Giovanni De Petris

Treatment of recurrent hepatitis C infection after liver transplantation with combination of pegylated interferon α2b and ribavirin: An open-label series

Background. Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) is universal. We aimed to evaluate the efficacy and safety of pegylated interferon (PEG-IFN) and ribavirin (RIB) in the treatment of post-OLT HCV recurrence. Methods. Thirty-seven patients with recurrent HCV after OLT were screened and began treatment. Nineteen patients have completed therapy. PEG-IFN was started at a dose of 0.5 &mgr;g/kg per week and titrated toward a maximum dose of 1.5 &mgr;g/kg per week. RIB was started at a dose of 400 mg per day and titrated toward a maximum of 1000 mg per day, as tolerated. Therapy continued for 1 year after HCV replication was undetectable by reverse transcriptase-polymerase chain reaction and was discontinued if there was no virologic clearance at 48 weeks. Results. Twelve patients (63%) completed the combination regimen. Therapy was discontinued in seven (37%) patients. Seven patients (37%) had undetectable viral load at the end of treatment. Of those, five patients (26%) had sustained viral response 6 months after discontinuation of therapy. Five patients (26%) had no virologic response. Necro-inflammatory score declined from 5.22 to 2.89 (P =0.05) in nonresponders versus 6.8 to 2.6 (P <0.01) in responders. Fibrosis stage did not change in either group. Genotype 1-infected patients had a lower likelihood of attaining end of treatment or sustained viral response (P <0.05 for both). Conclusions. Post-OLT HCV recurrence can be safely treated with PEG-IFN and RIB. Bone marrow toxicity, depression, and rejection are limiting factors that require aggressive management. There was short-term histologic benefit to the use of this regimen, even in those patients without viral clearance.

A Novel Histologic Scoring System to Evaluate Mucosal Biopsies From Patients With Eosinophilic Esophagitis

BACKGROUND & AIMS Eosinophilic esophagitis (EoE) is characterized by medically/surgically-resistant gastroesophageal reflux symptoms and dense squamous eosinophilia. Studies suggest that histologic assessment of esophageal eosinophilia alone cannot reliably separate patients with EoE from those with gastroesophageal reflux disease (GERD). Our goal was to develop an assay to identify EoE patients and perhaps differentiate EoE from other causes of esophageal eosinophilia. METHODS A monoclonal antibody specific for an eosinophil secondary granule protein (eosinophil peroxidase [EPX]) was developed and shown to specifically identify intact eosinophils and detect eosinophil degranulation in formalin-fixed specimens. A histopathologic scoring algorithm was developed to analyze data from patient evaluations; the utility of this algorithm was assessed by using archived esophageal tissues from patients with known diagnoses of EoE and GERD as well as controls from 2 tertiary care centers. RESULTS Intraobserver/interobserver blinded evaluations demonstrated a significant difference (P < .001) between scores of samples taken from control subjects, from patients with esophageal eosinophilia who had a diagnosis of EoE, and from patients with GERD (P < .001). This algorithm also was able to identify patients whose clinical course was suggestive of a diagnosis of EoE, but that nonetheless failed to reach the critical threshold number of > or =15 eosinophils in a high-power (40x) microscopy field. CONCLUSIONS A novel immunohistochemical scoring system was developed to address an unmet medical need to differentiate histologic specimens from patients with EoE relative to those with GERD. The availability of a unique anti-EPX-specific monoclonal antibody, combined with the ease/rapidity of this staining method and scoring system, will provide a valuable strategy for the assessment of esophageal eosinophilia.

Natural History of Post-Liver Transplantation Hepatitis C: A Review of Factors That May Influence Its Course

Our aim was to assess long‐term survival in patients transplanted for HCV‐related end‐stage liver disease (ESLD) and evaluate potentially modifiable predictors of survival. We performed a retrospective analysis of adult liver transplants (LT) at our institution for HCV‐related ESLD since the programs inception. Pertinent demographic, clinical, and biochemical information was retrieved from electronic medical records and histological data from 990 per‐protocol liver biopsies were collected. Three hundred eighty LT were performed at our institution during the study period, 206 patients were transplanted for HCV‐related ESLD; 6 died within 30 days of transplantation and were not included. The remaining 200 recipients (DDLT 168 LDLT 32) constituted the evaluable population. The demographics were as follows: 150 males, median age 53 years; median donor age 39 years; hepatocellular carcinoma (HCC) in 26%. Overall 1‐, 5‐, and 7‐year survival: 95%, 81%, and 79%; median survival 43 months, mortality 15%. Significant HCV recurrence (HAI ≥6 and/or fibrosis ≥2) was present in 49%, “early recurrence” (within 1 year of LT) in 30.5% and biopsy‐proven acute rejection was present in 27%. Factors with a significant negative impact on patient survival included: fibrosis stage ≥2 at 12‐month biopsy, advanced donor age, history of HCC and early acute rejection. Survival was similar regardless of the donor type (DDLT vs. LDLT). Early and aggressive HCV recurrence has a very heavy toll on patient survival. Prompt recognition and treatment of “rapid fibrosers” may impart benefit. As has been described before, avoidance of rejection and selection of young donors for HCV‐positive recipients will also improve survival in this population. On the basis of our findings, LDLT is a good option for HCV‐positive recipients. Liver Transpl 15:1872–1881, 2009.

Progression of Pancreatic Adenocarcinoma Is Significantly Impeded with a Combination of Vaccine and COX-2 Inhibition

With a 5-year survival rate of <5%, pancreatic cancer is one of the most rapidly fatal malignancies. Current protocols for the treatment of pancreas cancer are not as effective as we desire. In this study, we show that a novel Mucin-1 (MUC1)-based vaccine in combination with a cyclooxygenase-2 inhibitor (celecoxib), and low-dose chemotherapy (gemcitabine) was effective in preventing the progression of preneoplastic intraepithelial lesions to invasive pancreatic ductal adenocarcinomas. The study was conducted in an appropriate triple transgenic model of spontaneous pancreatic cancer induced by the KRASG12D mutation and that expresses human MUC1 as a self molecule. The combination treatment elicited robust antitumor cellular and humoral immune responses and was associated with increased apoptosis in the tumor. The mechanism for the increased immune response was attributed to the down-regulation of circulating prostaglandin E2 and indoleamine 2, 3,-dioxygenase enzymatic activity, as well as decreased levels of T regulatory and myeloid suppressor cells within the tumor microenvironment. The preclinical data provide the rationale to design clinical trials with a combination of MUC1-based vaccine, celecoxib, and gemcitabine for the treatment of pancreatic cancer.

Symptoms Have Modest Accuracy in Detecting Endoscopic and Histologic Remission in Adults With Eosinophilic Esophagitis

BACKGROUND & AIMS It is not clear whether symptoms alone can be used to estimate the biologic activity of eosinophilic esophagitis (EoE). We aimed to evaluate whether symptoms can be used to identify patients with endoscopic and histologic features of remission. METHODS Between April 2011 and June 2014, we performed a prospective, observational study and recruited 269 consecutive adults with EoE (67% male; median age, 39 years old) in Switzerland and the United States. Patients first completed the validated symptom-based EoE activity index patient-reported outcome instrument and then underwent esophagogastroduodenoscopy with esophageal biopsy collection. Endoscopic and histologic findings were evaluated with a validated grading system and standardized instrument, respectively. Clinical remission was defined as symptom score <20 (range, 0-100); histologic remission was defined as a peak count of <20 eosinophils/mm(2) in a high-power field (corresponds to approximately <5 eosinophils/median high-power field); and endoscopic remission as absence of white exudates, moderate or severe rings, strictures, or combination of furrows and edema. We used receiver operating characteristic analysis to determine the best symptom score cutoff values for detection of remission. RESULTS Of the study subjects, 111 were in clinical remission (41.3%), 79 were in endoscopic remission (29.7%), and 75 were in histologic remission (27.9%). When the symptom score was used as a continuous variable, patients in endoscopic, histologic, and combined (endoscopic and histologic remission) remission were detected with area under the curve values of 0.67, 0.60, and 0.67, respectively. A symptom score of 20 identified patients in endoscopic remission with 65.1% accuracy and histologic remission with 62.1% accuracy; a symptom score of 15 identified patients with both types of remission with 67.7% accuracy. CONCLUSIONS In patients with EoE, endoscopic or histologic remission can be identified with only modest accuracy based on symptoms alone. At any given time, physicians cannot rely on lack of symptoms to make assumptions about lack of biologic disease activity in adults with EoE. ClinicalTrials.gov, Number: NCT00939263.

Emergence of Gastrointestinal Basidiobolomycosis in the United States, With a Review of Worldwide Cases

BACKGROUND We examined the epidemiology, clinical manifestations, histopathology, management, and outcomes of gastrointestinal basidiobolomycosis, an uncommon manifestation of infection caused by the fungus Basidiobolus ranarum. METHODS In this retrospective observational cohort study, cases of gastrointestinal basidiobolomycosis in the United States were identified by reviewing medical records from Mayo Clinic Hospital (Phoenix, AZ) and contacting local infectious diseases specialists, pathologists, gastroenterologists, the Arizona Department of Health Services, health departments of adjacent states, the Armed Forces Institute of Pathology, and the US Centers for Disease Control and Prevention. A comprehensive literature review identified additional cases worldwide. RESULTS Of 44 patients (mean age, 37 years [range, 2-81 years]) with gastrointestinal basidiobolomycosis, most were from the United States (19 patients [43%], of whom 17 [89%] were from Arizona) or Saudi Arabia (11 [25%]). Most (28 [64%]) were previously healthy. Common chronic medical conditions among 15 patients (34%) were diabetes mellitus (8 patients [18%]) and gastric disorders (7 [16%]). Common findings were abdominal pain (37 patients [84%]) and a palpable abdominal mass (19 [43%]). Intraabdominal malignancy was the leading provisional diagnosis (19 patients [43%]). The large bowel was involved in 36 (82%), the small intestine in 16 (36%), and the liver or gallbladder in 13 (30%). Characteristic histopathologic findings were observed in 43 (98%). Eight patients (18%) died. Combined surgical intervention and antifungal therapy was the preferred treatment. CONCLUSIONS Gastrointestinal basidiobolomycosis is an emerging invasive fungal infection in desert regions of the US Southwest. Clinical findings mimic malignancy and inflammatory bowel disease. Surgical excision and prolonged antifungal therapy are associated with favorable outcomes.

Usefulness of PET/CT Imaging in Systemic IgG4-related Sclerosing Disease. A Report of Three Cases

Autoimmune pancreatitis is the pancreatic manifestation of a novel clinicopathological disorder called systemic IgG4-related sclerosing disease. Beside the pancreas, this entity affects other sites (salivary glands, orbit, lung, thyroid, gallbladder, biliary tree system, kidney, abdominal aorta, retroperitoneum, prostate, and lymph node) by infiltration with IgG4-positive plasma cells. Several case reports and small case series have demonstrated the utility of integrated positron emission tomography/computed tomography (PET/CT) in monitoring therapy and documenting relapse and flare-up of autoimmune pancreatitis. However, there are no reports on the usefulness of PET/CT in selecting extrapancreatic sites for tissue sampling. We herein demonstrate the clinical utility of integrated PET/CT in 3 cases of systemic IgG4-related sclerosing disease for targeting extrapancreatic biopsy sites.

Collagenous Gastritis Associated With Lymphocytic Gastritis and Celiac Disease

Collagenous gastritis is a rare disorder, with only 8 cases reported in the literature, 2 in children and 6 in adults. We report an additional case of collagenous gastritis in a 42-year-old man with celiac disease. A thickened (>10 microm) subepithelial collagen band with entrapped capillaries, fibroblasts, and inflammatory cells was seen in the stomach, associated with lymphocytic gastritis. The duodenal mucosa showed severe villous atrophy but no subepithelial collagen deposition. No evidence of lymphocytic or collagenous colitis was found in the colon. The patient became symptom-free on a gluten exclusion diet and showed partial improvement of histopathologic findings after 3 months. Collagenous gastritis is a rare disease, but a wider recognition of its histopathologic features and clinical associations may bring more cases to light and provide additional clues in determining its etiology and pathogenesis.

Hepatitis C virus recurrence in living donor liver transplant recipients.

Recurrence of hepatitis C virus (HCV) after liver transplantation (LT) is a universal phenomenon. Recent reports have suggested an earlier and more aggressive recurrence in the living donor liver transplant (LDLT) population. The aim of this study was to compare the histological recurrence of HCV after LDLT versus deceased donor transplantation (DDT). Twenty-nine patients underwent LT for HCV-related end-stage liver disease at our institution between April 2001 and March 2003 (42 months). Twenty patients underwent DDT, and nine patients LDLT. Laboratory data were collected on a weekly to biweekly basis and HCV PCR was performed before LT and 3–4 months and yearly post-LT. Liver biopsies were performed as needed and per institutional protocol at 7 days, at 4 months, and yearly thereafter. All biopsies were evaluated by a single pathologist and scored for rejection (Banff score) and chronic hepatitis (Ishak score system). The predominant genotype in the DDT and LDLT groups was genotype 1 (DDT=70%, LDLT=79%). HCV RNA titers pre-LT and 3–4 months after LT did not differ. The incidence of rejection was higher in the DDT group (P < 0.05). There was a trend toward improved lshak stage and grade in the LDLT group at 4 and 12 months post-LT, however, this trend did not reach statistical significance. No histological difference in the recurrence or severity rate was observed at 4 or 12 months post-LT in the DDT group vs. the LDLT group.

The histopathological approach to inflammatory bowel disease: a practice guide.

Inflammatory bowel diseases (IBDs) are lifelong disorders predominantly present in developed countries. In their pathogenesis, an interaction between genetic and environmental factors is involved. This practice guide, prepared on behalf of the European Society of Pathology and the European Crohn’s and Colitis Organisation, intends to provide a thorough basis for the histological evaluation of resection specimens and biopsy samples from patients with ulcerative colitis or Crohn’s disease. Histopathologically, these diseases are characterised by the extent and the distribution of mucosal architectural abnormality, the cellularity of the lamina propria and the cell types present, but these features frequently overlap. If a definitive diagnosis is not possible, the term indeterminate colitis is used for resection specimens and the term inflammatory bowel disease unclassified for biopsies. Activity of disease is reflected by neutrophil granulocyte infiltration and epithelial damage. The evolution of the histological features that are useful for diagnosis is time- and disease-activity dependent: early disease and long-standing disease show different microscopic aspects. Likewise, the histopathology of childhood-onset IBD is distinctly different from adult-onset IBD. In the differential diagnosis of severe colitis refractory to immunosuppressive therapy, reactivation of latent cytomegalovirus (CMV) infection should be considered and CMV should be tested for in all patients. Finally, patients with longstanding IBD have an increased risk for the development of adenocarcinoma. Dysplasia is the universally used marker of an increased cancer risk, but inter-observer agreement is poor for the categories low-grade dysplasia and indefinite for dysplasia. A diagnosis of dysplasia should not be made by a single pathologist but needs to be confirmed by a pathologist with expertise in gastrointestinal pathology.