensive care unit procedure. The extended dwell peripheral intravenous (EPIV) catheter is a 6-cm and 8-cm silicone catheter for peripheral vein insertion, which is a newer vascular access device than peripherally inserted central catheters (PICCs) and peripheral intravenous (PIV) catheter. Extended dwell peripheral intravenous catheters have been widely used in adults but evidence in neonates is lacking., Purpose: To explore indwell time, success rate, catheter-associated complications, and cost among EPIV catheters, PICCs, and PIV catheters in neonates., Methods: We retrospectively compare patient demographics, indwell time, success rate, and catheter-associated complications, and analyze the rate of hyaluronidase-treated intravenous (IV) fluid extravasation on neonates who had an EPIV catheter, a PICC, or a PIV catheter in a level III neonatal intensive care unit. We also estimate the insertion cost of these 3 vascular access devices on the basis of our hospital charges., Results: Extended dwell peripheral intravenous catheters were inserted in 432 neonates with an indwell time of 4.0 ± 2.3 (mean ± SD) days. Peripherally inserted central catheters were inserted in 202 neonates with an average indwell time of 7.3 ± 4.4 (mean ± SD) days, which was longer than EPIV catheters (P < .001). Peripherally inserted central catheters had a higher success rate of 83.6% than 71.7% of EPIV catheters, meaning succeeded in lasting through the completion of therapy (P = .001). Peripherally inserted central catheters were associated with 4 cases of life-threatening complications; none was seen in the EPIV catheter group. The incidence of hyaluronidase-treated IV fluid extravasation was less in EPIV catheter recipients (1.2%) than in the PIV catheter recipients (3.9%) (P = .004); none was in the PICC group. Cost savings were noted with using an EPIV catheter., Implications for Practice: Extended dwell peripheral intravenous catheter is a feasible option for neonatal vascular access., Implications for Research: These data provide a baseline for future studies to explore the efficacy and effectiveness of EPIV catheter in the neonates.

Central vein thrombosis is defined as thrombosis of the major vessels draining either the upper or lower extremities. It presents most commonly in the upper limb, where it affects the subclavian veins and the superior vena cava; in the lower limb, it affects the common iliac veins and the inferior vena cava. These different anatomical segments pose unique challenges in both acute and chronic settings, and this article will summarize the current best practice treatment options., Competing Interests: Conflict of Interest Disclosure: Dr. Black is a consultant for Cook Medical, C. L. Bard, Inc., W. L. Gore & Associates, Inc., VENITI, Inc., Phillips Healthcare, Medtronic, Boston Scientific, and OptiMed.

Purpose: The aim of this paper is to evaluate the safety and efficacy of endovascular revascularization of malignant superior vena cava syndrome (SVCS) and simultaneous implantation of a totally implantable venous access port (TIVAP) using a dual venous approach., Materials and Methods: Retrospectively, 31 patients (mean age 67 ± 8 years) with malignant CVO who had undergone revascularization by implantation of a self-expanding stent into the superior vena cava (SVC) (Sinus XL®, OptiMed, Germany; n = 11 [Group1] and Protégé ™ EverFlex, Covidien, Ireland; n = 20 [Group 2]) via a transfemoral access were identified. Simultaneously, percutaneous access via a subclavian vein was used to (a) probe the lesion from above, (b) facilitate a through-and-through maneuver, and (c) implant a TIVAP. Primary endpoints with regard to the SVC syndrome were technical (residual stenosis < 30%) and clinical (relief of symptoms) success; with regard to TIVAP implantation technical success was defined as positioning of the functional catheter within the SVC. Secondary endpoints were complications as well as stent and TIVAP patency., Results: Technical and clinical success rate were 100% for revascularization of the SVS and 100% for implantation of the TIVAP. One access site hematoma (minor complication, day 2) and one port-catheter-associated sepsis (major complication, day 18) were identified. Mean catheter days were 313 ± 370 days. Mean imaging follow-up was 184 ± 172 days. Estimated patency rates at 3, 6, and 12 months were 100% in Group 1 and 84, 84, and 56% in Group 2 (p = 0.338)., Conclusion: Stent-based revascularization of malignant SVCS with concomitant implantation of a port device using a dual venous approach appears to be safe and effective.

Background: The widespread use of central venous catheters, ports, pacemakers, and defibrillators has increased the incidence of benign superior vena cava syndrome (SVCS). This study aimed at reviewing the results of open and endovascular treatment of SVCS., Method: Medical literature databases were searched for relevant studies. Studies with more than five adult patients, reporting separate results for the SVC were included. Nine studies reported the results of endovascular treatment of SVCS including 136 patients followed up for a mean of 11-48 months. Causes of SVCS were central venous catheters and pacemakers (80.6%), mediastinal fibrosis (13.7%), and other (5.6%). Percutaneous transluminal angioplasty (PTA) and stenting was performed in 73.6%, PTA only in 17.3%, and thrombolysis, PTA, and stenting in 9%. Four studies reported the results of open repair of SVCS including 87 patients followed up between 30 months and 10.9 years. The causes were mediastinal fibrosis (58.4%), catheters and pacemakers (28.5%), and other (13%). Operations performed included a spiral saphenous interposition graft, other vein graft, PTFE graft, and human allograft. Thirteen patients required re-operations (15%) before discharge mainly for graft thrombosis., Results: In the endovascular group technical success was 95.6%. Thirty day mortality was 0%. Regression of symptoms was reported in 97.3%. Thirty-two patients (26.9%) underwent 58 secondary procedures. In the open group the 30 day mortality was 0%. Symptom regression was reported in 93.5%. Twenty-four patients (28.4%) underwent a total of 33 secondary procedures., Conclusions: Endovascular is the first line treatment for SVCS caused by intravenous devices, whereas surgery is most often performed for mediastinal fibrosis. Both treatments show good results regarding regression of the symptoms and mid-term primary patency, with a significant incidence of secondary interventions., (Copyright © 2016 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

Unlabelled: Essentials Sparse or outdated studies focus on thrombotic and bleeding risk in home parenteral nutrition (HPN). 236 HPN patients followed at a single center for a total of 684 patient-years were evaluated. Rates of venous thrombosis and major bleeding, and prevalence of vena cava syndrome are provided. Anticoagulants might reduce thrombosis risk, but population-specific safety concerns remain., Summary: Background Home parenteral nutrition (HPN) is necessary for patients with intestinal failure. Recurrent catheter-related thrombosis (CRT) is common, leading to infectious complications, pulmonary embolism, vascular access loss and intestinal transplantation. The efficacy and safety of anticoagulants are unknown in this setting and based on sparse and low-quality observational data. Objectives Our aim was to estimate the incidence of thromboembolic, bleeding and anticoagulant-related complications in HPN patients, and evaluate risk factors for first venous thrombosis (VT). Methods This retrospective cohort study included all adult patients followed for long-term HPN at our center between 1986 and 2014. Primary outcomes were symptomatic objectively diagnosed VT, encompassing CRT and venous thromboembolism, and major bleeding. Secondary outcomes were vena cava syndrome and heparin-induced thrombocytopenia or hypersensitivity. Results A total of 236 patients were included (median HPN duration, 17 months) and 136 received anticoagulants at HPN onset (57.6%). Overall, the annual incidence of first VT was 11.4% (95% confidence interval [95% CI], 8.6-14.7%); VT was associated with a personal history of thrombosis (adjusted hazard ratio, 2.22; 95% CI, 1.06-4.64), whereas anticoagulation seemed to account only for a mild protection (adjusted hazard ratio, 0.72; 95% CI, 0.36-1.44). The annual incidence of major bleeding was 4.3% for patients on anticoagulants vs. 1.8% for those off anticoagulants. Vena cava syndrome developed in 20.7% of patients with VT. One patient had isolated heparin-induced thrombocytopenia (0.6%) and four had heparin hypersensitivity (2.5%). Conclusions Patients on HPN have a significant risk of venous thrombosis, major bleeding and vena cava syndrome. Anticoagulants might reduce thrombosis risk, but population-specific safety concerns remain., (© 2016 International Society on Thrombosis and Haemostasis.)

Objective: This study aimed to assess the prevalence and etiologies of focal liver opacification (FLO) in the setting of superior vena cava (SVC) obstruction., Methods: An archival search using key words to identify patients with SVC obstruction or severe narrowing and who had computed tomographic scans with intravenous contrast was performed at our institution., Results: Thirty-one patients were included. Focal liver opacification was identified in 9 (29%). The most common direct causes of FLO and SVC obstruction were benign., Conclusions: Focal liver opacification caused by SVC obstruction is relatively common. Focal liver opacification is more commonly associated with benign causes of obstruction such as end-stage renal disease. Identifying FLO is important not only as an indirect sign of SVC obstruction but also must be distinguished from avidly enhancing liver masses. This study also reflects the overall recent increase in benign causes of SVC obstruction.

The risk factors for superior vena cava (SVC) obstruction after pediatric orthotopic heart transplantation (OHT) have not been identified. This study tested the hypothesis that pretransplant superior cavopulmonary anastomosis (CPA) predisposes patients to SVC obstruction. A retrospective review of the Pediatric Cardiac Care Consortium registry from 1982 through 2007 was performed. Previous CPA, other cardiac surgeries, gender, age at transplantation, and weight at transplantation were assessed for the risk of developing SVC obstruction. Death, subsequent OHT, or reoperation involving the SVC were treated as competing risks. Of the 894 pediatric OHT patients identified, 3.1% (n = 28) developed SVC obstruction during median follow-up of 1.0 year (range: 0 to 19.5 years). Among patients who developed SVC obstruction, 32% (n = 9) had pretransplant CPA. SVC surgery before OHT was associated with posttransplant development of SVC obstruction (p <0.001) after adjustment for gender, age, and weight at OHT and year of OHT. Patients with previous CPA had increased risk for SVC obstruction compared with patients with no history of previous cardiac surgery (hazard ratio 10.6, 95% confidence interval: 3.5 to 31.7) and to patients with history of non-CPA cardiac surgery (hazard ratio 4.7, 95% confidence interval: 1.8 to 12.5). In conclusion, previous CPA is a significant risk factor for the development of post-heart transplant SVC obstruction., (Published by Elsevier Inc.)

Background: Haemorrhage remains a complication of flexible bronchoscopy., Objectives: We aimed to measure the actual blood loss in patients at low risk of bleeding and to assess its association with the underlying pulmonary pathology, superior vena cava (SVC) syndrome, procedure(s) performed and laboratory values., Methods: We screened all patients scheduled for flexible bronchoscopy and enrolled 234 subjects over 18 months. Subjects with a history of haemorrhagic tendency, platelets <20 × 10(3)/µl, a history of anti-coagulation or anti-platelet therapy and a history or clinical evidence of liver failure were excluded. Blood loss during the procedure was measured from aspirated secretions with a haemoglobin detector and categorised into minimal (<5 ml), mild (5-20 ml), moderate (20-100 ml) and severe bleeding (>100 ml)., Results: Overall, 210 subjects had minimal, 19 had mild and 5 had moderate bleeding. No subject experienced severe blood loss. Patients with SVC syndrome had the highest mean blood loss (6.0 ml) when compared to bronchogenic carcinoma without SVC syndrome (p = 0.033) and other diagnosis (p = 0.026). The blood loss with trans-bronchial needle aspiration (TBNA, mean 3.4 ml) was significantly less than with TBNA combined with endobronchial or transbronchial biopsy (mean 5.0 ml, p < 0.001). Anaemia, a platelet count of 25-155 × 10(3)/µl and an international normalized ratio of >1.3 were not associated with an increased risk of bleeding., Conclusions: We found no severe bleeding in this cohort preselected to have a low clinical risk of bleeding. Moreover, our data suggest that clinical screening and a platelet count ≥20 × 10(3)/µl alone may be sufficient to identify low-risk patients., (Copyright © 2012 S. Karger AG, Basel.)

The superior vena cava syndrome (SVCS) comprises various symptoms due to occlusion of the SVC, which can be easily obstructed by pathological conditions (eg, lung cancer, due to the low internal venous pressure within rigid structures of the thorax [trachea, right bronchus, aorta]). The resulting increased venous pressure in the upper body may cause edema of the head, neck, and upper extremities, often associated with cyanosis, plethora, and distended subcutaneous vessels. Despite the often striking clinical presentation, SVCS itself is usually not a life-threatening condition. Currently, randomized controlled trials on many clinically important aspects of SVCS are lacking. This review gives an interdisciplinary overview of the pathophysiology, etiology, clinical manifestations, diagnosis, and treatment of malignant SVCS.

A 54-year-old man was transferred to our emergency department because of acute inferior myocardial infarction. However, ST-segment elevation resolved after intravenous nitrate administration on admission and coronary angiography revealed a nonobstructive atherosclerotic plaque at the mid-portion of the circumflex artery and a giant tortuous fistula from the right sinus of Valsalva to the superior vena cava. The patient was diagnosed with variant angina and coronary arteriovenous fistula after vasodilator treatment and maximal treadmill stress test. After effective medical treatment of variant angina and successful percutaneous coil embolization of the fistula, the patient had not experienced any angina episodes for 1 year. However, control coronary angiography revealed partial persistence of fistula flow because of new collateral vessels, bridging distal and proximal parts of the occluded segment. We present the first coexistence of coronary to superior vena cava fistula and variant angina in the literature. This report also shows the ability of coronary fistulas to develop collateral vessels, like coronary arteries.

Background: Superior vena cava syndrome (SVCS) is a rare complication of pacemaker implantation. Numerous methods have been employed to treat this condition, ranging from anticoagulation and thrombolysis to surgical interventions and stenting. However, thus far only small case series have been reported and there is no currently accepted standard of care., Methods: Our group preformed a PubMed literature search to identify cases of symptomatic SVCS that developed following implantation of permanent pacemakers or implanatable cardioverter defibrillators and were treated with one of five different modalities: anticoagulation, thrombolysis, venoplasty, stenting, and surgical reconstuction. Duration of follow-up and incidence of recurrence of symptoms were the main end-points., Results: One hundred and four eligible cases from 74 different publications were identified, in which SVCS presented at a median of 48 (range 0-396) months after device implantation. We found that over the last 40 years, conservative treatments have been replaced by surgical reconstruction, and most recently by stenting, as the most common therapeutic modality employed. Anticoagulation, thrombolysis, and venoplasty alone were all associated with high recurrence rates. Surgery and stenting were more successful: recurrence rates were 12% and 5% over a median follow-up of 16 (range: 2-179) and 9.5 (range: 2-60) months, respectively., Conclusions: Currently, transvenous stenting is the most common treatment used for pacemaker-related SVCS, usually with conservation of the implanted leads. Both surgery and stenting appear to be effective treatments, with low incidences of recurrent SVCS over the first 12 months, but there is unfortunately a paucity of data on long-term outcomes. (PACE 2010; 420-425).

Background: Superior vena cava syndrome (SVCS) is an association with a variety of benign and malignant etiologies. The aim of this study was to evaluate if malignant SVCS is a real medical emergency or if we are able to obtain a definite histological diagnosis before chemoradiotherapy., Materials and Methods: In this prospective case series study, we have evaluated epidemiological characteristics and the ability to obtain a definitive histological diagnosis before chemoradiotherapy and the role of chemoradiotherapy prior to obtaining tissue specimens on the results of diagnostic interventions in patients with malignant SVCS who came to thoracic surgery wards of Imam Khomeini (Tehran) and Ghaem and Imam Reza (Mashhad) hospitals in Iran from 2001 to 2006., Results: Among 50 patients with SVCS, the M/F ratio was 32/18. Mean age was 61.7 years, and the most common symptom was dyspnea (86%). We performed successful tissue sampling before chemoradiotherapy in 44 cases (88%), and histological diagnoses in 100% of these cases were established, but among the other 6 patients (12%) who received chemoradiotherapy first because of unstable general conditions, histological diagnoses were obtained in only one patient (16.7%) after chemoradiotherapy (P<0.01). No in-hospital deaths were reported among our cases., Conclusion: Because we are able to establish tissue specimens by minimally invasive methods in most SVCS cases and because chemoradiation may preclude obtaining an exact pathological diagnosis, we suggest performing diagnostic interventions prior to chemoradiation in patients with SVC syndrome and without emergent clinical conditions.

A case of a 54-year-old man who developed superior vena cava syndrome secondary to vascular fibrosis, 30 months after radical chemoradiation for stage III non-small cell lung cancer, is presented. The literature regarding the etiology, diagnosis and treatment of this rare entity is discussed.

Objective: To document our experience with superior vena cava obstruction in a black African population., Design: A retrospective study of clinical data collected from cancer registry, patients case noted, cardiothoracic surgical unit's and operating records between June 1975 and May 1999., Setting: University College Hospital, Ibadan, Nigeria which hosts a major cancer centre in the West African sub-region and also serves community clinics., Patients: All patients with superior vena cava (SVC) obstruction referred for evaluation and treatment., Main Outcome Measures: Patients who had clinical features related to SVC obstruction and full investigation including tissue diagnosis were collated. Methods of treatment of acute episodes, definitive treatment and outcome of SVC obstruction were studied., Results: One hundred and twenty nine consecutive patients with SVC obstruction were treated. There were 100 males and 29 females. Mean age was 36 +/- 15 years. The annual incidence increased from 2.3 patients per year during the first 12 years to 8.4 patients per year during the second 12 years. The most common symptoms were swelling of face, arms and chest-wall (87.6%) with associated venous congestion over these areas. Majority of the patients (73.8%) presented within 1 to 12 months of onsets of symptoms. Patients with benign diseases had longer duration of symptoms before presentation (mean 3 months) than those with malignant disease (mean 6 months). Majority of the patients (82.2%) had malignancy as the underlying cause of the SVC obstruction and 47.2% of the malignancy was bronchogenic carcinoma. Symptomatic relief and outcome was best in benign disease (7 out of 8 patients, 87.5%). Lymphomas had better outcome than bronchogenic carcinoma among the patients with malignant diseases., Conclusion: Patients with SVC obstruction should be carefully evaluated before treatment. This will enhance application of specific therapy.

Introduction: There is no standard definition for thyroid glands extending below the thoracic inlet, and there are no clear guidelines for pre-operatively identifying those patients that may require an intrathoracic approach. We therefore reviewed the current literature in order to establish the current practices regarding the management of retrosternal goitres (RSGs), and propose a classification system to aid pre-operative planning for this important group of patients., Materials and Methods: A PubMed Medline search was conducted using the search terms 'retrosternal', 'substernal', 'intrathoracic', 'mediastinal', 'goitre' and 'goiter', resulting in 626 hits. Exclusion criteria reduced the number of papers to the 34 used for this review., Results: A total of 34 papers totaling 2426 patients were included. Eighty-four percent of patients operated on for RSG were achieved via a cervical approach, with the remainder also requiring manubriotomy (3.1%), full sternotomy (6.6%) or thoracotomy (4%). Tracheomalacia occurred in 1% of patients and Superior Vena Cava syndrome (SVC) in 3.2%. There was a clear and highly significant association between the extent and definition of RSG and reported complications, as well as the approach used, with the incidence of tracheomalacia, SVC and need for intrathoracic approach increasing more than 10-fold in cases of RSG reaching the aortic arch., Discussion: There is a clear need to establish a common standard in the definition and description of the extent of RSG. Using our findings, we propose a new, simple, 3-grade classification system of RSGs, based on their relation with the aortic arch and the right atrium.

Background: Oral anticoagulants present multiple practical problems for patients undergoing chemotherapy. To assess the practice implications of anticoagulation therapy, a review was carried out., Methods: A review of all patients with cancer treated with warfarin for venous thromboembolism (VTE) over a 1-year-period was carried out. Adverse events and therapeutic efficacy were assessed and the extra volume of work involved in monitoring was quantified., Results: Fifty-five patients with cancer and VTE were treated with warfarin from 07/04 to 06/05. Twenty-one invasive interventions required disruption of anticoagulation. There were eight admissions for haemorrhage. Nine patients died while on warfarin. A total of 1,379 coagulation tests were performed. There were 382 extra dayward visits attributable to warfarin monitoring. On treatment, 13 patients (24%) were changed from warfarin therapy to low molecular weight heparin (LMWH)., Conclusions: This study identifies and quantifies the extra resource utilization with warfarin therapy in patients undergoing chemotherapy.

Purpose of Review: This review highlights recent data detailing the prevalence and characteristics of pleural effusions occurring in patients with superior vena cava syndrome., Recent Findings: Numerous case reports have described pleural effusions in conjunction with the superior vena cava syndrome. Recent data suggest that these effusions occur in 60% of superior vena cava syndrome cases. The effusions are small, usually occupying less than half the affected hemi-thorax, and occur about equally on either side or bilaterally. Although previously thought to be largely transudates, a large case series found that 18% of the effusions were chylous, with the remainder being exudates. None of the effusions sampled in the series were transudates. Occluded lymphatic flow from increased hydrostatic pressure in the superior vena cava and left brachiocephalic vein probably contributes to the development of chylous pleural fluid. The pathophysiology of the exudative effusions, however, remains unknown. Many factors, including diuresis, small pulmonary emboli, and the underlying inflammatory or malignant condition all likely contribute., Summary: Chylous or exudative pleural effusions occur in most patients with superior vena cava syndrome. The effusions are usually small and resolve upon correction of the underlying superior vena cava obstruction.

Objectives: The purpose of this research was to investigate the causes and symptoms of superior vena cava (SVC) obstruction or occlusion and report on the long-term results of transcatheter therapy., Background: Information on transcatheter therapy for SVC obstruction is limited., Methods: Superior vena cava catheterization interventions between August 1984 and April 2006 were reviewed. Patients were divided into 2 subgroups depending on whether or not they had previously undergone congenital cardiac surgery., Results: Sixty-three patients with median age of 3.7 years (range 1 month to 42 years) and weight of 13.3 kg (range 3 to 114 kg) were treated. Fifty patients (79%) were symptomatic, although only 50% had symptoms suggestive of SVC obstruction. Superior vena cava syndrome was more common in the non-cardiac surgical group (52% vs. 10%, p = 0.001). The mean gradient and SVC diameter improved from 10.8 +/- 5.8 mm Hg to 2.6 +/- 2.2 mm Hg (p < 0.001) and 3.1 +/- 2.7 mm to 9.1 +/- 3.8 mm, respectively (p < 0.001). The obstruction was adequately relieved in all 36 patients receiving stents and in 21 of 27 patients (78%) who had balloon dilation alone. Complications occurred in 12 patients (19%), all of whom had previously undergone cardiac surgery; 10 of these patients were successfully treated in the catheterization laboratory. Freedom from re-intervention did not differ between patients undergoing balloon dilation or stent implantation, but was longer in patients age >5 years at the time of intervention., Conclusions: Superior vena cava-related symptoms occur in only 50% of patients with hemodynamically significant SVC obstruction. Endovascular therapy is successful in relieving the stenosis and associated symptoms with good long-term results.

Background: In general, prognosis and impact of prognostic/predictive factors are assessed with Kaplan-Meier plots and/or the Cox proportional hazard model. There might be substantive differences from the results using these models for the same patients, if different statistical methods were used, for example, Boag log-normal (cure-rate model), or log-normal survival analysis., Methods: Cohort of 244 limited-stage small-cell lung cancer patients, were accrued between 1981 and 1998, and followed to the end of 2005. The endpoint was death with or from lung cancer, for disease-specific survival (DSS). DSS at 1-, 3- and 5-years, with 95% confidence limits, are reported for all patients using the Boag, Kaplan-Meier, Cox, and log-normal survival analysis methods. Factors with significant effects on DSS were identified with step-wise forward multivariate Cox and log-normal survival analyses. Then, DSS was ascertained for patients with specific characteristics defined by these factors., Results: The median follow-up of those alive was 9.5 years. The lack of events after 1966 days precluded comparison after 5 years. DSS assessed by the four methods in the full cohort differed by 0-2% at 1 year, 0-12% at 3 years, and 0-1% at 5 years. Log-normal survival analysis indicated DSS of 38% at 3 years, 10-12% higher than with other methods; univariate 95% confidence limits were non-overlapping. Surgical resection, hemoglobin level, lymph node involvement, and superior vena cava (SVC) obstruction significantly impacted DSS. DSS assessed by the Cox and log-normal survival analysis methods for four clinical risk groups differed by 1-6% at 1 year, 15-26% at 3 years, and 0-12% at 5 years; multivariate 95% confidence limits were overlapping in all instances., Conclusion: Surgical resection, hemoglobin level, lymph node involvement, and superior vena cava (SVC) obstruction all significantly impacted DSS. Apparent DSS for patients was influenced by the statistical methods of assessment. This would be clinically relevant in the development or improvement of clinical management strategies.

Airway obstruction and cardiovascular collapse may follow the induction of general anesthesia in patients with mediastinal masses. We present a case in which a patient with a diagnosis of an upper gastrointestinal bleed presented for an emergency cesarean delivery. At the conclusion of surgery, the patient had complete airway obstruction during an upper gastrointestinal endoscopy. Patients may encounter airway compromise during instrumentation of the esophagus, and the presence of an intrathoracic mass should be included in the differential diagnosis of airway obstruction.

Purpose: To evaluate the frequency of diagnosis and the characteristics of brachiocephalic vein and superior vena cava (SVC) thromboembolic disease., Background: Thromboembolic disease of the brachiocephalic veins or SVC rarely has been reported. In view of the frequent use of central venous access lines, it would seem that the percentage of hospitalized patients with thromboembolic disease of the brachiocephalic veins or SVC should be higher than is generally recognized., Methods: A retrospective search for thromboembolic disease involving the brachiocephalic veins and SVC was made of patients who were hospitalized over a 2-year period., Results: Thromboembolic disease of the brachiocephalic veins or SVC was diagnosed in 23 of 34,567 hospitalized adults (0.06%) who were > or = 20 years old. Two of 23 patients (8.7%) had pulmonary embolism. Cancer was present in 17 of 23 patients (74%), and 15 of 23 patients (65%) had central venous access lines. Edema of the arm, face, or neck was present in 21 of 23 patients (91%). Pain or discomfort was present 15 of 23 patients (65%)., Conclusion: Isolated brachiocephalic vein and SVC thrombosis occur in a sufficient number of hospitalized patients to merit consideration of the diagnosis in patients who have cancer, central venous access lines, or both. The signs and symptoms of brachiocephalic vein thrombosis have features in common with SVC syndrome as well as with upper extremity deep venous thrombosis. In a patient with appropriate clinical findings, venography or other imaging may be indicated.

Background: Many patients with previously implanted ventricular defibrillators are candidates for an upgrade to a device capable of atrial-ventricular sequential or multisite pacing. The prevalence of venous occlusion after placement of transvenous defibrillator leads is unknown. The purpose of this study was to determine the prevalence of central venous occlusion in asymptomatic patients with chronic transvenous defibrillator leads., Methods: Thirty consecutive patients with a transvenous defibrillator lead underwent bilateral contrast venography of the cephalic, axillary, subclavian, and brachiocephalic veins as well as the superior vena cava before an elective defibrillator battery replacement. The mean time between transvenous defibrillator lead implantation and venography was 45 +/- 21 months. Sixteen patients had more than 1 lead in the same subclavian vein. No patient had clinical signs of venous occlusion., Results: One (3%) patient had a complete occlusion of the subclavian vein, 1 (3%) patient had a 90% subclavian vein stenosis, 2 (7%) patients had a 75% to 89% subclavian stenosis, 11 (37%) patients had a 50% to 74% subclavian stenosis, and 15 (50%) patients had no subclavian stenosis., Conclusions: The low prevalence of subclavian vein occlusion or severe stenosis among defibrillator recipients found in this study suggests that the placement of additional transvenous leads in a patient who already has a ventricular defibrillator is feasible in a high percentage of patients (93%).

Oncologic emergencies may occur in patients who have no prior diagnosis of malignancy as well as in patients who are known to have cancer. It is important for the primary care practitioner to consider an oncologic cause for symptoms or problems that may bring a patient into the office. These symptoms often are vague and could be indicative of numerous problems frequently associated with individuals who have cancer. A brief overview of the most common oncologic emergencies is given, along with differential diagnostic possibilities and management strategies.

In a series of 35 consecutive patients, the presence of a permanent pacemaker appears to be a strong risk factor for developing superior vena cava syndrome after radiofrequency modification of the sinus node. Treatment of this complication with balloon venoplasty is as effective as surgical repair.

Purpose: Superior vena cava (SVC) reconstructions are rarely performed; therefore the need for surveillance and the results of secondary interventions are unknown., Methods: During a 14-year period 19 patients (11 male, 8 female; mean age 41.9 years, range 8 to 69 years) underwent SVC reconstruction for symptomatic nonmalignant disease. Causes included mediastinal fibrosis (n = 12), indwelling foreign bodies (n = 4), idiopathic thrombosis (n = 2), and antithrombin III deficiency (n = 1). Spiral saphenous vein graft (n = 14), polytetrafluoroethylene (n = 4), or human allograft (n = 1) was implanted., Results: No early death or pulmonary embolism occurred. Four early graft stenoses or thromboses (spiral saphenous vein graft, n = 2, polytetrafluoroethylene, n = 2) required thrombectomy, with success in three. During a mean follow-up of 49.5 months (range, 4.7 to 137 months), 95 imaging studies were performed (average, five per patient; range, one to 10 studies). Venography detected mild or moderate graft stenosis in seven patients; two progressed to severe stenosis. Two additional grafts developed early into severe stenosis. Four of 19 grafts occluded during follow-up (two polytetrafluoroethylene, two spiral saphenous vein graft). Computed tomography failed to identify stenosis in two grafts, magnetic resonance imaging failed to confirm one stenosis and one graft occlusion, and duplex scanning was inconclusive on graft patency in 10 patients. Angioplasty was performed in all four patients with severe stenosis, with simultaneous placement of Wallstents in two. One of the Wallstents occluded at 9 months. Repeat percutaneous transluminal angioplasty was necessary in two patients, with placement of Palmaz stents in one. Only one graft occlusion and one severe graft stenosis occurred beyond 1 year. The primary, primary-assisted, and secondary patency rates were 61%, 78%, and 83% at 1 year and 53%, 70%, and 74% at 5 years, respectively., Conclusion: Long-term secondary patency rates justify SVC grafting for benign disease. Postoperative surveillance with contrast venography is indicated in the first year to detect graft problems. Endovascular techniques may salvage and improve the patency of SVC grafts.

A woman with persistent pacemaker induced superior vena cava syndrome was stable for 10 years. Serial follow-up venography, however, demonstrated a continuous process of major vein occlusion and the development of collateral circulation, the effectiveness of which warrants a favorable prognosis in this pacemaker related syndrome.

Background: Heparin added to parenteral nutrition solutions may decrease the incidence of central venous thrombosis in patients receiving home parenteral nutrition. However, there are little data regarding the stability of heparin over time under conditions similar to those associated with home parenteral nutrition: low concentrations of heparin stored in solutions containing amino acids and high concentrations of dextrose for more than 24 hours., Methods: The activity of porcine mucosal heparin was measured over time using an antifactor Xa assay in six IV solutions: four parenteral nutrition solutions containing 25% dextrose; 5% amino acids; trace elements; electrolytes; and 3000, 5000, 10,000, or 20,000 units/L of heparin; one solution of 25% dextrose and 5000 units/L heparin; and one solution of 0.9% saline and 5000 units/L heparin., Results: In all solutions except 25% dextrose (without amino acids and additives), heparin activity remained stable within 4% of baseline up to 28 days. In the 25% dextrose solution, heparin activity declined by 3%, 6%, and 11% at 14, 21, and 28 days, respectively., Conclusion: Heparin activity was stable over time in the normal saline and parenteral nutrition solutions and decreased slightly from 2 to 4 weeks in the dextrose-containing solution. Based on these data, when home parenteral nutrition is administered containing components similar to the solutions used in this study, heparin may be added at the time of preparation of the home parenteral nutrition solution rather than just before administration, with no resultant loss of heparin activity over time [corrected].

Purpose: Two stent types (a new Wallstent and a Z-stent) were investigated in 30 patients with recurrent malignant superior vena caval syndrome (SVCS)., Methods: Eligibility requirements were that the patient had recurrent symptoms after appropriate radiation therapy, chemotherapy, or both; >/= 75% of the vessel was occluded; and there was collateral flow. Because of the limited availability of stents, it was not possible to perform a prospectively randomized study., Results: In the Z-stent group (17 patients), occlusion of the stent due to acute thrombosis occurred within 12 hr in 4 patients (24%), but in the other 13 patients (76%) symptoms disappeared completely. After 2 weeks the cavogram in these patients showed no signs of thrombosis, and 12 (61%) of the patients remained symptom-free. There was partial occlusion in 5 patients (29%), without relevant clinical symptoms. Of the 13 patients who received Wallstents, only 1 had an acute immediate thrombosis (8%). Symptoms disappeared completely in the other 12 patients and no signs of thrombosis were seen. However, after 2 weeks complete stent occlusion with SVCS was found in 3 patients (23%) and partial occlusion with minor clinical symptoms in 6 (46%). Only 3 patients (23%) had complete relief of the SVCS. The difference between the rates of occlusion of the two stents after 2 weeks was highly significant (p = 0.008)., Conclusions: The overall clinical success rate for long-term patency was 100% for the Z-stents and 69% for the new Wallstent. These results suggest that when used for this purpose, the new Wallstent is more thrombogenic at 2 weeks than the Z-stent.

Of 60 neonates who survived extracorporeal membrane oxygenation (ECMO) in our institution between June 1992 and March 1994, seven had either complete or partial superior vena cava (SVC) obstruction. When the patients with SVC obstruction were compared with those who had an echocardiogram after ECMO, no predisposing factors for the development of SVC thrombus could be found. Our data show that SVC thrombus may be a significant complication after ECMO.

In some patients with end-stage renal failure, arteriovenous fistulas cannot be created due to poor vessel conditions. Alternatively, hemodialysis (HD) can be performed using long-term central venous catheters. However, these dialysis catheters are associated with a presently unknown risk of superior vena cava (SVC) thrombosis. We examined 20 patients (11 female, 9 male, age 29-83 years) 1-48 (mean 15) months after transjugular insertion of a permanent single lumen silicone rubber HD catheter. All patients underwent both transthoracic (TTE) and biplane transesophageal (TEE) echocardiography. TTE visualized the catheter only when its tip was localized in the right atrium (2 patients), but did not succeed in adequate imaging of the SVC. In contrast, TEE allowed high quality imaging of the SVC in all patients and detected a SVC thrombosis in 6 patients; in 3 of them, caval thrombosis was subtotal. One additional patient showed a thrombus attached to the catheter tip alone. Dwelling time of catheters since insertion in the SVC was not significantly different in patients with and without thrombosis. Reduced blood flow during HD was observed in 5 of 7 patients with catheter-associated thrombi but also in 4 of 13 patients without evidence for caval thrombosis by TEE. It is concluded that thrombotic occlusion of the SVC is frequent in patients with long-term central venous access; it does not necessarily correlate with clinical signs but can easily be detected by TEE. Patients with long-term central venous hemodialysis catheters should undergo transesophageal echocardiography at regular intervals.

Four cases of pacemaker-related SVC obstruction or syndrome are reported. While two of them lacked any symptom suggestive of SVC obstruction, the other two presented with mild symptoms. None of them received any treatment. One died from a cause unrelated to SVC obstruction, while the others presented no change in their clinical status. A review of the literature suggests that neither thrombotic nor fibrotic obstruction in patients with pacemaker leads is strictly related to the number of abandoned leads, the presence of severed leads, or the time elapsing from pacemaker implant. The diagnosis is clinically made and is confirmed by venography. Only one of the reported deaths is attributable to SVC obstruction. The remaining cases from the literature responded to treatment with heparin, thrombolytic agents, angioplasty, or surgery.

Background: The aim of this study was to analyze the features of the superior vena cava syndrome (SVCS) as initial characteristics in small-cell lung cancer: incidence, dissemination of disease, diagnostic procedures, efficacy and toxic effects of chemotherapy, and median survival in patients with SVCS., Methods: In a prospective series of 724 patients with biopsy-proved small-cell lung cancer seen during a 6-year period, we reviewed data from patients who also had SVCS., Results: The incidence of SVCS was 87 of 724 at the time of diagnosis. Initial emergency radiation therapy was not used in these patients. Diagnostic procedures in these patients were not associated with mortality. Rapid initiation of intensive chemotherapy, often with heparin therapy, resulted in complete or partial responses in 81% and no response in 12%; data were not evaluable in 7%. Two of these 87 patients died of aplasia within 4 weeks of chemotherapy. Median survival was not significantly different in the patients with SVCS (median, 42 weeks) and without SVCS (median, 40 weeks). A significant increase in initial brain metastases at the time of diagnosis was observed in patients with SVCS (22% vs 11%)., Conclusions: Intensive chemotherapy is the first line of therapy in small-cell lung cancer. Histologic diagnostic procedures must be performed in patients with SVCS to adapt the treatment to the underlying cause. Initial emergency radiotherapy, before diagnosis or chemotherapy, does not seem to be useful in these patients. Computed tomography of the brain should be performed routinely in patients with SVCS, and prophylactic brain irradiation could be helpful in such patients. Apparently SVCS is not a poor prognostic factor in treated small-cell lung cancer.

Gianturco-Rösch expandable Z-stents were used in 22 patients with superior vena cava syndrome (SVCS). Stents were placed in all patients in the SVC and in 17 patients, also into the innominate veins. Stent placement resulted in complete relief of symptoms in all patients. Twenty-one patients had no SVCS recurrence from 1 to 16 months, to their death, or to the present time. SVCS recurred only in 1 patient 9 months after stent placement due to tumor ingrowth and secondary thrombosis. Based on ours and on other reported experiences, expandable metallic stents are effective devices for treatment of the SVCS which is difficult to manage by other means.

Superior vena cava (SVC) syndrome is a critical condition in which an intrathoracic mass lesion compresses the SVC and promotes the development of head and upper body edema and cyanosis. SVC syndrome develops in 10% of patients with a right-sided malignant intrathoracic mass lesion. Diagnostic evaluation and emergency therapy are always necessary to assess and alleviate airway obstruction, cerebral venous hypertension and symptoms secondary to mediastinal compression. Radiation therapy and venous bypass of the obstructed SVC are both used successfully as early treatment. Although radiation therapy to the malignant process may provide initial decompression, a more sustained decrease in venous pressure occurs in patients who also undergo decompressive SVC surgical bypass. SVC bypass should be considered early in the course of patients with profound cerebral or laryngeal edema, patients with extensive thrombosis of the SVC, and in rare patients afflicted with severe venous hypertension and in whom a tissue diagnosis requires a mediastinal exploration.

Two hundred twenty upper extremity radionuclide venograms were performed using upper extremity injection of 5 mCi of Tc-99m DTPA in each arm of patients with indwelling central lines. Evidence of obstruction was found in 123 patients, collateral flow without anatomic obstruction in six patients, and a slow-flow pattern in 12 patients. Twenty-six of these also underwent upper extremity contrast venography within 48 hours of the scan. Contrast venograms and radionuclide venograms agreed in 19 patients (16 correctly identified as obstructed, three correctly identified as unobstructed). Six patients showed the slow-flow pattern without collaterals or obstruction. Subsequently, six follow-up contrast studies showed no evidence of obstruction or collaterals. The authors conclude that obstruction with collateral flow on radionuclide venograms correctly predicts obstruction. However, the slow-flow pattern does not and should not be used as the sole criterion to diagnose partial obstruction.

The incidence, response to chemotherapy treatment and prognostic value in the prediction of the Superior Cave vein syndrome (SVCS) surveillance were retrospectively studied in a group of 125 patients presenting microcytic pulmonary carcinoma. We found SVCS in 20 cases (16% of the total group of patients), there were no statistically significant differences between the limited or diseminated stages. All patients were initially treated with polychemotherapy. The efficacy of this treatment to eliminate the symptoms of SVCS could be evaluated in 17 cases while in the other 3 cases that was not possible give the early or toxic death of the patients. Fourteen out of the 17 patients with evaluable SVCS (82%) achieved a complete remission of the syndrome with chemotherapy which parallel with the achievement of a partial or complete response of the primary tumor and its metastasis. The SVCS only reappeared in one case at the moment of tumor recurrence. The remission of symptoms was quickly initiated after treatment and was completed in most cases one week after treatment was started. An statistically significant difference was not observed between the surveillance of patients who presented SVCS at time of diagnosis and those who did not. Given that both groups were balanced with regard to the rest of the prognostic factors (the disease stage, Karnofsky's index, sex, or treatment) the SVCS does not constitute a pejorative prognostic factor in the prediction of surveillance in microcytic pulmonary carcinoma.

The experience at the Cleveland Clinic from 1982 to 1990 using thrombolytic therapy for superior vena cava (SVC) syndrome was retrospectively reviewed. Sixteen patients, 11 of whom had indwelling central venous catheters, were treated with either urokinase (n = 11) or streptokinase (n = 5). Either urokinase (4,400 U/kg bolus followed by 4,400 U/kg/h) or streptokinase (250,000 U bolus followed by 100,000 U/h) was used, and venograms were performed before and after. Overall, 56 percent of patients had complete clot lysis and relief of symptoms. Thrombolytic therapy was effective in eight (73 percent) of 11 patients receiving urokinase and one (20 percent) of five patients receiving streptokinase. Of those with a central venous catheter, eight (73 percent) of 11 patients were successfully lysed, whereas only one (20 percent) of five patients was successfully lysed if no catheter was present. If thrombolytic therapy was performed less than or equal to five days of symptom onset, seven (88 percent) of eight patients were successful, if thrombolytic therapy was performed greater than five days after symptom onset, two (25 percent) of eight patients were successful. Symptoms were relieved and the catheter was preserved in patients in whom thrombolytic therapy was effective. Factors predicting success were as follows: (1) the use of urokinase compared with streptokinase; (2) the presence of a central venous catheter; and (3) a duration of symptoms less than or equal to five days.

Total parenteral nutrition (TPN) today is a fundamental procedure in the treatment of critically ill patients, especially if they have serious gastrointestinal diseases. However, use of the central venous catheter is connected with a very important morbidity. At the "Istituto di Patologia Chirurgica" and at the "Intensive Care Unit" of the University of Ferrara, we analyzed 59 cases of deaths from different diseases, on whom a postmortem examination had been performed. Twenty-seven patients had had no central venous catheter: none of them presented thrombosis of the central veins. Thirty-two patients had had a central venous catheter for TPN: five of them presented thrombosis of the central veins at the post-mortem examination. Except for one case who had thrombosis connected with a carcinoma of the right main bronchus, four cases (12.9%) presented thrombosis due to the central venous catheter. The subclavian vein seems to be more commonly connected with thrombosis than the jugular vein.

Cardiac manifestations of secondary tumors of the heart exert their effects directly by endocardial, myocardial, epicardial or cavitary deposits (metastatic lesions); indirectly via tumor products such as carcinoma; or mediated by therapy (chemotherapy, radiation) to treat the primary neoplasm. Part II of this review summarizes certain direct effects of noncardiac tumors on the heart including superior and inferior vena cava syndromes, pulmonary artery and vein obstruction or compression, myocardial implants, and intracavitary metastases. Many of these direct effects may be noninvasively diagnosed by computed tomography, magnetic resonance imaging and/or two-dimensional echocardiography.

One hundred and fifty-nine patients with symptoms of superior vena caval obstruction who presented to two major hospitals over a 10-year period, from 1970 to 1979, were reviewed. Lung cancer was the most common histological diagnosis. The most common symptoms were dyspnoea and a feeling of fullness in the head. The most common physical findings were dilatation of the neck or chest wall veins, or oedema of the face and arms. Superior mediastinal widening was the most common radiological abnormality. No significant morbidity was associated with any diagnostic procedure. Only patients with lymphoma had a significantly longer survival period, both from the diagnosis of the disease, and from the onset of the symptoms of superior vena caval obstruction. There is no evidence that superior vena caval obstruction is an absolute medical emergency. Appropriate diagnostic steps should be undertaken to establish the histological diagnosis. The prognosis for some tumour types may be improved by combined modality therapy (chemotherapy plus radiotherapy).