Nancy Ho

Temporal trends in the relative prevalence of dysphagia etiologies from 1999-2009

AIM To examine the relative prevalence and temporal variation of dysphagia etiologies in patients undergoing upper endoscopy (EGD) over the past decade. METHODS EGDs with the indication of dysphagia at an urban, university medical center in 1999, 2004 and 2009 were retrospectively identified from the electronic medical record. The entire patient chart, including EGD, pathology, manometry, radiographic and clinician reports, was reviewed for demographic and clinical data and to determine the etiology of dysphagia. The number of EGDs in which an esophageal biopsy was performed was also noted. Gastroesophageal reflux disease (GERD) as a cause of dysphagia independent of peptic stricture was defined by symptoms with erosive esophagitis or symptom response to proton pump inhibition (PPI). Cases of eosinophilic esophagitis (EoE) were defined by an appropriate clinical history and histological criteria of ≥ 15 eosinophils per high powered field. PPI-responsive esophageal eosinophilia was not routinely reported prior to 2008. Statistical analysis was performed using one-way analysis of variance to analyze for trends between 1999, 2004 and 2009 and a post-hoc Tukey analysis was performed following a significant main effect. RESULTS A total of 1371 cases (mean age 54 years, 43% male) met pre-specified inclusion criteria with 191, 504 and 675 cases in 1999, 2004 and 2009, respectively. Patients were older in 2004 compared to 2009 (mean ± SD, 54.0 ± 15.7 years vs 52.3 ± 16.8 years, P = 0.02) and there were more males in 1999 compared to 2004 (57.5% vs 40.8%, P = 0.005). Overall, GERD (27.6%) and EoE (7.7%) were the most common identifiable causes of dysphagia. An unspecified diagnosis accounted for 21% of overall cases. There were no significant differences in the relative prevalence of achalasia or other motility disorders, peptic stricture, Schatzkis ring, esophageal cancer or unspecified diagnoses over the 10-year time period. There was, however, a decrease in the relative prevalence of GERD (39.3% vs 24.1%, P < 0.001) and increases in the relative prevalence of EoE (1.6% vs 11.2%, P < 0.001) and oropharyngeal disorders (1.6% vs 4.2%, P = 0.02) from 1999 to 2009. Post-hoc analyses determined that the increase in relative prevalence of EoE was significant between 1999 and 2009 as well as 2004 and 2009 (5.4% vs 11.6%, P < 0.001), but not between 1999 and 2004 (1.6% P 5.4%, P = 0.21). On the other hand, the decrease in relative prevalence of GERD was significant between 1999 and 2009 and 1999 and 2004 (39.3% vs 27.7%, P = 0.006), but not between 2004 and 2009 (27.7% vs 24.1%, P = 0.36). There were also significantly more EGDs in which a biopsy was obtained in 1999 compared to 2009 (36.7% vs 68.7%, P < 0.001) as well as between 2004 and 2009 (37.5% vs 68.7%, P < 0.001). While total EGD volume did increase over the 10-year time period, the percentage of EGDs for the indication of dysphagia remained stable making increasing upper endoscopy an unlikely reason for the observed increased prevalence of EoE. CONCLUSION EoE has emerged as a dominant cause of dysphagia in adults. Whether this was due to a rise in disease incidence or increased recognition is unclear.

De-N-acetyl GM3 Promotes Melanoma Cell Migration and Invasion through Urokinase Plasminogen Activator Receptor Signaling–Dependent MMP-2 Activation

We have recently discovered that de-N-acetyl GM3 [NeuNH(2)LacCer, d-GM3], a derivative of ganglioside GM3, is specifically expressed in metastatic tumor cells and that its expression correlates with an enhanced metastatic phenotype. Although the classic N-acetylated form of GM3 (NeuAcLacCer, c-GM3) is found in both normal and tumor cells, metastatic tumor cells (but not other cells) predominantly express d-GM3 (82-95% of total GM3). d-GM3 expression is mainly found in metastatic melanomas, but not in benign nevi or the majority of primary melanomas. Using metastatic (d-GM3-positive) and poorly invasive (d-GM3-negative) human melanoma cell lines, we found that d-GM3 stimulates cell migration and invasion by increasing the expression and activation of urokinase-like plasminogen activator (uPA). Further studies showed that d-GM3 activates matrix metalloproteinase-2 (MMP-2), but not MMP-9, when uPA receptor signaling is activated. These results implicate d-GM3 as a specific marker for metastatic melanoma and a novel therapeutic target for neoplastic diseases.

Treatment With Anakinra, a Recombinant IL-1 Receptor Antagonist, Unlikely to Induce Lasting Remission in Patients With CGD Colitis

Treatment With Anakinra, a Recombinant IL-1 Receptor Antagonist, Unlikely to Induce Lasting Remission in Patients With CGD Colitis

Clostridium difficile diarrhea and fecal transplantation.

To the Editor:We thank Dr Martin for his thoughts1 regarding our letter. Indeed, we set out to highlight the safety, effectiveness, and favorable cost profile of fecal transplantation (FT) in the treatment of Clostridium difficile diarrhea. We are pleased that 50 years2 after it was first described,

Lacking the incentive to cure? Recurring clostridium difficile diarrhea and our reluctance to use fecal transplantation

To the Editor: Fecal transplantation (FT) is almost surely an efficacious therapy for recurrent and refractory Clostridium difficile (C.diff)-associated diarrhea, yet it remains underused in clinical practice. Our ongoing reluctance to embrace FT as an adjunctive therapy for a morbid condition, with few alternative treatments, represents the flipside to another problematic phenomenon in modern medicine: the hasty and widespread use of untested therapies. In recent years, a number of commentators have drawn attention toward the latter problem, and numerous mechanisms have been put forth to explain our collective failure to slow the spread of costly and unproven technology—including misguided enthusiasm generated by industry-sponsored studies, researcher conflicts of interest, and the pervasive belief among the lay public that newer means better. The case of FT serves as a contrasting example of our odd treatment of a medical practice—the case of an efficacious, though unprofitable therapy, which goes ignored. In this commentary, we will discuss FT alongside an emerging therapy for refractory C.diff diarrhea—monoclonal antibodies against the C. diff toxin. Antibody treatment has garnered much praise, whereas fundamental studies are flawed. In contrast, FT has a promising evidence base, yet continues to be ignored. The comparison of the 2 therapies is evidence that our dissemination of new practices is in need of rethinking. C. diff infection, diarrhea, and colitis are a spectrum of gastrointestinal disorders caused by the overgrowth of the bacteria C. diff, which can be difficult to eradicate. In the last decade, the incidence of C. diff-associated diarrhea has risen dramatically. Severe strains have emerged, with mortality rates as high as 7% in some isolates. Fluoroquinolone resistance and increased toxin production have been implicated as causal factors in the rise of such strains. Conventional therapy includes the use of oral vancomycin, oral or intravenous metronidazole. Cure rates remain far lower than desired, with 15% to 30% of patients having recurrent infection with cessation of therapy. As such, the need for adjunctive treatments has increased for the countless patients who experience life-threatening infection or recurrent antibiotic failure. FT involves the rectal infusion of donor feces, which alters the colonic biome, and may check the growth of the Clostridium species. Beginning in 1958, case reports have detailed the success of FT in the treatment of refractory C. diff infection. Since that time, over 150 patients with C. diff diarrhea treated with FT have been described in the literature, with an overall cure rate over 90%. Follow up ranged from a few weeks to a few years in this data set. Although none of the studies of FT have been randomized controlled trials, there is evidence to suggest that with a clear direction and overwhelming magnitude of treatment effect, observational studies rival randomized controlled trials results. Perhaps then, the failure to conduct proper randomized trials, given promising early results, is enough to constitute neglecting this therapeutic strategy. A 90% cure rate surpasses many other medical practices that are widely studied and performed. In contrast, consider the case of 2 neutralizing, fully human monoclonal antibodies targeted against the C. diff toxins A and B, which were described in a N Engl J Med study. The study showed that the administration of intravenous antibody therapy decreased the rate of recurrence of C. diff infection from 25 of 99 patients (25%) in the placebo group to 7 of 101 patients (7%) in the antibody group at 3 months follow-up. However, time to recovery from acute infection, severity of diarrhea, and length of hospitalization went unchanged. In addition, the rate of recurrence beyond 3 months was not reported. The editorial praised the study, and boasted about the possibilities of this novel therapeutic strategy. However, the fundamental flaw of the study was ignored. During data collection, the endpoint of the trial was altered. The initial endpoint was rate of resolution of diarrheal illness, which ultimately went unimproved. The altered endpoint was the rate of relapse after resolution. Such a change threatens the validity of the study’s conclusion, as it may represent post-hoc data analysis and multiple hypothesis testing. At the very least, the endpoint shift demonstrates the failure of antibody therapy to cure acute illness, whereas FT retains promise for this indication. The fact that monoclonal antibodies toward C. diff toxin are being developed suggests that novel therapies, even at tremendous cost, are potentially feasible for this clinical entity. The ongoing failure to explore FT highlights our fickle treatment of a cheap, but potentially effective practice. Part of our reluctance may be due to an increased risk of transmission of infectious disease with FT; however, with the use of screened donors, this risk is likely no greater than with other forms of transplantation, which are already widely in use. Some have cited a visceral repugnance to FT as another reason it is not widely used; however, it is unclear why FT should be more aesthetically objectionable than the disease itself, which can cause nearly incessant diarrhea. Ultimately, we conclude that FT has been ignored precisely because it is unprofitable. Such an observation, if true, is not only disappointing, but may necessitate other methods of health policy regulation besides comparative effectiveness and systems level reform. As we continue to study the practice of medicine, it is important to examine both the sources of enthusiasm for new technologies, and the barriers toward other promising, though technically simple cures. Our curious treatment of FT as adjunctive treatment for recurrent and refractory C. diff diarrhea highlights the continued need for a rational and systematic appraisal of medical therapy.

Publication Trends Among Internal Medicine Residents and Graduates

Internal medicine residency programs must teach research principles and residents must engage in scholarship, in accordance with current Accreditation Council for Graduate Medical Education (ACGME) program requirements, enacted in 1994. Inadequate demonstraion of this requirement is among the most frequent easons programs are cited by ACGME. Despite the strength, duration, and enforcement of this requirement, little is known regarding to what degree residents participate in research and whether the principles taught in residency continue through fellowship and beyond. One survey of 390 program directors found that 25% of residents at university programs completed case reports and that 10% published articles in peer-reviewed journals during residency. Another survey of residents, presenting scholarly work at a conference, found that 39 of 73 residents (53%) presented a clinical vignette and that 34 of 73 residents (47%) displayed a research abstract. An earlier survey of program directors estimated that 62% of their residents would complete an acceptable research project in 1 academic year. Each of these previous studies has limitations. All 3 are small cross-sectional surveys with variable response rates. Some required reporting of research endeavors y program directors, which may be inaccurate or

Submucosal Colonic Masses in a Patient With Familial Tumoral Calcinosis

A 26-year-old woman visited the clinic complaining of heartburn. On the basis of a tentative diagnosis of gastroesophageal reflux disease (GERD), the potassium-competitive acid blocker vonoprazan was prescribed, but it did not relieve the symptom. Upper endoscopy showed an anisakis larva at the lower end of the esophagus (a), and the parasite was endoscopically removed (b). After the endoscopic procedure, the heartburn immediately subsided. The esophagus is a rare insertion site of upper gastrointestinal anisakiasis, which is characterized by severe abdominal pain several hours after eating raw fish. Esophageal anisakiasis may have an unusual presentation that mimics GERD. (Informed consent was obtained from the patient to publish these images.)

Su1353 Longstanding Chronic Granulomatous Disease Colitis Does Not Increase the Risk of Colorectal Cancer

Introduction: Chronic granulomatous disease (CGD) is an immunodeficiency syndrome caused by a defective NADPH oxidase complex. Afflicted patients are unable to produce adequate reactive oxygen metabolites to neutralize microorganisms within macrophages. Approximately 50% of CGD patients develop gastrointestinal (GI) disease that shares features of both Crohns disease and ulcerative colitis. In patients with pediatric-onset ulcerative colitis, the cumulative risk for colorectal cancer (CRC) is 2% at 10 years (yrs) and 8% at 20 yrs. While the increased risk of CRC among patients with longstanding inflammatory bowel disease (IBD) is well established, the incidence of CRC among CGD patients with longstanding colitis has not been described. Methods: Patients with CGD colitis were identified from a database comprised of 279 CGD patients seen at the NIH from 1972 to 2011. To allow for adequate endoscopic, pathologic, and clinical follow-up, 78 patients with evidence of CGD colitis seen between 1990 and 2010 were identified, and patients with disease duration >10 yrs were used for formal analysis. The clinical and endoscopic reports over the 10 year follow-up period were reviewed, and the colonic biopsies were reexamined when available. Demographic information, duration of disease, endoscopic findings, and treatment and surgical history were extracted from the electronic medical records. The primary endpoint was the evidence of dysplasia or development of CRC. Results: Of the 78 patients, 20 had disease for >10 yrs. Notably, no colonic dysplasia or CRC were seen at the time of the biopsies in any of these patients. Of the 20 patients with disease > 10 yrs, 8 had biopsies available for formal reexamination. On reexamination, no patients were found to have colonic dysplasia or CRC. For all 20 patients, the average age at diagnosis was 10 years, with the median duration of disease of 16.7 yrs. Polyps were noted in 5 of 20 patients, 3 of which were inflammatory, 1 hyperplastic and 1 normal mucosa. No patients were diagnosed with colorectal cancer during follow-up. Conclusions: Despite long-standing inflammation, there was no dysplasia or CRC among 20 patients with CGD after a median of 16.7 years of follow up. In addition, no cases of colonic dysplasia or CRC were found in any patients with CGD colitis. The incidence of CRC among patients with CGD colitis appears to be lower than the incidence among patients with IBD. In fact, there are no reported cases of malignant polyps, dysplasia, or any gastrointestinal cancers in the short term or long term data. Although limited by a retrospective study design, these data suggest that the development of CRC in the setting of chronic inflammation may be influenced by NADPH activity, suggesting superoxide metabolism as a possible target to prevent oncogenesis.