Initial Histologic Response Research Articles

Long-term efficacy of proton pump inhibitors as a treatment modality for eosinophilic esophagitis

BackgroundProton pump inhibitors (PPIs) are a first-line treatment for EoE, but data are limited concerning response durability. We aimed to determine long-term outcomes in EoE patients responsive to PPI-therapy. MethodsWe conducted a retrospective cohort study of newly diagnosed adults with EoE who had initial histologic response (<15 eosinophils per high-power-field) to PPI-only therapy. We extracted data regarding their subsequent clinical course and outcomes. We compared findings between the initial PPI-response endoscopy and the final endoscopy, and assessed factors associated with loss of PPI response. ResultsOf 138 EoE patients with initial histologic response to PPI, 50 had long-term endoscopic follow-up, 40 had clinical follow-up, 10 changed treatments, and 38 had no long-term follow-up. Of those with endoscopic follow-up, mean follow-up-time was 3.6 ± 2.9 years; 30 and 32 patients (60%; 64%) maintained histologic and symptom responses, respectively. However, fibrotic endoscopic findings of EoE were unchanged. Younger age (aOR 1.05, 95% CI: 1.01–1.11) and dilation prior to PPI treatment (aOR 0.21, 95% CI: 0.05–0.83) were the only factors associated with long-term loss of PPI response. ConclusionsLong-term histologic and clinical response rates for PPI therapy were 60% and 64%, respectively. Younger age and dilation at baseline were associated with histologic loss of response. These data can inform long-term EoE treatment selection.

Rapid Recurrence of Eosinophilic Esophagitis Activity After Successful Treatment in the Observation Phase of a Randomized, Double-Blind, Double-Dummy Trial

Eosinophilic esophagitis (EoE) is chronic and recurs if treatment is discontinued. We aimed to determine rates of recurrence, and whether initial treatment with oral viscous budesonide (OVB) resulted in less recurrence than fluticasone from a multidose inhaler (MDI). This was the observation phase of a randomized, double-blind, double-dummy trial comparing OVB with MDI for initial EoE treatment. Subjects with a histologic response (<15 eosinophils/high-power field) in the trial entered an observation phase in which treatment was discontinued and symptoms were monitored. Patients underwent an endoscopy or a biopsy when symptoms recurred or at 1 year. We analyzed time to symptom recurrence and assessed endoscopic severity and histologic relapse (≥15 eosinophils/high-power field) at follow-up endoscopy. Thirty-three of the 58 subjects (57%) had symptom recurrence before 1 year. The overall median time to symptom recurrence was 244 days. There was no difference in the rate of symptom recurrence for subjects treated with OVB vs MDI (hazard ratio, 1.04; 95% CI, 0.52-2.08). At symptom recurrence, 78% of patients had histologic relapse. The patients had significant increases in mean Dysphagia Symptom Questionnaire score (3.8 vs 8.7; P < .001), and the EoE Endoscopic Reference Score (1.3 vs 4.6; P < .001) compared with end of treatment. EoE disease activity recurred rapidly after initial histologic response to topical steroids (either OVB or MDI). Because most subjects had recurrent endoscopic and histologic signs not reliably detected by symptoms, maintenance therapy should be recommended in EoE patients achieving histologic response to topical steroids. Clinicaltrials.gov no: NCT02019758.

Response to Proton Pump Inhibitor Therapy in a Racially Diverse Cohort of Pediatric Eosinophilic Esophagitis

Introduction: Eosinophilic Esophagitis (EoE) is a chronic immunologic disorder characterized by esophageal dysfunction and dense esophageal eosinophilia. The incidence rates are 5.1 and 7 per 100,000 person years in children and adults respectively, and is described to affect a predominantly caucasian population. An initial histologic response to Proton Pump Inhibitor has long been viewed as favoring Gastroesophageal reflux disease and its use is thus proposed in the diagnostic approach. It is evident from recent literature that PPI therapy has an anti-eosinophil effect, thereby inducing a histologic response independent of GERD status. We investigated the response to the initial PPI regimen in a uniquely diverse cohort of children with EoE. Methods: We performed a retrospective review of data pertaining to children referred to the multidisciplinary EoE clinic at Children's National Medical Center (CNMC). We included children with EoE (peak >15 eos/hpf at any esophageal level) who underwent a histologic reassessment after 8 weeks of PPI (1-3 mg/kg/day) at CNMC. Histologic response was defined as 5-15 eos/hpf and remission as <5 eos/hpf. Results: We reviewed data for 71 children with EoE, age 8 mo-17 yr (6 yr), Caucasian 26 (36.6%), and 43% African Americans (AA) among non-Caucasians. Only 15 children met inclusion criteria comprising of 73% males, 53% non-Caucasians including 33% AA, age range 1-17 yr (7.6 yr). Histologic remission with minimal symptomatic improvement occurred in only 1 patient. The pre-PPI and post-PPI therapy peak eos/hpf were 10-100 (52) and 1-100 (54), p = 0.74). Conclusion: We did not observe PPI therapy as sufficient to alter esophageal histologic status favorably in contrast to adults with EoE. To our knowledge, our Pediatric EoE, is the only uniquely non Caucasian predominant cohort reported to date. The retrospective nature, variable regimens, and absence of formal GERD investigations are limitations of the study. Extending the analysis to additional patients is expected to provide useful insight into PPI effects in EoE.

Food elimination diets are effective for long-term treatment of adults with eosinophilic oesophagitis.

Limited data describe the long-term efficacy of dietary elimination in eosinophilic oesophagitis (EoE). To assess the long-term outcomes of food elimination diets for treatment of adults with EoE. We conducted a retrospective cohort study at our centre analysing all EoE patients receiving a food elimination diet without concomitant steroids. Baseline data were abstracted using standardised collection forms. Follow-up data from a mean 24.9-month period were collected for patients with a histological response to a food elimination diet during and after food reintroduction. The main outcomes were symptomatic, endoscopic and histological responses. Of 52 patients, 18 received a 6-food food elimination diet, 32 received targeted diet, and two received a 6-food food elimination diet with targeted elimination. There were 21 (40%) patients with an initial histological response. Responders reported less dysphagia after treatment (95% baseline vs 11%; P = .001) and at the end of follow-up (95% baseline vs 33%; P = .008). Significant and durable endoscopic improvements were recorded at the same time points: Endoscopic reference score: 3.2 vs 0.7; P = .001; and 3.2 vs 1.7; P = .06. Histological findings improved after the most restrictive diet in responders (49.8 vs 4.1 eosinophils per high-power field; P = .001) and remained suppressed in the 10 initial responders maintaining compliance at the end of follow-up (5.2 eosinophils per high-power field). Among EoE patients responding to a food elimination diet and remaining adherent, maintenance dietary therapy produced durable long-term symptomatic, endoscopic and histological disease control. These long-term data confirm that a food elimination diet is an effective maintenance treatment option in select adults with EoE.

Diminishing Effectiveness of Long-Term Maintenance Topical Steroid Therapy in PPI Non-Responsive Eosinophilic Esophagitis.

Objectives:While topical corticosteroids are first-line therapy for eosinophilic esophagitis (EoE), the data regarding long-term effectiveness are lacking. We aimed to determine long-term histologic and endoscopic outcomes of maintenance therapy in EoE steroid responders.Methods:We performed a retrospective study of adults with EoE at UNC Hospitals who had initial histologic response (<15 eos/hpf) after 8 weeks of topical steroids, and maintained on therapy. Endoscopic and the histologic data were recorded at baseline and follow-up endoscopies. Multivariable logistic regression was performed to assess loss of treatment response by steroid dose at recurrence, and Kaplan–Meier analysis to calculate durability of disease remission.Results:Of 55 EoE patients with initial response to swallowed/topical fluticasone or budesonide over a median 11.7 months, 33 had at least two follow-up EGDs. Of these patients, 61% had histologic loss of response and worse endoscopic findings. There was no difference in baseline steroid dose (P=0.55) between the groups, but those maintained on their initial dose had lower odds (OR: 0.10; 95% CI: 0.01, 0.90) of loss of response compared to those who had subsequent dose reduction. On survival analysis, 50% had loss of response to steroids by 18.5 months and 75% by 29.6 months.Conclusions:In adult EoE steroid responders, loss of treatment response is common, and is associated with a steroid dose reduction. Routinely lowering doses for maintenance steroids may provide inferior outcomes.

Transient PPI Responsive Esophageal Eosinophilia May Be a Clinical Sub-phenotype of Pediatric Eosinophilic Esophagitis

Eosinophilic esophagitis (EoE) and gastroesophageal reflux (GERD) both cause esophageal eosinophilia. Reports show that esophageal eosinophilia meeting criteria for EoE may respond to acid suppression mono-therapy. Consensus guidelines have termed this entity "PPI-responsive esophageal eosinophilia" (PPIRee) and recommend a trial with proton-pump inhibitors (PPIs) prior to a definitive EoE diagnosis. The mechanisms of PPIRee and whether this represents a sub-phenotype of GERD, a sub-phenotype of EoE, or its own distinct entity remain unclear. A database search revealed children who had an initial histologic response to PPI monotherapy but had recurrence of esophageal eosinophilia and symptoms despite continued PPI therapy. In order to understand the patterns of esophageal inflammatory cells during PPI therapy we performed quantitative immunohistochemistry for mast cells, CD1a positive antigen presenting cells, and CD45RO memory T cells. Four pediatric patients (mean age 9.5years) had a mean peak eosinophil count of 52eos/hpf which initially resolved completely during PPI mono-therapy. However, despite continued PPI therapy, endoscopic abnormalities and pan-esophageal eosinophilia recurred (mean peak eosinophil count of 64eos/hpf). There was no seasonal variation or lack of PPI adherence that explained the return of eosinopihlia. Similar to eosinophilia, mastocytosis and CD45RO cells were transiently decreased during PPI therapy. PPIs appear to be capable of transiently resolving multiple inflammatory cell subsets including eosinophils, mast cells, and CD45RO cells. Our data suggest that patients with PPIRee should have continued monitoring for EoE during PPI monotherapy. The numbers of patients in whom PPIRee is a transient phenomenon and whether PPIRee represents a sub-phenotype of EoE in children merits further investigation.

Survival after recurrent osteosarcoma: Data from 3 European Osteosarcoma Intergroup (EOI) randomized controlled trials

BackgroundRecurrence after osteosarcoma usually leads to death; thus prognostic factors for survival are of great importance. MethodsBetween 1983 and 2002, the European Osteosarcoma Intergroup accrued 1067 patients to 3 randomized controlled trials of pre- and post-operative chemotherapy for patients with resectable non-metastatic high-grade osteosarcoma of the extremity. Control treatment in all trials was doxorubicin 75mg/m2 and cisplatin 100mg/m2. The comparators were additional high-dose methotrexate (BO02), T10-based multi-drug regimen (BO03) and G-CSF intensified-DC (BO06). Post-recurrence survival (PRS) was investigated on combined data with standard survival analysis methods. ResultsMedian recurrence-free survival was 31months; 8 recurrences were reported more than 5years after the diagnosis. In 564 patients with a recurrence (median 13months post-randomisation), there was no difference in post-relapse survival between treatment arms. Patients whose disease recurred within 2years after randomization had a worse prognosis than those recurring after 2years. Patients with good initial histological response to pre-operative chemotherapy had a better overall survival after recurrence than poor responders. Local relapse was more often reported after limb-saving procedures (2 versus 8%; amputation versus limb-saving), independent of the primary tumour site. Site of first recurrence (local 20%, lung 62%, “other” 19%) affected survival, as patients recurring with non-lung distant metastases only or any combination of local relapse, lung metastases and non-lung metastases (=group “other”) had significantly worse overall survival (local 39%, lung 19%, “other” 9% at 5years). ConclusionsThese data describing a large series of patients with recurrent extremity osteosarcoma confirm the relationship between early recurrence and poor survival. There was better PRS in patients after good histological response to pre-operative chemotherapy, or with local-only recurrence.

Liposomal Muramyl Tripeptide Phosphatidyl Ethanolamine: Ifosfamide-Containing Chemotherapy In Osteosarcoma

Liposomal muramyl tripeptide phosphatidyl ethanolamine (L-MTP-PE) is a synthetic biological investigational agent used for treating osteosarcoma. It has been used in both canine and human osteosarcoma to reduce pulmonary metastases, the most common pattern of treatment failure for sarcomas. L-MTP-PE has been well tolerated using the concept of biological cancer therapy during chemotherapy. The use of L-MTP-PE with ifosfamide is the best studied combination with single agent chemotherapy. This may represent a new treatment choice for osteosarcoma patients receiving ifosfamide. Such patients include those with a poor initial histological response to primary therapy and/or metastatic disease including pulmonary metastases. Reduction of side effects of L-MTP-PE, such as fever and/or flu-like symptoms, with ibuprofen has not reduced efficacy. Since improved symptom control is possible using drug combinations that are especially effective for delayed nausea, outpatient high-dose ifosfamide chemotherapy combined with L-MTP-PE may lead to a safe and effective therapy while maintaining the patients' quality of life.

Long-Term Efficacy of Intravesical Bacillus Calmette-Guerin for Carcinoma in Situ: Relationship of Progression to Histological Response and p53 Nuclear Accumulation

Purpose We assessed the influence of the histological response to intravesical bacillus Calmette-Guerin (BCG) and the prevalence of p53 nuclear accumulation on the clinical behavior of patients with carcinoma in situ. Materials and Methods Of 60 patients with Bergquist grade 3 carcinoma in situ 13 had primary and 47 had secondary carcinoma in situ. Patients received 6 weekly instillations and nonresponders received an additional 6 instillations at 2-week intervals. No maintenance was administered. Median followup was 48 months. The p53 nuclear accumulation was detected by immunohistochemical analysis with antibody PAb 1801. Results The complete histological response rate to BCG therapy was 64%, which decreased to 52% at 4 years. BCG was more effective for treatment of primary than secondary carcinoma in situ (complete response rate 85 versus 57%, respectively). The 45% progression rate was related to the initial histological response occurring in 26% of patients with a complete versus 77% with a partial and no response. Consequently, the progression rate was only 8% for primary versus 57% for secondary carcinoma in situ. Of the patients receiving only 1 course of BCG 40% had progression compared to 62% of those who received 2 courses. Patients in whom both courses failed had a progression rate of 89%. Intravesical BCG converted the p53 nuclear immunoreactivity from positive to negative in 73% of the 26 patients expressing reactivity before treatment, of whom 68% also had a complete response. The progression rate was related to the prevalence of p53 nuclear reactivity after but not before treatment (90% of patients with versus 37% without p53 nuclear accumulation had progression). All 3 complete responders with p53 nuclear reactivity after BCG had progression, which suggests that molecular genetic change may precede histological change. Complete responders without p53 nuclear accumulation after BCG treatment experienced the lowest progression rate (21%). Conclusions Our results suggest that patients with a persistent complete histological response and without p53 nuclear accumulation after BCG treatment can be followed conservatively. Cystectomy should be considered in all other patients.

Induction of angiogenesis by intraperitoneal injection of asbestos fibers

Tumors and activated macrophages release angiogenic factors that stimulate migration and proliferation of capillaries. We studied the development of angiogenesis before the appearance of mesotheliomas in C57B1/6 mice. Weekly i.p. injections of crocidolite asbestos fibers produced mesotheliomas after 30-50 wk. The initial histologic response to asbestos fibers was a nodular lesion on the peritoneal lining composed of clusters of fibers, activated macrophages, and proliferating mesenchymal cells. The earliest visible evidence of angiogenesis was seen surrounding 7% of these lesions 14 days after a single injection of 200 micrograms of crocidolite asbestos fibers. After six weekly injections, 30% of the lesions containing asbestos fibers were surrounded by a capillary network radiating toward the center of the lesion. Other mineral fibers, including chrysotile asbestos and fiberglass, also induced angiogenesis after six weekly injections. In contrast, only 8% of the lesions containing short asbestos fibers (90.6% less than or equal to 2.0 microns) and 9% of the lesions containing silica particles showed evidence of angiogenesis. We conclude that tumorigenic mineral fibers induce angiogenesis in the peritoneal lining, whereas nontumorigenic mineral particles or short asbestos fibers are less effective. Ingrowth of new blood vessels around clusters of asbestos fibers may facilitate the later emergence of mesotheliomas at these sites.

Immunopathology of Dermal Reactions Induced by Schistosoma Mansoni Cercariae and Cercarial Extract *

Abstract Mice infected with Schistosoma mansoni and normal mice were exposed to viable S. mansoni cercariae, and the exposed areas were biopsied at ½, 1, 2, 4, 8, 16, 24, 36, 48, and 120 hours. The initial histologic response (2–8 hours after challenge) of previously infected animals was characterized by edema and a progressive, predominantly polymorphonuclear infiltrate. By 16 and 24 hours, the schistosomules were the foci of intense mixed cell infiltrates, and by 36 and 48 hours, dense mononuclear infiltrates were evident. Normal mice showed only edema and slight polymorphonuclear infiltrates, and by 16 hours most of the schistosomules had migrated through the dermis. Intradermal challenge of infected and uninfected mice with a crude saline cercarial extract produced reactions similar to those described for the two groups after cercarial penetration. Normal mice were also challenged by cercarial exposure or injection of cercarial extract after passive transfer of either lymphoid cells or serum from infected or normal mice. Sera from infected mice passively immunized normal mice, which then responded with an early (5-hour) polymorphonuclear infiltrate against cercariae. Lymphoid cells from infected mice passively immunized normal mice which then developed a late (30-hour) mononuclear infiltrate against either schistosomules or cercarial extract. It is concluded that mice develop both humoral and cell-mediated immune responses against the cercarial stage of S. mansoni.