Francesca M. Ruggiero

Herpes simplex-induced fulminant hepatitis in adults: a call for empiric therapy.

Herpes simplex-induced fulminant hepatitis is an infrequently reported cause of hepatitis in adults. Pregnant females and patients with impaired cellular immunity may be at increased risk, although healthy adults have been affected. The diagnosis may be underrecognized due to nonspecific presenting symptoms and lack of typical cutaneous herpes lesions. We present three cases of fatal herpes simplex fulminant hepatitis. Our review of case reports of herpes simplex hepatitis in adults demonstrates improved survival with intravenous acyclovir therapy. We believe that empiric use of acyclovir should be considered while the diagnostic evaluation of non-acetaminophen-induced fulminant hepatitis is underway. Recognition of characteristic liver function abnormalities seen with fulminant herpes simplex hepatitis include marked elevation of transaminases with AST > ALT and a mild hyperbilirubinemia (anicteric hepatitis), and they should prompt acyclovir therapy. This is especially true when there are no obvious risk factors for other forms of hepatitis.

Variance in the Interpretation of Cervical Biopsy Specimens Obtained for Atypical Squamous Cells of Undetermined Significance

We sought to determine whether the variability in dysplasia rates in cases of atypical squamous cells of undetermined significance (ASCUS) reflects variability in interpretation of cervical biopsy specimens. In phase 1, 124 biopsy specimens obtained because of a cytologic diagnosis of ASCUS were reviewed independently by 5 experienced pathologists. Diagnostic choices were normal, squamous metaplasia, reactive, indeterminate, low-grade squamous intraepithelial lesion (LSIL), and high-grade squamous intraepithelial lesion (HSIL). The rate of dysplasia ranged from 23% to 51%. All pathologists agreed in 28% of cases. In 52% of cases, the diagnoses ranged from benign to dysplasia. The overall interobserver agreement was poor. In phase 2, 60 cervical biopsy specimens (21 obtained for ASCUS, 22 for LSIL, and 17 for HSIL) were evaluated using the same diagnostic choices. Agreement was better in biopsies performed for HSIL and LSIL compared to those for ASCUS. Intraobserver reproducibility in the interpretation of biopsies performed for ASCUS ranged from poor to excellent. We conclude that variability in the interpretation of biopsy specimens plays an important role in the differences in rates of dysplasia reported for the follow-up of ASCUS.

Therapy with the Opioid Antagonist Naltrexone Promotes Mucosal Healing in Active Crohn’s Disease: A Randomized Placebo-Controlled Trial

BackgroundEndogenous opioid peptides have been shown to play a role in the development and/or perpetuation of inflammation. We hypothesize that the endogenous opioid system is involved in inflammatory bowel disease, and antagonism of the opioid–opioid receptor will lead to reversal of inflammation.AimsA randomized double-blind placebo-controlled study was designed to test the efficacy and safety of an opioid antagonist for 12xa0weeks in adults with active Crohn’s disease.MethodsForty subjects with active Crohn’s disease were enrolled in the study. Randomized patients received daily oral administration of 4.5-mg naltrexone or placebo. Providers and patients were masked to treatment assignment. The primary outcome was the proportion of subjects in each arm with a 70-point decline in Crohn’s Disease Activity Index score (CDAI). The secondary outcome included mucosal healing based upon colonoscopy appearance and histology.ResultsEighty-eight percent of those treated with naltrexone had at least a 70-point decline in CDAI scores compared to 40% of placebo-treated patients (pxa0=xa00.009). After 12xa0weeks, 78% of subjects treated with naltrexone exhibited an endoscopic response as indicated by a 5-point decline in the Crohn’s disease endoscopy index severity score (CDEIS) from baseline compared to 28% response in placebo-treated controls (pxa0=xa00.008), and 33% achieved remission with a CDEIS score <6, whereas only 8% of those on placebo showed the same change. Fatigue was the only side effect reported that was significantly greater in subjects receiving placebo.ConclusionsNaltrexone improves clinical and inflammatory activity of subjects with moderate to severe Crohn’s disease compared to placebo-treated controls. Strategies to alter the endogenous opioid system provide promise for the treatment of Crohn’s disease.

GI Polyposis and Glycogenic Acanthosis of the Esophagus Associated With PTEN Mutation Positive Cowden Syndrome in the Absence of Cutaneous Manifestations

A 62-yr-old man was referred for management of GI polyposis. Large bowel polyps were initially diagnosed >25 yr ago, and the patient had undergone multiple colonoscopies and polypectomies. Personal and family history were notable for thyroid goiter and hypothyroidism. Physical examination was notable for lingular papillomatosis. No cutaneous lesions were seen. Upper endoscopy revealed esophageal glycogen acanthosis. There were multiple polyps throughout the stomach and the small and large intestines. Histology of these polyps showed multiple cell types including juvenile polyps, inflammatory polyps with fibromuscular proliferation and lamina propria ganglion cells, and focal adenomatous change. A clinical diagnosis of Cowden syndrome was made. Mutation analysis revealed a variant in exon 8 of the PTEN gene. Direct sequencing revealed a germline heterozygous C.892–895InsA, which is predicted to result in a truncated PTEN protein. Cowden syndrome is an underdiagnosed, underrecognized, autosomal dominant, inherited syndrome. For the gastroenterologist, esophageal acanthosis and multiple hamartomatous polyps should suggest the diagnosis. Sensitive molecular diagnostic tests looking for mutations in the appropriate genes are clinically available. Together with genetic counseling, molecular diagnostic testing will allow more accurate risk assessment and surveillance for cancer for both the patient and family members.

Intestinal perforation : A common complication of scleroderma

The known intestinal complications of systemicsclerosis (SSc) stem mainly from motor disturbances.Autopsy findings were studied to identify anatomicabnormalities that may be associated with this disease. Descriptions of intestinal organs at autopsywere compared in 16 patients with SSc and 18 patientswith systemic lupus erythematosus (SLE), a relateddisease control. There was a high incidence ofperforation in SSc (7 of 16 patients) compared to SLE (1 of18 patients) (P < 0.05). In SSc, perforationsinvolved all parts of the bowel: transmural esophagealfibrosis (after heater probe cautery), dehiscence ofsuture line after gastric resection, perforatedduodenal ulcers (N = 2), terminal ileal ischemia, anddiverticulitis (N = 2). Two of the perforations in SScwere silent and were discovered at autopsy. The oneperforation in SLE was due to full-thickness necrosis fromvasculitis. This study suggests that the intestinalwalls of patients with SSc are inherently weak; thegastroenterologist should keep this in mind whenperforming invasive procedures.

A single nucleotide polymorphism of the cholecystokinin-B receptor predicts risk for pancreatic cancer

There currently are no tests available for early diagnosis or for the identification of patients at risk for development of pancreatic cancer. We report the discovery of single nucleotide polymorphism (SNP) in the cholecystokinin B receptor (CCKBR) gene predicts survival and risk of pancreatic cancer. Growth of human pancreatic cancer is stimulated by gastrin through the CCKBR and an alternatively spliced isoform of the CCKBR gene called CCKCR. One hundred and ten surgically resected benign and malignant pancreatic tissues as well as normal pancreas were prospectively evaluated for CCKBR genotype and protein expression. Analysis demonstrated the expression of the spliced isoform, CCKCR, was associated with a (SNP) (C > A) at position 32 of the intron 4 (IVS 4) of the CCKBR gene. Since the SNP is within an intron, it has not previously been identified in the GWAS studies. Only patients with the A/A or A/C genotypes, exhibited immunoreactivity to a selective CCKCR antibody. Survival among pancreatic cancer patients with the A-SNP was significantly shorter (p = 0.0001, hazard ratio = 3.63) compared with individuals with C/C genotype. Other variables such as surgical margins, lymph node status, histologic grade or adjuvant chemotherapy were not associated with survival. Furthermore, having one or two of the A-alleles was found to increase the risk of pancreatic adenocarcinoma by 174% (p = 0.0192) compared with the C/C wild type. Cancer cells transfected to overexpress the CCKCR demonstrated increased proliferation over controls. Genetic screening for this SNP may aid in early detection of pancreatic cancer in high risk subjects.

T-cell activation Rho GTPase–activating protein expression varies with inflammation location and severity in Crohn's disease

BACKGROUNDnThe T-cell activation Rho GTPase-activating protein (TAGAP) gene has a regulatory role in T cell activation. We have previously suggested a correlation between the TAGAP-associated single nucleotide polymorphism rs212388 and protection from anal sepsis in Crohns disease (CD) patients. The present study sought to evaluate TAGAPs expression in colonic tissue of CD patients with varying disease severity and location.nnnMATERIALS AND METHODSnFive transverse, 17 left, and five sigmoid colectomy specimens from 27 CD patients with varying disease severity (16 male, mean age at diagnosis 26.4xa0±xa02.2xa0y) were evaluated for TAGAP messenger RNA expression. Fisher exact, Mann-Whitney, and Welch two-sample t-tests were used for statistical evaluation. Immunohistochemistry confirmed results.nnnRESULTSnPatients with tissue demonstrating lower TAGAP messenger RNA expression (less than the overall mean) were younger at diagnosis (mean age 21.1xa0±xa06.3 versus 32.5xa0±xa013xa0y, Pxa0=xa00.009). Increased TAGAP expression was seen in moderate or severely diseased tissue versus tissue with no or mild disease (RQxa0=xa01.3xa0±xa00.34 versus 0.53xa0±xa00.09, Pxa0=xa00.050). This was the most dramatic in the sigmoid colon (Pxa0=xa00.041). TAGAP expression was increased in more distal tissue with a significant difference seen when comparing transverse versus sigmoid colon with moderate or severe disease (0.51xa0±xa00.14 versus 1.9xa0±xa00.37, Pxa0=xa00.049).nnnCONCLUSIONSnColonic expression of TAGAP in CD patients varied according to disease severity and location, being the most elevated in patients with severe disease in the sigmoid colon. Whether changes in TAGAP expression are a result of disease response or inherent to the disease pathophysiology itself remains to be determined. This gene warrants further investigation for its role in CD.

The revised Bethesda guidelines: extent of utilization in a university hospital medical center with a cancer genetics program

BackgroundIn 1996, the National Cancer Institute hosted an international workshop to develop criteria to identify patients with colorectal cancer who should be offered microsatellite instability (MSI) testing due to an increased risk for Hereditary Nonpolyposis Colorectal Cancer (HNPCC). These criteria were further modified in 2004 and became known as the revised Bethesda Guidelines. Our study aimed to retrospectively evaluate the percentage of patients diagnosed with HNPCC tumors in 2004 who met revised Bethesda criteria for MSI testing, who were referred for genetic counseling within our institution.MethodsAll HNPCC tumors diagnosed in 2004 were identified by accessing CoPath, an internal database. Both the Tumor Registry and patients electronic medical records were accessed to collect all relevant family history information. The list of patients who met at least one of the revised Bethesda criteria, who were candidates for MSI testing, was then cross-referenced with the database of patients referred for genetic counseling within our institution.ResultsA total of 380 HNPCC-associated tumors were diagnosed at our institution during 2004 of which 41 (10.7%) met at least one of the revised Bethesda criteria. Eight (19.5%) of these patients were referred for cancer genetic counseling of which 2 (25%) were seen by a genetics professional. Ultimately, only 4.9% of patients eligible for MSI testing in 2004 were seen for genetic counseling.ConclusionThis retrospective study identified a number of barriers, both internal and external, which hindered the identification of individuals with HNPCC, thus limiting the ability to appropriately manage these high risk families.

Giant fundic polyp complicating attenuated familial adenomatous polyposis.

This case details the development of a rapidly growing polypoid mass in the proximal stomach in a patient with known attenuated familial adenomatous polyposis. Surgical resection was required and histology showed hyperplasia with extensive areas of dysplastic adenomatous change. This case illustrates that patients with the attenuated form of familial adenomatous polyposis are at risk for multiple neoplasia distinct from those patients with the classic form of familial adenomatous polyposis.

Liver transplantation with a strongly positive crossmatch: Case study and literature review

A positive crossmatch has been associated with increased risk in liver transplantation. To study the clinical significance of preformed donor‐specific human leukocyte antigen antibodies (DSAs) in liver transplantation, we reviewed patients who underwent liver transplantation with a strongly positive flow cytometry crossmatch. DSAs were evaluated with a Luminex solid phase assay. The complement‐fixing ability of DSAs was tested with a complement component 1q (C1q) assay. Using an assay correlation between complement‐dependent cytotoxicity crossmatch, flow cytometry crossmatch, and DSA results, we reviewed the effects of DSAs on the outcomes of our patients as well as reported cases in the literature. Five of 69 liver recipients had a strongly positive crossmatch: 4 had a positive T cell crossmatch [median channel shift (MCS)u2009=u2009383.5u2009±u200938.9], and 5 had a positive B cell crossmatch (MCSu2009=u2009408.8u2009±u200952.3). The DSAs were class I only in 1 patient, class I and II in 3 patients, and class II only in 1 patient. Cholestasis, acute rejection, or both were observed in 3 of the 4 patients with a positive T cell crossmatch with an MCS approximately greater than 300. The C1q assay was positive for 3 patients. Two had either persistent cholestasis or early acute rejection. One patient who was treated with preemptive intravenous immunoglobulin had an unremarkable outcome despite a positive C1q result. One of the 2 patients with a negative C1q assay experienced persistent cholestasis and early and recurrent acute rejection; the other had an unremarkable outcome. None of the patients died or lost a graft within the first year of transplantation. Our study suggests that human leukocyte antigen antibody screening, flow cytometry crossmatch MCS levels, DSA mean fluorescent intensity levels, and C1q assays may be useful in assessing the risk of antibody‐mediated rejection and timely interventions in liver transplantation. Liver Transpl 19:1001–1010, 2013.