Preexisting Edema Research Articles

Peripheral oedema as an adverse effect of treatment of secondary progressive multiple sclerosis with siponimod: A case series

Siponimod is a sphingosine 1-phosphate receptor (S1P) modulator used to treat secondary progressive multiple sclerosis (SPMS). We report 3 SPMS patients treated with siponimod who developed new or worsening peripheral oedema soon after commencing treatment. In one case, peripheral oedema resulted in immobility. Siponimod-related peripheral oedema deserves wider recognition due to the potential for morbidity and over-investigation. Clinicians should assess for pre-existing oedema and coexisting conditions that may predispose to developing peripheral oedema prior to commencing siponimod.

Progression of diabetic retinopathy following uncomplicated phacoemulsification: A prospective study from South India.

The aim of this study was to study the progression of diabetic retinopathy (DR) and macular edema in uncomplicated phacoemulsification in patients with diabetes mellitus with a follow-up of 6 months. A prospective, nonrandomized study was conducted on patients with established or no DR in a known case of diabetes mellitus undergoing cataract surgery by phacoemulsification, with no intraoperative complications. Detailed ophthalmic evaluation including fundus examination was done in all cases, and DR staging was done. Optical coherence tomography and fundus fluorescein angiography were done in indicated cases. Fundus evaluation was done during the follow-up visits in 3 weeks, 3 months, and 6 months postsurgery and the tests were repeated if necessary. In the current study, there was a statistically significant improvement in best-corrected visual acuity after cataract surgery compared to the preoperative value. From the 330 eyes we analyzed, there was a progression of DR in only 18 eyes (5.45%) following phacoemulsification. There was a statistically significant increase in central macular thickness (CMT) at 3 weeks postoperative (433.82 ± 137.572) compared to that of the preoperative CMT (295.98 ± 97.959). From the 22 eyes which showed a progression of diabetic maculopathy, 11 eyes had developed new-onset macular edema following the cataract surgery, 11 eyes had progression of preexisting edema, and 4 of them had to undergo intravitreal anti-vascular endothelial growth factor injections as the treatment. The chance of progression of DR staging is low after uncomplicated phacoemulsification, on a short term. However, the chances of worsening of macular edema as well as worsening of proliferative stages should be kept in mind while advising a patient for cataract surgery.

Risk factors for peritumoral edema after radiosurgery for intracranial benign meningiomas: a long-term follow-up in a single institution.

Peritumoral edema (PTE) is recognized as a complication following stereotactic radiosurgery (SRS). The aim of this paper was to evaluate the risk of post-SRS PTE for intracranial benign meningiomas and determine the predictive factors. Between 2006 and 2021, 227 patients with 237 WHO grade I meningiomas were treated with Novalis linear accelerator SRS. All patients were treated with a single-fraction dose of 11-20 Gy (median 14 Gy). The median tumor volume was 3.32 cm3 (range 0.24-51.7 cm3). The median follow-up was 52 months (range 12-178 months). The actuarial local tumor control rates at 2, 5, and 10 years after SRS were 99.0%, 96.7%, and 86.3%, respectively. Twenty-seven (11.9%) patients developed new or worsened post-SRS PTE, with a median onset time of 5.2 months (range 1.2-50 months). Only 2 patients developed post-SRS PTE after 24 months. The authors evaluated factors related to new-onset or worsened PTE after SRS. In univariate analysis, initial tumor volume > 10 cm3 (p = 0.03), total marginal dose > 14 Gy (p < 0.001), preexisting edema (p < 0.0001), tumor location (p < 0.001), parasagittal location (p < 0.0001), superior sagittal sinus (SSS) involvement (p < 0.0001), and SSS invasion (p < 0.015) were found to be significant risk factors. In multivariate analysis, total marginal dose > 14 Gy (HR 3.38, 95% CI 1.37-8.33, p = 0.008), preexisting SRS edema (HR 12.86, 95% CI 1.09-4.15, p < 0.0001), tumor location (HR 2.13, 95% CI 1.04-3.72, p = 0.027), parasagittal location (HR 8.84, 95% CI 1.48-52.76, p = 0.017), and SSS invasion (HR 0.34, 95% CI 0.13-0.89, p = 0.027) were significant risk factors. Twelve (5.3%) patients were symptomatic. Ten of 27 patients had complete resolution of neurological symptoms and edema improvement with steroid treatment. Steroid treatment failed in 2 patients, who subsequently required resection for PTE. Radiosurgery is a safe and effective method of treating benign intracranial meningiomas according to long-term follow-up. We also identified total marginal dose > 14 Gy, preexisting PTE, parasagittal location, and SSS invasion as predictors of post-SRS PTE. Risk factors for post-SRS PTE should be considered in meningioma treatment.

Challenges in Diagnostic and Management of Nephritic Syndrome in Diabetic Nephropathy Patient: a Case Report

The clinical presentation of patients with acute glomerulonephritis (GN) varies widely, from asymptomatic to clinical presentations of acute kidney injury (AKI), edema, and hypertension. Diagnosis of GN in patients with diabetic nephropathy (DN) is a challenge due to pre-existing edema, hypertension, and decreased renal function. Likewise in terms of management of steroid immunosuppressants related to blood sugar regulation. It has been reported that 35-year-old male patients with diabetes mellitus (DM) with DN whose kidney function deteriorated rapidly. The patient complained of cola-red urine and decreased urine volume the day before admission. Physical examination showed blood pressure of 160/95 mmHg, bilateral leg edema, active chronic ulcer in the left lower leg, hemoglobin level was 8.7 g / dl, leukocytes 17.400 / ul, serum urea level 96 mg / dl, serum creatinine level 7.01 mg / dl, ASTO titer + 800 IU / ml, macroscopic hematuria, and albuminuria +4 on urinalysis. Ultrasonography revealed enlarged kidney size and signs of acute renal inflammation. Based on these data the patient was diagnosed clinically as rapidly progressive GN due to post-infectious GN. The patient received 3 days of pulse methyl prednisolone therapy continued orally, blood sugar regulation with insulin, RAS blockers, intravenous antibiotics and ulcer debridement. After 1 week of therapy, clinical and laboratory improvements were found and at the next follow-up renal function returned to baseline about 2 weeks later.

Management of Pre-existing Macular Edema With Intravitreal Dexamethasone Implant in Eyes Undergoing Cataract Surgery

Purpose: The purpose of this study was to assess the efficacy and safety of intraocular dexamethasone implant (IDI) for pre-existing macular edema due to retinal vein occlusion (RVO), diabetes, and uveitis in eyes undergoing cataract surgery. Methods: A retrospective, noncomparative study was conducted. The medical record database was searched for patients meeting criteria of macular edema treated with IDI prior to cataract surgery. Results: Twenty-two patients had macular edema due to RVO (14 or 63.6%), diabetes (5 or 22.7%), or uveitis (3 or 13.6%). None had complications during cataract surgery. Thirteen (60%) were female with a mean age of 64 years (range, 25-82 years). The mean interval of dexamethasone implantation to cataract extraction was 49 days. The mean interval to follow-up optical coherence tomography was 65 days. Mean logarithm of the minimum angle of resolution (logMAR) visual acuity (VA) improved from .94 (20/150–) to .56 (20/70+) ( P = .004), with an average gain in VA measuring +0.37 logMAR (3 line gain). Mean central retinal thickness decreased from 474 to 378 μm ( P = .006) with an average reduction of 96 μm ( P = .006). Mean macular volume decreased from 10.29 mm3 to 9.78 mm3 ( P = .0002) with an average reduction of 0.51 mm3. Two patients developed postoperative ocular hypertension requiring treatment with topical antihypertensive agents. One had a combined glaucoma filtering procedure at the time of cataract surgery because of a history of ocular hypertension. Conclusions: The majority of this cohort had improved macular edema due to RVO, diabetes, and noninfectious uveitis while undergoing cataract surgery. IDI is an effective and safe treatment in these at-risk eyes.

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

This study evaluated development of edema in patients receiving PI3K/mTOR/CDK4/6 targeted therapy for metastatic breast cancer (MBC). 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. 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 ≥ 30kg/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. 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.

Safety and results of anti-PD1 combined with radiosurgery for the treatment of melanoma brain metastases.

9552 Background: Anti-PD1 are now pivotal in the treatment of metastatic melanoma (MM). Some concerns have emerged regarding the risk/benefit ratio of their combination with stereotactic radiosurgery. Methods: Retrospective assessment of the interaction between Gamma-Knife radiosurgery (GKRS) and anti-PD1 in terms of toxicity and OS in mm patients (pts) with BM. Patients were included if they were under anti-PD1 (PRE) at time of GKRS, or if they had started anti-PD1 concomitantly with GKRS (CO), or had received anti-PD1 within 3 months after GKRS (POST). Results: Among 47 pts who received GKRS and anti-PD1 during their disease course, 35 fulfilled PRE or CO or POST criteria (anti PD1 1st line therapy in 10 pts and 2d or more in 25 pts). One pt died before radiological evaluation. GKRS targeted a single BM in 10 pts and multiple BMs in 24 (max 19 BMs). Out of the 128 BMs treated, 6 cases of increase of preexisting edema (4.7%) and 8 hemorrhages (6.25%) occurred in 12 pts, but only 5 events (5%) were regarded as Adverse Radiation effects (ARE), being symptomatic in 3 pts (8% of pts). One BM had to be resected because of the occurrence of a symptomatic hemorrhage with hemiparesis 9 month after treatment. Median follow- up from GKRS was 13.7 mths. Median overall survival (OS) from GKRS and 1st BM were 14.8 and 26.5 mths respectively, with 6 and 12 mths 0S rates from GKRS of 65.7% and 57%, respectively. Local failure was observed in 5 pt. Median time to new BM was 12.6 mths. There was no significant difference in outcomes in pts, depending on PRE, CO and POST conditions. Conclusions: In this series, the largest to date of pts with BMs treated by GKRS and anti-PD1,ARE were within the expected range and survival rates appear promising. Given the natural propensity of MM-BMs for bleeding and edema our data do not support an increased risk with the combination of GKRS and anti-PD1. Regarding the timing between anti-PD1 administration and GKRS our data do not support a higher efficacy or higher toxicity among the 3 following potential mechanisms: immuno- sensitization to radiation (PRE), immuno-radio direct synergy (CO) or radiosensitization to immunotherapy (POST).

Edema following Gamma Knife radiosurgery for parasagittal and parafalcine meningiomas.

Stereotactic radiosurgery (SRS) has been shown to offer a high probability of tumor control for Grade I meningiomas. However, SRS can sometimes incite edema or exacerbate preexisting edema around the targeted meningioma. The current study evaluates the incidence, timing, and degree of edema around parasagittal or parafalcine meningiomas following SRS. A retrospective review was undertaken of a prospectively maintained database of patients treated with Gamma Knife radiosurgery at the University of Virginia Health System. All patients with WHO Grade I parafalcine or parasagittal meningiomas with at least 6 months of clinical follow-up were identified, resulting in 61 patients included in the study. The median radiographic follow-up was 28 months (range 6-158 months). Rates of new or worsening edema were quantitatively assessed using volumetric analysis; edema indices were computed as a function of time following radiosurgery. Statistical methods were used to identify favorable and unfavorable prognostic factors for new or worsening edema. Progression-free survival at 2 and 5 years was 98% and 90%, respectively, according to Kaplan-Meier analysis. After SRS, new peritumoral edema occurred or preexisting edema worsened in 40% of treated meningiomas. The median time to onset of peak edema was 36 months post-SRS. Persistent and progressive edema was associated with 11 tumors, and resection was undertaken for these lesions. However, 20 patients showed initial edema progression followed by regression at a median of 18 months after radiosurgery (range 6-24 months). Initial tumor volume greater than 10 cm3, absence of prior resection, and higher margin dose were significantly (p<0.05) associated with increased risk of new or progressive edema after SRS. Stereotactic radiosurgery offers a high rate of tumor control in patients with parasagittal or parafalcine meningiomas. However, it can lead to worsening peritumoral edema in a minority of patients. Following radiosurgery, transient edema occurs earlier than persistent and progressive edema. Longitudinal follow-up of meningioma patients after SRS is required to detect and appropriately treat transient as well as progressive edema.

Gamma Knife radiosurgery of large skull base meningiomas.

Stereotactic radiosurgery (SRS) has become a common treatment modality for intracranial meningiomas. Skull base meningiomas greater than 8 cm3 in volume have been found to have worse outcomes following SRS. When symptomatic, patients with these tumors are often initially treated with resection. For tumors located in close proximity to eloquent structures or in patients unwilling or unable to undergo a resection, SRS may be an acceptable therapeutic approach. In this study, the authors review the SRS outcomes of skull base meningiomas greater than 8 cm3 in volume, which corresponds to a lesion with an approximate diameter of 2.5 cm. The authors reviewed the data in a prospectively compiled database documenting the outcomes of 469 patients with skull base meningiomas treated with single-session Gamma Knife radiosurgery (GKRS). Seventy-five patients had tumors greater than 8 cm3 in volume, which was defined as a large tumor. All patients had a minimum follow-up of 6 months, but patients were included if they had a complication at any time point. Thirty patients were treated with upfront GKRS, and 45 were treated following microsurgery. Patient and tumor characteristics were assessed to determine predictors of new or worsening neurological function and tumor progression following GKRS. After a mean follow-up of 6.5 years (range 0.5-21 years), the tumor volume was unchanged in 37 patients (49%), decreased in 26 patients (35%), and increased in 12 patients (16%). Actuarial rates of progression-free survival at 3, 5, and 10 years were 90.3%, 88.6%, and 77.2%, respectively. Four patients had new or worsened edema following GKRS, but preexisting edema decreased in 3 patients. In Cox multivariable analysis, covariates associated with tumor progression were 1) presentation with any cranial nerve (CN) deficit from III to VI (hazard ratio [HR] 3.78, 95% CI 1.91-7.45; p<0.001), history of radiotherapy (HR 12.06, 95% CI 2.04-71.27; p=0.006), and tumor volume greater than 14 cm3 (HR 6.86, 95% CI 0.88-53.36; p=0.066). In those patients with detailed clinical follow-up (n=64), neurological function was unchanged in 37 patients (58%), improved in 16 patients (25%), and deteriorated in 11 patients (17%). In multivariate analysis, the factors predictive of new or worsening neurological function were history of surgery (OR 3.00, 95% CI 1.13-7.95; p=0.027), presentation with any CN deficit from III to VI (OR 3.94, 95% CI 1.49-10.24; p=0.007), and decreasing maximal dose (OR 0.76, 95% CI 0.63-0.93; p=0.007). Tumor progression was present in 64% of patients with new or worsening neurological decline. Stereotactic radiosurgery affords a reasonable rate of tumor control for large skull base meningiomas and does so with a low incidence of neurological deficits. Those with a tumor less than 14 cm3 in volume and without presenting CN deficit from III to VI were more likely to have effective tumor control.

P08.01 * RESPONSE TO T-DM1 IN HER2-POSITIVE BREAST CANCER BRAIN METASTASES (BM)

BACKGROUND: Management of BM mainly relies on local treatment approaches including whole brain radiotherapy (WBRT), radiosurgery, and neurosurgery depending on number and size of BM. Of note, WBRT is associated with severe late-toxicity. Recently, lapatinib plus capecitabine (LapCap) as primary systemic treatment in oligosymptomatic patients (pts) with multiple Her2-positive BM was shown to achieve considerable response and delay the need for WBRT. T-DM1 (trastuzumab-emtansine) is an antibody-drug conjugate linking trastuzumab (T) to an anti-microtubule agent. T-DM1 provides activity in pts progressing upon T and has lower toxicity as compared to LapCap. Here, we investigated the activity of T-DM1 in newly diagnosed or progressive BM. PATIENTS AND METHODS: Six pts (median age 55 years) with Her2-positive breast cancer and BM were treated with T-DM1. Two asymptomatic pts received T-DM1 as first line therapy for brain metastatic disease, while four pts received local therapy before and had documented CNS progression at inclusion. T-DM1 was administered intravenously at a dose of 3.6 mg/kg body weight every three weeks; re-assessment of disease status was performed every three cycles. At baseline and restaging, MRI was performed. CNS response was defined as a reduction of lesion size of ≥50%. RESULTS: Median follow-up was 6 months (m). All pts had received prior T, 3/6 (50%) had already received LapCap, and 2/6 (33.3%) pertuzumab. Currently, 4/6 pts (66.6%) are assessable for CNS response. Two/4 pts (50%) had partial remission, while one patient progressing upon prior local therapy had stable disease. One/6 (16.6%) patient had minor response on MRI but no reduction of pre-existing brain oedema and increasing cortisol doses and was therefore deemed PD. A significant LVEF drop was observed in one heavily pretreated patient. CONCLUSION: This prospective case series again indicates that systemic therapy offers activity in Her2-positive BM. Currently, primary systemic treatment with LapCap remains the standard of care. Still, T-DM1 is well tolerated and offers relevant clinical activity; therefore, the role of T-DM1 in BM should be investigated in larger studies.

2.10. Racking the brain! Cerebral edema on postmortem computed tomography compared to forensic autopsy

Objective Cerebral swelling is a typical finding on postmortem computed tomography (PMCT). Detection of pre-existing brain edema despite normal postmortem changes is merely based on visual judgment, dependent on the investigator׳s experience, as there are no standards yet. The purpose of this study was to evaluate the diagnostic reliability in differentiation between of pre-existing cerebral edema and physiological postmortem brain swelling on PMCT compared to forensic autopsy and to establish diagnostic criteria for intoxication or asphyxia as cause of death. Methods and materials The study collective included 200 deceased (142 males and 58 females), ranging from 20–88 years. In retrospect 109 cases (out of 200 deceased) were evaluated regarding the following parameters: tonsillar herniation, the width of the outer and inner cerebrospinal spaces and by Hounsfield (HU) measurements of the gray and white matter related to the distinct age groups and causes of death. Results were compared to the findings of subsequent autopsy as gold standard for diagnosing cerebral edema. Results Cerebral edema (despite normal postmortem swelling) can be assessed reliable by PMCT based on narrowed temporal horns and with symmetrical herniation of the cerebral tonsils ( p p 20 HU and the grey to white matter ratio (GWR) was higher than >1.58. Conclusion Generalized brain edema despite normal postmortem changes can be differentiated on PMCT and white and grey matter HU measurement helps to determine the cause of death in cases of intoxication or asphyxia.

Strategies for Diagnosis and Prevention of Venous Thromboembolism during Pregnancy

Pregnancy and the postpartum period have an increased incidence of venous thromboembolism (VTE). The condition is unique during this period for several reasons. Primarily, because there is complexity in diagnosing this condition in view of altered physiology and preexisting edema in pregnancy and also because there are restrictions on the use of certain drugs and a need for vigilant monitoring of anticoagulant activities of drugs during the period. The problem is compounded and assumes the highest order of significance since two lives are involved and all the investigations and management done should also take into account the potential adverse effects on the foetus. In order to prevent the development of VTE during pregnancy, sound clinical evaluation for risk factors, risk stratification, and optimal use of resource both mechanical and pharmacological is necessary. This paper details strategies in preventing development of deep vein thrombosis and treatment of VTEs.

Drug-induced oedema

SummaryBesides more classical aetiologies for oedema such as heart failure, liver cirrhosis, nephrotic syndrome and chronic venous insufficiency, in practice we increasingly observe iatrogenic or drug-induced oedema as adverse events. Many drugs have the potential to cause oedema or to worsen pre-existing oedema prior to the initiation of drug therapy. Drug-induced oedema is frequently caused by calciumchannel-blockers of the dihydropyridine-type but can also be caused by dihydralazine and minoxidil which are less frequently prescribed. Other drugs which may support the formation of oedema are diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), ACE-inhibitors or AT1-receptor-antagonists (angioedema) and thiazolidinediones/glitazones which are used as oral anti-diabetics.This review focuses on drug-induced oedema, pathophysiological considerations and potential treatment and management strategies from a clinical-pharmacological perspective.

Neuroimaging and quality-of-life outcomes in patients with brain metastasis and peritumoral edema who undergo Gamma Knife surgery

Gamma Knife surgery (GKS) has been shown to be effective for treating many patients with brain metastasis. Some brain metastases demonstrate significant peritumoral edema; radiation may induce cerebral edema or worsening preexisting edema. This study was conducted to evaluate the imaging and neurobehavioral outcomes in patients with preexisting peritumoral edema who then undergo GKS. Between August 2003 and January 2008, 63 cases of brain metastasis with significant peritumoral edema (> 20 cm(3)) were prospectively studied. The study inclusion criteria were as follows: 1) a single metastatic lesion with significant edema (perilesional edema signal volume on FLAIR > 20 cm(3)); and 2) inclusion of only 1 lesion > 20 cm(3) in the study (in cases of multiple lesions noted on FLAIR images). All patients received MR imaging with pulse sequences including T1-weighted imaging and FLAIR with or without contrast and T2-weighted imaging at an interval of 3 months. A neurological assessment and Brain Cancer Module (BCM-20) questionnaire were obtained every 2-3 months. Kaplan-Meier, Cox regression, and logistic regression were used for analysis of survival and associated factors. At the time of GKS, the median Karnofsky Performance Scale (KPS) score was 70 (range 50-90), and the mean BCM-20 score was 45.5 +/- 6.1. The mean tumor volume (+/- standard deviation) was 5.2 +/- 4.6 cm(3) with corresponding T2-weighted imaging and FLAIR volumes of 59.25 +/- 37.3 and 62.1 +/- 38.8 cm(3), respectively (R(2) = 0.977, p < 0.001). The mean edema index (volume of peritumoral edema/tumor volume) was 17.5 +/- 14.5. The mean peripheral and maximum GKS doses were 17.4 +/- 2.3 and 35 +/- 4.7 Gy, respectively. The median survival was 11 months. The longer survival was related to KPS scores >or= 70 (p = 0.008), age < 65 years (p = 0.022), and a reduction of > 6 in BCM-20 score (p = 0.007), but survival was not related to preexisting edema or tumor volume. A reduction in BCM-20 score of > 6 was related to decreased volume in T1-weighted and FLAIR imaging (p < 0.001). Thirty-eight (79.2%) of 48 patients demonstrated decreased tumor volume and accompanied by decreased T2-weighted imaging and FLAIR volume. Eight (16.7%) of the 48 patients exhibited increased or stable tumor volume. A margin dose > 18 Gy was more likely to afford tumor reduction and resolution of peritumoral edema (p = 0.005 and p = 0.006, respectively). However, prior external-beam radiation therapy correlated with worsened preexisting peritumoral edema (p = 0.013) and longer maintenance of corticosteroids (p < 0.001). Patients demonstrating a reduction in the BCM-20 score > 6, age < 65 years, and KPS score >or= 70 exhibited longer survival. Significant preexisting edema did not influence the tumor response or clinical outcome. The resolution of edema was related to better quality of life but not to longer survival.

Gamma knife surgery of superficially located meningioma

The authors analyzed tumor control rates and complications in patients with superficially located meningiomas after gamma knife surgery (GKS). Between 1998 and 2003, GKS was performed in 23 patients with 26 lesions in whom follow-up imaging for 1 year or more was available. The male/female ratio was 1:22. The mean age was 59 years. The median tumor volume was 4.7 cm3, and the mean margin dose was 16 Gy at the 50% isodose line. Peritumoral edema was revealed on magnetic resonance (MR) imaging in four patients before GKS. Magnetic resonance imaging and clinical examinations were performed every 6 months after GKS. The mean follow-up duration was 32 months. The tumor shrank in eight cases, was stable in 17, and enlarged in one; thus 25 (95%) of 26 tumors were controlled. A peritumoral high signal on T2-weighted MR images was found in eight lesions and preexisting edema was aggravated in three lesions after GKS. Ten of these 11 patients complained of severe headache, and three patients experienced neurological deficits at the same time after a mean latency of 3 months; however, high signal was not demonstrated on imaging before 6 months on average. Steroid agents, when required, gave relief to all patients. The complication rate was 43% (10 of 23 cases). High signal disappeared in nine patients and decreased in the remaining two. High signal was associated with a high integral dose and a large tumor volume. Tumor shrinkage at the last follow-up examination was more prominent in the patients with symptomatic high signal (p = 0.03). There was a good tumor control rate with a high complication rate. Longer follow up of more patients is needed. Adjusting the dose-volume relationship should be considered to reduce complications.

Gamma knife surgery of superficially located meningioma

Object. The authors analyzed tumor control rates and complications in patients with superficially located meningiomas after gamma knife surgery (GKS). Methods. Between 1998 and 2003, GKS was performed in 23 patients with 26 lesions in whom follow-up imaging for 1 year or more was available. The male/female ratio was 1:22. The mean age was 59 years. The median tumor volume was 4.7 cm3, and the mean margin dose was 16 Gy at the 50% isodose line. Peritumoral edema was revealed on magnetic resonance (MR) imaging in four patients before GKS. Magnetic resonance imaging and clinical examinations were performed every 6 months after GKS. The mean follow-up duration was 32 months. The tumor shrank in eight cases, was stable in 17, and enlarged in one; thus 25 (95%) of 26 tumors were controlled. A peritumoral high signal on T2-weighted MR images was found in eight lesions and preexisting edema was aggravated in three lesions after GKS. Ten of these 11 patients complained of severe headache, and three patients experienced neurological deficits at the same time after a mean latency of 3 months; however, high signal was not demonstrated on imaging before 6 months on average. Steroid agents, when required, gave relief to all patients. The complication rate was 43% (10 of 23 cases). High signal disappeared in nine patients and decreased in the remaining two. High signal was associated with a high integral dose and a large tumor volume. Tumor shrinkage at the last follow-up examination was more prominent in the patients with symptomatic high signal (p = 0.03). Conclusions. There was a good tumor control rate with a high complication rate. Longer follow up of more patients is needed. Adjusting the dose—volume relationship should be considered to reduce complications.

Phase II Trial of Bortezomib in Mantle Cell Lymphoma.

We report the results of a phase II trial of an investigational new drug bortezomib (PS-341, Velcade) for the treatment of mantle cell lymphoma. Advanced stage previously untreated patients or those given up to two prior chemotherapy regimens were eligible. Additional entry criteria included measurable nodal disease, minimum laboratory requirements, and written informed consent. Central pathology review, to confirm eligibility and the presence of cyclin D1, was required after study entry. Accrual was closed July 2004 having reached the preplanned target of 30 patients. Bortezomib 1.3 mg/m2 IV bolus was given days 1, 4, 8 and 11 in 3-week cycles. Patients were assessed by CT scanning after every two cycles of therapy and response assessed according to International Working Group recommendations (Cheson B, J Clin Oncol 1999). Non progressors were to receive a maximum of 4 cycles. Responding patients were to receive bortezomib for 2 cycles following documentation of maximal partial response (PR) or complete response (CR). To date demographic data are available on 26 patients. The median age was 67 (48–78 yrs), all had stage 3 or 4 disease (55% bone marrow involvement), 7 were female and 10 had received no prior chemotherapy. A median of 4 treatment cycles has been given (range 1–7) and 25 patients are evaluable for toxicity. Grade ≥ 2 adverse effects thought to be related to study drug occurred as follows: anorexia 8%, nausea 16%, vomiting 4%, diarrhea 20%, fatigue 60%, dizziness 4%, sensory neuropathy 12%, edema 8%, hypotension 4%, vascular leak syndrome 4%, arthralgia 12%, myalgia 12%, neuropathic pain 12%, dyspnea 12%, rash 12%. Nine patients discontinued therapy because of toxic effects (6 of whom had neuropathy or myalgia). During accrual of the first 14 patients, 5 serious adverse events occurred in patients with pre-existing edema, dyspnea, and/or effusion. Therefore, the eligibility criteria were amended to exclude such patients thereafter and no further serious adverse events have occurred. To date, 24 patients are evaluable for response. Of the 10 patients having no prior chemotherapy there were 3 PR (range 2.5–14.8m) 6 SD (1.3–13.6m) and 1 PD for a response of 30%. Of the 14 previously treated patients we obtained 1 CRu (14.1m), 4 PR (2.4–13.1m), 7 SD (1.2–14.3m) and 2 PD. The overall response rate is 33% (95% C.I. 16–55%) but interestingly it is similar in both previously untreated and treated groups. We conclude that bortezomib is an active agent in mantle cell lymphoma, but at this dose and schedule complete remission is rare. Since higher doses will not be possible given the frequency of neuropathy and myalgia, alternative schedules or novel combinations with other active agents will be of interest to pursue.

Water permeability and TCDD-induced edema in zebrafish early-life stages.

A common response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure in teleost embryos is blue-sac disease, characterized by pericardial and yolk-sac edema. The cellular and extracellular fluids of freshwater fish are hyperosmotic compared to the surrounding water. In order to be in osmotic balance, freshwater fish must maintain a barrier to minimize water entry and excrete excess water that passes the barrier. We hypothesized that edema observed in TCDD-exposed zebrafish was caused by a failure of a barrier to incoming water. As a test of this hypothesis, we removed the osmotic gradient that drives water entry by increasing the osmolarity of the surrounding water with mannitol. Abolishing the osmotic gradient between the interior body fluids and the water environment of the developing zebrafish significantly reduced both pericardial and yolk-sac edema. When added after edema formation had already started, mannitol only partially reversed pre-existing edema. An alternate hypothesis is that TCDD impairs water excretion, allowing water to accumulate as edema fluid. However, we were unable to demonstrate an alteration in kidney function: expression of early markers for kidney development appeared normal, and we did not observe TCDD-induced changes in kidney filtration. An alteration in the overall shape of the kidney was observed, but this may be a consequence of compression by edema. In conclusion, TCDD exposure may inhibit the function of a permeability barrier to water, which is critical for maintaining osmotic balance in early development.

Edema following Gamma-Knife® radiosurgery for intracranial meningiomas

Purpose/Objective: Stereotactic radiosurgery is a primary or adjuvant treatment option for patients with unresected, incompletely resected, and recurrent benign, atypical and malignant intracranial meningiomas. Based on previously reported series, local control rates for meningiomas treated with Gamma-Knife® stereotactic radiosurgery (GKSRS) are approximately 90%. However, one potentially serious complication of GKSRS is symptomatic cerebral edema requiring steroid treatment or open surgery. The purpose of this study was to determine the predictive factors for developing cerebral edema after GKSRS in patients with intracranial meningioma. Materials/Methods: Clinical and radiographic data were collected on 19 patients with 23 intracranial meningiomas (21 benign, 2 atypical/malignant) treated with GKSRS at Wake Forest University Baptist Medical Center between September 1999 and December 2000 (16 women, 3 men; age range 28-87 years; mean age, 65.5 years). The most common tumor locations were parasagittal (39%) and posterior fossa (22%). The median tumor volume was 4 cc (range 0.4 to 18.5 cc). 6 tumors had image-based peritumoral edema before GKSRS while 17 tumors had no edema. A median dose of 14 Gy (range 9-18 Gy) was delivered to the tumor margin (50% isodose line). Median follow up time was 1.4 years. Kaplan-Meier methodology was used to estimate actuarial incidence. Proportional hazard regressions with likelihood ratio tests were used to assess predictors for the development of edema or worsening edema after GKSRS. Results: After GKSRS, 39% (9/23) of tumors developed new or worsening image-based cerebral edema. The actuarial incidence of edema was 22% at 6 months, 39% at 12 months, and 59% at 18 months. 7 of 9 tumors (78%) developed symptomatic edema requiring steroid therapy after GKSRS. One patient refused steroid treatment and died of edema-associated complications. The actuarial incidence of edema causing symptoms and requiring steroid therapy was 26% at 6 and 12 months and 41% at 18 and 24 months. Predictive factors for the development of edema or worsening edema after GKSRS were parasagittal location (p = 0.006), tumor volume (p = 0.005) and the presence of image-based pretreatment edema (p = 0.06). Of the tumors with edema or worsening edema after GKSRS, 78% were parasagittal and 78% were large (> 4cc). Of the 17 tumors without pre-existing edema, 24% (4/17) developed new edema, whereas 83% (5/6) of tumors with pre-existing edema developed worsening edema after GKSRS. At last follow-up, 91% of 23 tumors were locally controlled. Of the 2 tumors which progressed, one was benign and the other malignant. Conclusions: In our experience, 39% of meningiomas treated with GKSRS developed new or worsening image-based cerebral edema. The incidence of new or worsening edema with parasagittal tumors, tumors > 4 cc in volume, and tumors associated with pre-GKSRS peritumoral edema was 78%, 78%, and 83%, respectively, including one edema-associated death. Select patients with large, parasagittal meningiomas demonstrating peritumoral edema should be considered for other treatment options such as open surgery or conventionally fractionated 3D conformal RT.

SOFT TISSUE RECONSTRUCTION FOR CALCANEAL FRACTURES OR OSTEOMYELITIS

A systematic approach of the surgical management of a calcaneal fracture can minimize the potential of soft tissue complications. When reducing a closed calcaneal fracture, the incision used affects the postoperative complications. The L-shaped incision with the horizontal limb lying on the lateral glabrous junction ensures maximum blood flow to either side of the incision. Whether or not the wound can be closed primarily depends on the preexisting edema, the lost calcaneal height, and the delay between the fracture and reduction (Fig. 20). The wrinkle test is a good indicator that the incision can be closed primarily if the amount of height restored is minimal. If the edema is too great, steps should be taken to reduce it sufficiently to allow successful wound closure. If the wound, after reduction, is too wide to allow primary closure, an ADM flap laterally or an AHM flap medially should be used. For larger defects, a free flap should be considered. The three important steps to reconstruction of soft tissue defects around the calcaneus include good blood supply, a infection-free wound, and the simplest soft tissue reconstructive option that covers the wound successfully. Adequate blood supply can be determined by the use of Doppler. If the supply is inadequate, revascularization is necessary before proceeding. Achieving a clean wound requires aggressive debridement, intravenous antibiotics, and good wound care. Adjuncts that can help in achieving a clean wound include topical antibiotics (silver sulfadiazine), the VAC, and hyperbaric oxygen. Osteomyelitis has to be treated aggressively. Any suspicious bone has to be removed. Only clean, healthy, bleeding bone is left behind. Antibiotic beads can be useful when there is doubt as to whether the cancellous bone is infection-free. The beads are not a substitute for good debridement, however. Soft tissue reconstruction ranges from delayed primary closure to the use of microsurgical free flaps (Fig. 21). When bone or hardware is exposed, a muscle flap should cover the wound because of the extra blood supply it carries with it. The soft tissue option depends on the width of the wound. For wounds 1 cm wide or less, the options include allowing the wound to close by secondary intention (VAC), delayed primary closure, or a local muscle flap. For wounds 2 cm wide or less, allowing the wound to close by secondary intention (VAC) and a local muscle flap are the best options. For wider wounds, one has to assess whether the local muscle flap has sufficient bulk to close the defect. If it does, it is the simplest solution. If the local muscle is inadequate, a microsurgical free flap has to be used. The VAC sometimes can convert a large wound to a smaller wound so that a local muscle flap can be used. This procedure takes time, however, and adds to the cost of the repair.