Mark B. Pochapin

Treatment of Complicated Sarcoidosis with Infliximab Anti–Tumor Necrosis Factor-α Therapy

Sarcoidosis is a systemic inflammatory disorder characterized by noncaseating granulomatous infiltration of any organ. The inflammatory process may be accelerated by the release of tumor necrosis factor- (TNF-) from resident macrophages, resulting in further recruitment of inflammatory cells (1, 2). When necessary, treatment normally includes corticosteroids, which act in part by suppressing TNF- synthesis (3). The effectiveness of thalidomide and pentoxifylline in some cases may similarly reflect inhibitory properties of these agents on the TNF- pathway (4). Infliximab is a chimeric monoclonal humanmurine antibody against human TNF-. It is currently approved for use only in patients with rheumatoid arthritis or Crohn disease. We describe an unusual case of sarcoidosis, manifested by severe protein-losing enteropathy and proximal myopathy, in which the patient responded dramatically to infliximab therapy. Treatment, however, was complicated by the development of hypercoagulability associated with anticardiolipin antibodies. Case Report A 72-year-old woman presented with severe diarrhea and proximal muscle weakness. In 1975, the patient had undergone jejunoileal bypass surgery for treatment of obesity. She subsequently developed bypass-associated wrist arthritis that necessitated antibiotic and indomethacin therapy. Since her last synovitis flare, which occurred in the mid-1980s, indomethacin therapy was continued intermittently for osteoarthritis. The patient was in good health until June 1999, when she developed abdominal discomfort and loose stools. Results on endoscopy and colonoscopy were unrevealing. She subsequently developed persistent, frequent, watery brown diarrhea; protein-losing enteropathy; hypoalbuminemia; facial swelling; and pedal edema. Stool 1-antitrypsin levels were markedly elevated. Serum antigliadin IgA titers were increased slightly. However, small-bowel biopsy samples revealed normal mucosa and were inconsistent with celiac sprue, bacterial overgrowth, Whipple disease, or any other specific diagnosis. Gluten-free and lactose-free diets and empiric courses of antibiotic therapy to treat possible bacterial overgrowth were unhelpful. By December 1999, the serum albumin level was 23 g/L (Figure; day 0). The patient also reported having proximal muscle weakness, with increasing difficulty combing her hair and rising from a chair. Physical and laboratory findings at this time are outlined in the Table. Figure. Changes in serum albumin level. Table. Physical and Laboratory Findings in Patient at the Time of Sarcoidosis Diagnosis Results on computed tomography of the chest revealed pulmonary nodules suspicious for granulomas and axillary, precarinal, and pretracheal lymphadenopathy; however, no mesenteric lymphadenopathy was seen on computed tomography of the abdomen. Mammography showed calcification of a left axillary lymph node. Perfusion abnormalities on ultrasonography in the right triceps and right vastus medialis muscles were consistent with an inflammatory myopathy; generalized atrophy was seen. Tissue samples from axillary lymph-node and bone-marrow biopsies demonstrated noncaseating granulomas that were highly suggestive for sarcoidosis. No evidence of malignancy was seen. Stains and cultures for acid-fast bacilli and fungi were negative. Biopsy samples of the right quadriceps revealed type 2 fiber atrophy but no inflammatory or granulomatous infiltration. Intravenous methylprednisolone, 1.0 g/d for 3 days, followed by oral methylprednisolone, 0.8 mg/kg of body weight per day, initially improved muscle strength and enzyme abnormalities. Intravenous administration of high-dose methylprednisolone was repeated 4 and 8 weeks later, but myopathic symptoms became refractory to treatment. Moreover, her enteropathy was unresponsive, and the serum albumin level decreased to 18 g/L (Figure). Anasarca and peripheral weeping ensued. We began subcutaneous administration of methotrexate, 10 mg/wk. To treat possible bacterial overgrowth, we empirically added ciprofloxin, 250 mg twice daily, and metronidazole, 500 mg twice daily. Four weeks later, the patient developed acute anuric renal failure. Use of all medications except methylprednisolone was discontinued, and hemodialysis was initiated. Renal biopsy findings were consistent with acute tubular necrosis (possibly resulting from continued indomethacin use) and showed no evidence of inflammation, granulomas, or amyloid. The patient was bed bound and continued to have unremitting diarrhea. At month 9 of the current illness, infliximab (Remicade, Centocor, Malvern, Pennsylvania), 5 mg/kg of ideal body weight, was administered intravenously. Within 2 days, the patient was able to leave her bed and rise from a chair independently. Within 1 week, she began having formed stool and was ambulating unassisted. Infliximab was administered again at 2 weeks. Within 1 month, the patient returned to work and lived independently. Her diarrhea resolved completely. The highest serum albumin level reached was 36 g/L (Figure), and her edema subsequently improved dramatically. According to computed tomography, the pulmonary nodules and intrathoracic lymphadenopathy completely resolved. Serum angiotensin-converting enzyme levels returned to normal (530 nkat/L). Several days after receiving a third dose of infliximab at 6 weeks, the patient developed venous thrombosis at a hemodialysis catheter site and multiple necrotizing skin ulcerations on her legs. Skin biopsy samples revealed extensive thrombosis of small arteries without evidence of vasculitis. Antinuclear and antidouble-stranded DNA antibodies remained undetectable, but very high titers of anticardiolipin IgM antibodies (100 U [normally <9 U]) and slightly elevated titers of anticardiolipin IgG antibodies (17 U [normally <14 U]) were found. Levels of protein C, protein S, and antithrombin III were normal. Infliximab therapy was discontinued. Soft bowel movements returned, and serum albumin level returned to 23 g/L. However, before diarrhea recurred, oral thalidomide therapy, 100 mg/d, was initiated. Stool consistency normalized, and serum albumin level increased to 30 g/L. Discussion Infliximab was an attractive therapeutic option in our patient for several reasons. First, increasing evidence has demonstrated that TNF- is central in the pathogenesis of sarcoidosis. Second, use of a parenteral medication was desirable because it would ensure bioavailability in the context of malabsorption. Third, many steroid-sparing medications, in particular methotrexate, presented unacceptable risks in a patient with renal failure. Finally, the effectiveness of infliximab for Crohn disease, another granulomatous disorder, provided an important precedent. Although noncaseating granulomas remain the hallmark of sarcoidosis, their mere presence does not indicate clinically significant disease. Sarcoidosis is often diagnosed incidentally, and granulomas may occur in various tissues without clinical manifestations. The events leading from quiescent to active disease are not fully known, but TNF- may help promote disease activity. Spontaneous release of TNF- by alveolar macrophages is greater in patients with active disease than in patients with inactive or corticosteroid-treated disease (1, 3). Moreover, in quiescent sarcoidosis, high levels of TNF- released from alveolar macrophages may positively predict disease progression (2). Reports of sarcoidosis with protein-losing enteropathy have been sparse (5, 6), while the incidence of proximal myopathy is approximately 0.25% (7). Notably, no granulomas were found in small-bowel or muscle biopsy samples in our patient. One possible explanation is sampling error. Alternatively, overt granulomatous infiltration of these tissues may not be required for the observed clinical manifestations. Previous reports of protein-losing enteropathy in sarcoidosis have similarly failed to demonstrate granulomas in intestinal mucosa (5, 6). In particular, our patients clinical profile closely resembles that of a patient described by Lindgren and colleagues (6): Both had normal small-bowel histologic findings, no mucosal or mesenteric granulomatous infiltration, and enteropathy that was refractory to corticosteroids while other disease manifestations responded. It is possible that because intestinal permeability is increased in active sarcoidosis (8), plasma proteins may leak abnormally into the intestinal lumen in susceptible patients (6). Protein-losing enteropathy has also been reported after jejunoileal bypass surgery, but blunted villi and lymphocytic and plasma cell infiltration of the lamina propria are characteristic in these cases (9). In the largest review of sarcoidosis with proximal myopathy, 16% of muscle biopsy samples revealed no granulomas (10); this percentage is similar to the percentage20%of negative biopsy findings in patients who have sarcoidosis without weakness (7). Therefore, overt granulomatous infiltration of muscle is neither necessary nor sufficient for myopathic symptoms to occur. Our patients rapid response to antiTNF- therapy indicates involvement of either TNF- or processes closely downstream. Indeed, TNF-, acting synergistically with interferon-, is directly toxic to myocytes in vitro (11). Because circulating monocytes express interferon- in active sarcoidosis (12), similar effects may occur in vivo. Accordingly, the absence of granulomas in bowel and muscle indicates that the putative enteropathic and myopathic effects of TNF- may not be specific to sarcoidosis. Thus, antiTNF- therapy may also be useful in treating enteropathy or myopathy in other inflammatory illnesses. Our patients medical history included a jejunoileal bypass procedure and associated inflammatory arthritis. We speculate that the bypass provided a rich pool of microbial antigens that fueled pathogenic immunologic pathways and fomented autoimmune and inflammatory diatheses. In jejunoileal bypass-as

Endoscopic Ultrasound-Guided Fine-Needle Aspiration Cytology Diagnosis of Solid-Pseudopapillary Tumor of the Pancreas A Rare Neoplasm of Elusive Origin but Characteristic Cytomorphologic Features

Clinical histories, endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) material, and immunohistochemical stains performed on cell block samples of 6 solid-pseudopapillary tumors of the pancreas (SPTPs) were reviewed in the cases of 5 females (13-58 years) and 1 man (57 years); all had abdominal pain. Preliminary cytologic diagnoses at endoscopy included 1 SPTP 2 low-grade neoplasms, and 3 pancreatic endocrine tumors. Variable numbers of branching fragments with central capillaries and myxoid stroma were seen in the smears of 5 of 6 cases but were more apparent in the cell block material of all cases. The cells had bland nuclear features and rare grooves. Extensive necrosis was noted in 1 case and rare mitotic figures in 1. SPTPs showed strong cellular immunoreactivity for vimentin and focal weak keratin reactivity. Neuron-specific enolase, alpha1-antitrypsin, and alpha1-antichymotrypsin stains performed in 2 cases were strongly positive. Subsequent surgical resection confirmed all diagnoses. EUS-guided FNA diagnosis of SPTP is accurate. The characteristic branching papillae with myxoid stroma are best seen in cell block slides. Clinical setting, cytomorphologic features, and immunostains of the cell block help distinguish SPTP from pancreatic endocrine tumors, acinar cell carcinoma, and papillary mucinous carcinoma.

Increasing Incidence of Rectal Cancer in Patients Aged Younger Than 40 Years An Analysis of the Surveillance, Epidemiology, and End Results Database

The incidence of rectal cancer in the United States in young patients is considered to be low. Underestimating this incidence may result in a failure to diagnose younger patients with rectal cancer in a timely manner.

Comparison of Linear Array Endoscopic Ultrasound and Helical Computed Tomography for the Staging of Periampullary Malignancies

Background: The purpose of this study was to compare linear array endoscopic ultrasound (EUS) and helical computed tomography (CT) scan in the preoperative local staging evaluation of patients with periampullary tumors.Methods: Patients evaluated with EUS and CT for suspected periampullary malignancies from 1996 to 2000 were analyzed. Surgical/pathology staging results were the reference standard.Results: Forty-eight patients (28 men and 20 women; mean age, 62 ± 4.9 years; range, 18–90 years) were identified. Malignancy was histologically confirmed in 44 patients. Parameters evaluated included tumor size, lymph node metastases, and major vascular invasion. EUS was significantly more sensitive (100%), specific (75%), and accurate (98%) than helical CT (68%, 50%, and 67%, respectively) for evaluation of the periampullary mass (P < .05). In addition, EUS detected regional lymph node metastases in more patients than helical CT. Sensitivity, specificity, and accuracy of EUS were 61%, 100%, and 84%, in comparison to 33%, 92%, and 68%, respectively, with CT. Major vascular involvement was noted in 9 of 44 patients. EUS correctly identified vascular involvement in 100% compared with 45% with CT (P < .05).Conclusions: Linear array EUS was consistently superior to helical CT in the preoperative local staging of periampullary malignancies.

How Drugs are Developed and Approved by the FDA: Current Process and Future Directions

OBJECTIVES:This article provides an overview of FDAs regulatory processes for drug development and approval, and the estimated costs associated with the development of a drug, and also examines the issues and challenges facing the FDA in the near future.METHODS:A literature search was performed using MEDLINE to summarize the current FDA drug approval processes and future directions. MEDLINE was further utilized to search for all cost analysis studies performed to evaluate the pharmaceutical industry R&D productivity and drug development cost estimates.RESULTS:While the drug approval process remains at high risk and spans over multiple years, the FDA drug review and approval process has improved, with the median approval time for new molecular drugs been reduced from 19 months to 10 months. The overall cost to development of a drug remains quite high and has been estimated to range from

Commercial molecular panels are of limited utility in the classification of pancreatic cystic lesions.

868M to

The American College of Gastroenterology and the 80% by 2018 Colorectal Cancer Initiative: A Multifaceted Approach to Maximize Screening Rates

1,241M USD. Several new laws have been enacted, including the FDA Safety and Innovation Act (FDASIA) of 2013, which is designed to improve the drug approval process and enhance access to new medicines.CONCLUSIONS:The FDAs improved processes for drug approval and post-market surveillance have achieved the goal of providing patients with timely access to effective drugs while minimizing the risk of drug-related harm. The FDA drug approval process is not without controversy, as a number of well-known gastroenterology drugs have been withdrawn from the US market over the past few years. With the approval of the new FDASIA law, the FDA will continue to improve their processes and, working together with the ACG through the FDA-Related Matters Committee, continue to develop safe and effective drugs for our patients.

The use of a low fat diet in the treatment of acute pancreatitis

The PathfinderTG biomarker panel is useful in the evaluation of pancreatic cysts that have clinical features suspicious for malignancy, but its utility in classifying fine-needle aspiration biopsies from small pancreatic cystic lesions is yet to be proven. We used morphology to classify 20 pancreatic cyst cytology aspirates, all of which met radiographic criteria for close observation. Cases were cytologically classified as consistent with pseudocyst, serous cystadenoma, or mucinous neoplasm with low-grade, intermediate-grade, or high-grade dysplasia and analyzed for carcinoembryonic antigen. Redpath Integrated Pathology Inc. rendered diagnoses of nonmucinous (reactive/indolent or serous) or mucinous (low-risk or at risk) cyst on the basis of results of the PathfinderTG panel (KRAS mutations, DNA content, and loss of heterozygosity at microsatellites linked to tumor suppressor genes). Cytologic and commercial laboratory diagnoses were concordant in only 7 (35%) cases. Seven cysts classified as mucinous with low-grade dysplasia by cytology were interpreted as nonmucinous on the basis of the PathfinderTG panel, 2 of which were resected mucinous cysts. Two pancreatitis-related pseudocysts were misdiagnosed as low-risk mucinous cysts; 1 mucinous cyst with low-grade dysplasia was considered at risk for neoplastic progression using the PathfinderTG panel. Only 1 cyst misclassified as pseudocyst by cytology, but low-risk mucinous cyst by molecular analysis, proved to be a mucinous cystic neoplasm with low-grade dysplasia after surgical resection. We conclude that the PathfinderTG panel may aid the classification of pancreatic lesions, but is often inaccurate and should not replace cytologic evaluation of these lesions.

4507 Endoscopic ultrasound accurately stages and directs the surgical management of rectal carcinoma.

The American College of Gastroenterology and the 80% by 2018 Colorectal Cancer Initiative: A Multifaceted Approach to Maximize Screening Rates

2017 Emily Couric Memorial Lecture: Colorectal Cancer: Polyps, Prevention, and Progress

Purpose: A low fat diet hypothetically stimulates less pancreatic lipase secretion than a diet with a higher fat content, yet very little data exists on whether the use of a low fat diet during the oral refeeding of patients with acute pancreatitis improves recovery from the disease.