Safety and efficacy of endoscopic spray cryotherapy for esophageal cancer.

Although surgery is traditionally the standard of care for esophageal cancer, esophagectomy carries significant morbidity. Alternative endoscopic therapies are needed for patients who are not candidates for conventional treatment. The objective of this study is to assess the safety, efficacy, and tolerability of spray cryotherapy of esophageal adenocarcinoma. This study includes patients with esophageal adenocarcinoma who had failed or were not candidates for conventional therapy enrolled retrospectively and prospectively in an open-label registry and patients in a retrospective cohort from 11 academic and community practices. Endoscopic spray cryotherapy was performed until biopsy proven local tumor eradication or until treatment was halted due to progression of disease, patient withdrawal or comorbidities. Eighty-eight patients with esophageal adenocarcinoma (median age 76, 80.7% male, mean length 5.1 cm) underwent 359 treatments (mean 4.4 per patient). Tumor stages included 39 with T1a, 25 with T1b, 9 with unspecified T1, and 15 with T2. Eighty-six patients completed treatment with complete response of intraluminal disease in 55.8%, including complete response in 76.3% for T1a, 45.8% for T1b, 66.2% for all T1, and 6.7% for T2. Mean follow-up was 18.4 months. There were no deaths or perforations related to spray cryotherapy. Strictures developed in 12 of 88 patients (13.6%) but were present before spray cryotherapy in 3 of 12. This study suggests that endoscopic spray cryotherapy is a safe, well-tolerated, and effective treatment option for early esophageal adenocarcinoma.

Safety and efficacy of endoscopic spray cryotherapy for Barrett's dysplasia: results of the National Cryospray Registry.

Retrospective series have shown the efficacy of endoscopic spray cryotherapy in eradicating high-grade dysplasia (HGD) in Barrett's esophagus (BE); however, prospective data are lacking, and efficacy for low-grade dysplasia (LGD) is unclear. The aim of this study was to assess the efficacy and safety of spray cryotherapy in patients with LGD or HGD. A multicenter, prospective open-label registry enrolled patients with dysplastic BE. Spray cryotherapy was performed every 2-3 months until there was no endoscopic evidence of BE and no histological evidence of dysplasia, followed by surveillance endoscopies up to 2 years. Primary outcome measures were complete eradication of dysplasia (CE-D) and complete eradication of all intestinal metaplasia (CE-IM). Ninety-six subjects with Barrett's dysplasia (67% HGD; 65% long-segment BE; mean length 4.5 cm) underwent 321 treatments (mean 3.3 per subject). Mean age was 67 years, 83% were male. Eighty patients (83%) completed treatment with follow-up endoscopy (mean duration 21 months). In patients with LGD, rate of CE-D was 91% (21/23) and rate of CE-IM was 61% (14/23). In HGD, CE-D rate was 81% (46/57) and CE-IM was 65% (37/57). In patients with short-segment BE (SSBE) with any dysplasia, CE-D was achieved in 97% (30/31) and CE-IM in 77% (24/31). There were no esophageal perforations or related deaths. One subject developed a stricture, which did not require dilation. One patient was hospitalized for bleeding in the setting of non-steroidal anti-inflammatory drug use. In the largest prospective cohort to date, data suggest endoscopic spray cryotherapy is a safe and effective modality for eradication of BE with LGD or HGD, particularly with SSBE.

Eosinophilic infiltration of the esophagus following endoscopic ablation of Barrett's neoplasia.

To assess the incidence of esophageal intra-epithelial eosinophilic infiltration following endoscopic ablation of Barrett's esophagus (BE), a retrospective study of consecutive cases of endoscopic ablation of BE with dysplasia or cancer using radiofrequency ablation (RFA) and spray cryotherapy at two centers in the United States was performed. Post-ablation eosinophilia was defined as ≥ 5 eosinophils per high power field during post-treatment surveillance. Twenty of 122 patients (16%) undergoing ablation developed esophageal eosinophilia after ablation, including 8/77 (10%) treated with RFA and 12/44 (27%) treated with cryotherapy. No patient had clinical or endoscopic findings of or risk factors for eosinophilic esophagitis. Esophageal eosinophilia persisted in 30% over a median of 20.2 months. On multivariate analysis, post-ablation eosinophilia was independently associated with increasing BE segment length (adjusted odds ratio 1.46 for every 2-cm increase, 95% confidence interval 1.24-1.71) and cryotherapy as the ablation modality (adjusted odds ratio 5.23, 95% confidence interval 1.67-16.39). Esophageal eosinophilic infiltration after endoscopic ablation with RFA and cryotherapy is common and is associated with the BE segment length and treatment modality. The clinical significance of post-ablation eosinophilia is unclear.

Recurrent disease following endoscopic ablation of Barrett's high-grade dysplasia with spray cryotherapy.

BACKGROUND AND AIMS: Recurrent disease after endoscopic ablation of Barrett's esophagus should be detected early to prevent malignant progression. We assessed the incidence and patterns of disease recurrence in patients after liquid nitrogen spray cryotherapy ablation of Barrett's esophagus with high grade dysplasia (HGD), including the area below the neosquamocolumnar junction (NSCJ). PATIENTS AND METHODS: This is a single-center, retrospective study of prospectively collected data on consecutive cases of endoscopic ablation with liquid nitrogen spray cryotherapy for Barrett's HGD. Post-treatment surveillance biopsies were obtained of suspicious lesions and in 4 quadrants every 1 cm in the treated esophagus and just below the NSCJ. Primary outcome measures were location and histology of recurrent disease. RESULTS: 36 patients (median age 62 years, 92% men) were enrolled, and 11 (30%) developed recurrent disease in a median of 6.5 months; three developed a second recurrence. Ten recurrences (71%) were identified below the NSCJ in 9 patients, including HGD (4), low grade dysplasia (LGD) (2), and intestinal metaplasia (4). Six recurrences were identified in the treated esophagus in five patients, including intramucosal cancer (1), HGD (1), and intestinal metaplasia (4). Two patients had recurrent disease involving both locations. Ultimately 33 patients (92%) achieved a complete response. Diagnosis in the remaining three was LGD (1) and intestinal metaplasia (2). CONCLUSION: Most patients with recurrent intestinal metaplasia with or without dysplasia after ablation achieve a complete response. Recurrent disease commonly involves the area just below the NSCJ. Surveillance endoscopies should include this area to accurately identify patients with disease recurrence.

Argon plasma coagulation, bipolar cautery, and cryotherapy: ABC's of ablative techniques.

A variety of endoscopic ablation modalities are available for the treatment of Barrett's esophagus. Multiple studies have evaluated the use of argon plasma coagulation, mostly in nondysplastic Barrett's esophagus. Significant variations in technique, end points, and follow-up exist between studies, but in most cases argon plasma coagulation is associated with unacceptable rates of persistent intestinal metaplasia and recurrence after completion of treatment. In addition, serious adverse events including perforation and stricture formation are reported. Multipolar electrocoagulation has been studied less thoroughly, but in prospective trials significant rates of persistent and recurrent intestinal metaplasia have also been reported. Lasers and heater probes have been tried in small numbers. Endoscopic cryotherapy ablation is a relatively new technique with studies focusing on high-grade dysplasia and early-stage cancer in high-risk patients. It has an acceptable safety profile, and early results show response in a significant number of patients in whom other modalities have failed.

Evaluation of performance of EUS-FNA in preoperative lymph node staging of cancers of esophagus, lung, and pancreas.

We reviewed the cytologic and histologic diagnoses and EUS report of 77 consecutive patients who had undergone EUS-FNA preoperative staging for esophageal, lung, and pancreatic cancers at our institution. A total of 122 EUS-FNA lymph nodes were identified. Thirty of 77 cases had histologic follow-up. Using surgical node staging and/or surgical resection as the reference standard, the sensitivity, specificity, accuracy, and positive and negative predictive values were 75%, 95%, 89%, 86%, and 90%, respectively, for EUS-FNA node staging. We compared cytologically malignant and benign lymph node groups with eight EUS parameters including the total number of lymph nodes found by EUS, the shape, margin, long axis, short axis, echogenicity, location of the lymph node, and EUS tumor staging. We found that the short axis is the best EUS feature to predict malignancy. Lymph nodes found in an abdominal location in esophageal and lung cancer are likely malignant.

Examining lactate in severe TBI using proton magnetic resonance spectroscopy.

PRIMARY OBJECTIVE: Clinical management of acute traumatic brain injury (TBI) has emphasized identification of secondary mechanisms of pathophysiology. An important objective in this study is to use proton magnetic resonance spectroscopy (pMRS) to examine early metabolic disturbance due to TBI. RESEARCH DESIGN: The current design is a case study with repeated measures. METHOD AND PROCEDURE: Proton magnetic resonance imaging was used to examine neurometabolism in this case of very severe brain trauma at 9 and 23 days post-injury. MRI was performed on a clinical 1.5 Tesla scanner. MAIN OUTCOMES AND RESULTS: These data also reveal that pMRS methods can detect lactate elevations in an adult surviving severe head trauma and are sensitive to changes in basic neurometabolism during the first month of recovery. CONCLUSIONS: The current case study demonstrates the sensitivity of pMRS in detecting metabolic alterations during the acute recovery period. The case study reveals that lactate elevations may be apparent for weeks after severe neurotrauma. Further work in this area should endeavour to determine the ideal time periods for pMRS examination in severe TBI as well as the ideal locations of data acquisition (e.g. adjacent or distal to lesion sites).

Enbucrilate for gastric varices: extended experience in 92 patients.

AIM: We assessed N-2-butyl-cyanoacrylate (enbucrilate) in 92 patients with gastric variceal bleeding under an FDA-approved investigation. These results extend our prior report of the first 44 patients. METHOD: Injection was performed with enbucrilate and ethiodol (1:1). Eighty patients had portal hypertension and 12 had splenic vein thrombosis. RESULTS: In the portal hypertensive group, re-bleeding from gastric varices was seen in 4 of 80 (5%) from 0 to 72 h, 5 of 76 (6.5%) from > 72 h to 3 months and 9 of 51 (17%) from > 3 months to 1 year. Re-bleeding and survival were significantly related to the Child-Pugh class. In the splenic vein thrombosis group (n = 12), there was early rebleeding in 2 (17%) patients from 0 to 72 h, 1 (8%) from > 72 h to 3 months and none in the chronic phase (> 3 months to 1 year) although 1-year survival in this group was only 6 (50%) due to the underlying malignancy in most. Serious embolization was suspected in 2 patients (2%). CONCLUSION: Enbucrilate offers an important intervention in gastric variceal bleeding which should be further studied in the US. A randomized trial is warranted to compare this intervention to radiological therapy.

Transcriptional profiling suggests that Barrett's metaplasia is an early intermediate stage in esophageal adenocarcinogenesis.

To investigate the relationship between Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC), we determined gene expression profiles of discrete pathological stages of esophageal neoplasia using a sequence-verified human cDNA microarray. Fifty one RNAs, comprising 24 normal esophagi (NE), 18 BEs, and nine EACs were hybridized to cDNA microarrays. Five statistical analyses were used for the data analysis. Genes showing significantly different expression levels among the three sample groups were identified. Genes were grouped into functional categories based on the Gene Ontology Consortium. Surprisingly, the expression pattern of BE was significantly more similar to EAC than to NE, notwithstanding the known histopathologic differences between BE and EAC. The pattern of NE was clearly distinct from that of EAC. Thirty-six genes were the most differentially modulated, according to these microarray data, in BE-associated neoplastic progression. Twelve genes were significantly differentially expressed in cancer-associated BE's plus EAC (as a single combined tissue group) vs noncancer-associated BE's. These genes represent potential biomarkers to diagnose EAC at its early stages. Our results demonstrate that molecular events at the transcriptional level in BE are remarkably similar to BE's-associated adenocarcinoma of the esophagus. This finding alarmingly implies that BE is biologically closer to cancer than to normal esophagus, and that the cancer risk of BE is perhaps higher than we had imagined. These findings suggest that changes modulated at the molecular biologic level supervene earlier than histologic changes, and that BE is an early intermediate stage in the process of EAC.

Global gene expression profiling in Barrett's esophagus and esophageal cancer: a comparative analysis using cDNA microarrays.

In order to identify and contrast global gene expression profiles defining the premalignant syndrome, Barrett's esophagus, as well as frank esophageal cancer, we utilized cDNA microarray technology in conjunction with bioinformatics tools. We hybridized microarrays, each containing 8000 cDNA clones, to RNAs extracted from 13 esophageal surgical or endoscopic biopsy specimens (seven Barrett's metaplasias and six esophageal carcinomas). Hierarchical cluster analysis was performed on these results and displayed using a color-coded graphic representation (Treeview). The esophageal samples clustered naturally into two principal groups, each possessing unique global gene expression profiles. After retrieving histologic reports for these tissues, we found that one main cluster contained all seven Barrett's samples, while the remaining principal cluster comprised the six esophageal cancers. The cancers also clustered according to histopathological subtype. Thus, squamous cell carcinomas (SCCAs) constituted one group, adenocarcinomas (ADCAs) clustered separately, and one signet-ring carcinoma was in its own cluster, distinct from the ADCA cluster. We conclude that cDNA microarrays and bioinformatics show promise in the classification of esophageal malignant and premalignant diseases, and that these methods can be applied to small biopsy samples.

Gender-related differences in acute rehabilitation lengths of stay, charges, and functional outcomes for a matched sample with spinal cord injury: a multicenter investigation.

OBJECTIVE: To examine the effects of gender on length of stay (LOS), treatment costs, and outcomes by using a matched sample of patients with spinal cord injury (SCI). DESIGN: A 2 x (15 x 3) mixed, block design was used retrospectively to analyze the impact of gender on subjects matched for age, American Spinal Injury Association (ASIA) motor impairment classification, and level of neurologic injury. SETTING: Twenty medical centers in the federally sponsored Spinal Cord Injury Model Systems project. PARTICIPANTS: One thousand seventy-four adult patients with SCI admitted between 1988 and 1998 were assessed at acute-care admission, inpatient rehabilitation admission, and inpatient rehabilitation discharge. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: ASIA motor index and FIM instrument admission, discharge, and efficiency scores; rehabilitation LOS and medical care charges; and discharge disposition. RESULTS: Analysis revealed no gender-related differences in FIM motor scores on admission and discharge. No differences in FIM motor efficiencies or daily change were observed. No significant differences were found for ASIA motor scores on acute-care admission and rehabilitation discharge. No differences in acute rehabilitation LOS and charges were observed. No gender-related differences were seen in the likelihood of discharge to an institutional setting. CONCLUSION: Gender was not a significant factor in functional outcome of SCI patients after acute rehabilitation.

Factors associated with balance deficits on admission to rehabilitation after traumatic brain injury: a multicenter analysis.

OBJECTIVE: To evaluate how demographics, measures of injury severity, and acute care complications relate to sitting and standing balance in patients with traumatic brain injury (TBI). DESIGN: Multicenter analysis of consecutive admissions to designated TBI Model Systems of Care (TBIMS). SETTING: Ten National Institute for Disability and Rehabilitation Research TBI Model System centers for coordinated acute and rehabilitation care. PARTICIPANTS: 908 adults with TBI were included in the study. MAIN OUTCOME MEASURES: Sitting and standing balance were assessed within 72 hours of admission to inpatient rehabilitation. RESULTS: Age less than 50 years had a significant association with normal sitting and standing balance (P =.001 and.05, respectively). Measures of severity of traumatic brain injury, including admission Glasgow Coma Score, length of posttraumatic amnesia (PTA), length of coma, and acute care length of stay were each significantly related to impaired sitting and standing balance ratings (P <.01). Initial abnormalities in pupillary response had a significant relationship with impairment of sitting (P =.009) but not standing balance. Incidence of respiratory failure, pneumonia, soft tissue infections, and urinary tract infections were all related to impaired sitting balance (P <.01). Presence of intracranial hemorrhages did not have a significant relationship with either sitting or standing balance. Intracranial compression had a significant relationship with standing (P =.05) but not sitting balance. A discriminant function analysis, which included neuroradiological findings, injury severity, and medical complications, could not accurately predict impaired balance ratings. CONCLUSIONS: This study demonstrated that rehabilitation admission balance ratings have a significant relationship with age, multiple measures of severity, and acute care medical complications after TBI. Prospective studies are indicated to evaluate the role balance at rehabilitation admission plays in the functional prognosis of patients with TBI.

Use of antiepileptics in traumatic brain injury: a review for psychiatrists.

In recent years, the number of new antiepileptic agents has been growing, as have the potential applications. Traumatic brain injury (TBI) patients often present with behavioral disturbances that may be amenable to treatment with antiepileptic drugs. These conditions include bipolar disorder, as well as posttraumatic seizures and agitation. We review treatment of these three conditions with newer agents, as well as past literature on treatment with older antiepileptic drugs. We also review the pharmacology of newer antiepileptic drugs and summarize reports that indicate possible utility in the TBI population. Although there is a paucity of evidence for brain injury patients specifically, experience with similar groups suggests that these drugs may be useful. Further trials are indicated to clarify the role of the new antiepileptic agents, which may offer more tolerable side effect profiles than do current treatments.

Hypermethylated APC DNA in plasma and prognosis of patients with esophageal adenocarcinoma.

BACKGROUND: The adenomatous polyposis coli (APC) locus on chromosome 5q21-22 shows frequent loss of heterozygosity (LOH) in esophageal carcinomas. However, the prevalence of truncating mutations in the APC gene in esophageal carcinomas is low. Because hypermethylation of promoter regions is known to affect several other tumor suppressor genes, we investigated whether the APC promoter region is hypermethylated in esophageal cancer patients and whether this abnormality could serve as a prognostic plasma biomarker. METHODS: We assayed DNA from tumor tissue and matched plasma from esophageal cancer patients for hypermethylation of the promoter region of the APC gene. We used the maximal chi-square statistic to identify a discriminatory cutoff value for hypermethylated APC DNA levels in plasma and used bootstrap-like simulations to determine the P: value to test for the strength of this association. This cutoff value was used to generate Kaplan-Meier survival curves. All P values were based on two-sided tests. RESULTS: Hypermethylation of the promoter region of the APC gene occurred in abnormal esophageal tissue in 48 (92%) of 52 patients with esophageal adenocarcinoma, in 16 (50%) of 32 patients with esophageal squamous cell carcinoma, and in 17 (39.5%) of 43 patients with Barrett's metaplasia but not in matching normal esophageal tissues. Hypermethylated APC DNA was observed in the plasma of 13 (25%) of 52 adenocarcinoma patients and in two (6.3%) of 32 squamous carcinoma patients. High plasma levels of methylated APC DNA were statistically significantly associated with reduced patient survival (P =.016). CONCLUSION: The APC promoter region was hypermethylated in tumors of the majority of patients with primary esophageal adenocarcinomas. Levels of hypermethylated APC gene DNA in the plasma may be a useful biomarker of biologically aggressive disease in esophageal adenocarcinoma patients and should be evaluated as a potential biomarker in additional tumor types.

Photodynamic therapy for esophageal cancer. Update.

Although clinical studies with photodynamic therapy have been conducted for over 25 years, only recently has this technique become widely available for the treatment of esophageal cancer. Studies have demonstrated that it is as effective as Nd:YAG therapy for advanced esophageal malignancies while technically being somewhat easier to perform. Preliminary studies in early esophageal cancer also show effectiveness. In many ways, PDT is still in its infancy, and its exact role compared to other endoscopic treatments of esophageal cancer remains to be defined. It is expected that the development of new photosensitizers and light delivery systems will further expand the role of PDT in the diagnosis and management of esophageal neoplasms.

Assessment of physiatrists' knowledge and perspectives on the use of opioids: review of basic concepts for managing chronic pain.

Previous studies of physicians have elucidated knowledge gaps and misconceptions about the use of opioids for the treatment of chronic pain. The recent approval of a pain management subspecialty certification for physiatrists will create higher expectations of the field regarding the treatment of chronic pain. Five hundred randomly chosen physiatrists were surveyed with a 50.6% response rate. Ninety-eight percent of respondents treat patients with chronic noncancer pain diagnoses, and 37% occasionally treat patients with cancer-related pain. Seventy percent of respondents underestimated the percentage of patients with cancer-related pain that could experience relief with oral analgesics. Only 17% underestimated the percentage of advanced cancer patients that experience significant pain. Eight percent of respondents incorrectly answered that a patient, regardless of diagnosis, would become addicted to opioids by taking an opioid daily. Only 25% identified the correct definition of addiction. Questions regarding side effects revealed that 10% of respondents incorrectly believed that opioid-induced respiratory depression is common in patients whose oral morphine dose exceeds 100 mg per day. Eighty percent of respondents preferred long-acting preparations, and 92% preferred set dosing schedules for the treatment of chronic pain. Rapidly evolving concepts regarding the implementation of pharmacologic regimens for chronic pain diagnoses require health care professionals who are trained to administer these treatments. Overall, the survey results are encouraging regarding physiatrists' knowledge about the use of opioids to treat patients with chronic pain.

Opioids for managing patients with chronic pain: community pharmacists' perspectives and concerns.

Previous studies of pharmacists have suggested poor availability of opioids and apprehension about dispensing these drugs. This pilot study surveyed 52 randomly selected New Jersey community pharmacists (response rate = 69%). Reluctance to stock opioids was attributed to concerns about robbery by 14% and to concerns about federal or state investigation by 17%. No correlation was found between respondents who had a high degree of concern about robbery and those who had incurred previous robbery. Of the 20% of respondents who had incurred a prior federal or state investigation, none expressed more than minimal concern about opioid regulatory issues. Pharmacist confidence in the acceptability of opioids for chronic pain was 75% for malignant pain in patients with no history of opioid abuse and declined to 3% for nonmalignant pain in patients with a history of opioid abuse.

Anti-p53 antibodies in patients with Barrett's esophagus or esophageal carcinoma can predate cancer diagnosis.

BACKGROUND & AIMS: We previously discovered anti-p53 antibodies predating a cancer diagnosis in subjects at increased risk for liver, lung, breast, and prostate cancer. Recently, we reported a significant correlation (P < 0.017) between p53 antibodies and p53 mutations in patients with late-stage esophageal carcinoma. Because others have reported p53 mutations and overexpression of p53 protein in Barrett's esophagus, we studied p53 antibodies in plasma of 88 serially endoscoped patients: 36 with Barrett's metaplasia, 23 with esophageal squamous cell carcinoma, 10 with esophageal adenocarcinoma, and 19 with esophagitis or normal esophagus. METHODS: We used enzyme immunoassay, immunoblotting, and immunoprecipitation assays for p53 antibodies; polymerase chain reaction, denaturant gradient gel electrophoresis, and sequencing for p53 mutations; and immunohistochemistry for p53 protein. RESULTS: p53 antibodies were detected in 4 patients with Barrett's esophagus, including 1 with dysplasia that later progressed to adenocarcinoma, and in 10 cancer patients (P = 0.002) (8 squamous and 2 adenocarcinoma), 2 of whom (1 squamous, 1 adenocarcinoma) had antibodies before cancer was diagnosed. Other patient groups were too small for informative statistical analysis. Six antibody-positive cancer patients had p53 mutations, whereas 2 patients with cancer and 1 with Barrett's esophagus with antibodies had p53 protein overexpressed in esophageal tissues. CONCLUSIONS: Patients with Barrett's esophagus and esophageal cancer can develop p53 antibodies that may predate the clinical diagnosis of malignancy.