Current and experimental antibody-based therapeutics: insights, breakthroughs, setbacks and future directions.

The premise of targeted therapy was born from an intimate understanding of the unique biological pathways and endpoints which are implicated in the development of different disease states and conditions. In addition, the identification of the most appropriate drugs to use for targeted drug therapy has aided in growing interest of the pharmaceutical industry to allocate more resources to monoclonal antibody (mAb) therapeutics. This being the case, it is important to understand antibody based therapeutics, some of the currently Food and Drug Administration (FDA)-approved mAbs in different disease states, as well as the future direction of mAb therapies. In this article, we will provide a critical overview, and discuss a selection of antibody based therapeutics, including their bioengineered structural and functional elements. Furthermore, a segment of the currently FDA-approved mAb antibody therapies, those in research, or in investigation for disease states and conditions ranging from autoimmune disease, inflammatory response, immunosuppression, cancer, including antibody-drug conjugates, immunotherapy, and exciting prospects for antiplatelet and antithrombotic monoclonal antibody therapeutics will be reviewed. Finally, we will discuss our predictions and aspirations for the future directions of mAb-based therapeutic interventions.

Expert second-opinion pathology review of lymphoma in the era of the World Health Organization classification.

BACKGROUND: The World Health Organization (WHO) classification of hematologic malignancies, published in 2000, was designed to improve diagnostic accuracy by incorporating the latest in scientific understanding. The impact of the WHO classification on the frequency of diagnostic discrepancy in lymphoma is unknown. METHODS: We reviewed all second-opinion pathology of lymphoma at our National Cancer Institute-designated Comprehensive Cancer Center (NCI-CCC) from January to June 2001 and from January to June 2006. Discrepancies between submitted and second-opinion diagnoses were scored based upon an a priori grading schema. RESULTS: Major diagnostic revision was rendered in 65 of 365 cases (17.8%) in 2001 and 58 of 354 (16.4%) in 2006 (P=NS). Including cases reviewed and revised beforehand at another NCI-CCC, rates of major diagnostic revision were 21.4% and 18.6%, respectively (P=NS). Discrepancy rates varied by diagnosis, from Hodgkin lymphoma (10%) to Burkitt's lymphoma (75%). No association was seen for age, gender, race/ethnicity, biopsy type, or nature of referring center. CONCLUSIONS: Clinically meaningful diagnostic revision occurs frequently with expert pathology review for a diagnosis of lymphoma. Despite the WHO classification, rates of diagnostic revision at our institution in 2001 and 2006 did not differ significantly. Given the potential harm from misdiagnosis, expert hematopathology review should be considered the standard of care.

A Case of Cervical Disc Herniation with Paresthesia in Both Arms and Tic Mimicking Motions / 대한소아신경학회지

Intervertebral disc herniation is rare in children and is reportedly related with disc calcification and traumatic injury. We report an 8 years old girl, who complained of tingling sensation in both arms and intentional tic like neck stretching for about 1 month. She had got unnoticed whiplash Injury 2 weeks before symptoms. She also had been taking lessons for taekwondo for one and half year. Physical examination was unremarkable. Her symptoms got aggravated over the next 4 weeks. Plain vertebral x-ray showed no abnormalities, but cervical spinal MRI revealed disc central herniations at C 5-6 and C 6-7 levels. We concluded that her paresthesia and tic like motion were related with cervical disc herniation from hyperflexion neck injury.

CD20-negative large-cell lymphoma with plasmablastic features: a clinically heterogenous spectrum in both HIV-positive and -negative patients.

BACKGROUND: Plasmablastic lymphoma (PBL) has been described as a rapidly progressive and almost invariably fatal CD20- VS38c+ diffuse large-cell lymphoma with plasmablastic features, almost exclusively involving the jaw and oral mucosa in HIV-positive patients. METHODS: From 2001 to 2003 we evaluated 12 men with PBL, and report the pathology, clinical findings, treatment and outcome. Six of 12 were HIV-positive while among the others, one was post-renal transplant, one had ulcerative colitis and four had no known immunodeficiency. RESULTS: Tumor growth pattern, in general, showed cohesiveness and a starry-sky pattern; the morphology varied from typical plasmablastic to centroblastic cells. Partial immunophenotypes were (+/total): CD138, 11 of 12 (91.7%); MIB1 10 of 11 (4+, range 75-95%); p63/VS38c, nine of 10 (90%); EBV, eight of 11 (73%); LCA(CD45), two of 12 (16.7%); HHV8/LANA, zero of 10; ALK, zero of seven; and CD20, zero of 12. Three had stage IE and nine stage IV disease. Nine of 12 had an intermediate/high International Prognostic Index or high-risk disease. Computed tomography and positron emission tomography scan in four of 12 revealed extensive bone metastases. Eight of 12 are alive after treatment, with a median follow-up of 11+ months (range 1-24). Of the HIV-positive patients, five of six are alive with a median follow-up of 17 months. CONCLUSIONS: It appears that PBL are heterogenous in terms of clinical presentation and morphology. The outcome presented here is superior to that originally reported.

Frequency and costs of echo endoscope repairs: results of a survey of endosonographers.

BACKGROUND AND STUDY AIMS: The need for repair of endoscopic ultrasound (EUS) equipment appears to be frequent and expensive. To better quantify the costs associated with echo endoscope failure, a survey of endosonographers was carried out. METHODS: A survey questionnaire concerning echo endoscope damage and repair and consequences of echo endoscope downtime over a 12-month period was sent to members of the American Society of Gastrointestinal Endoscopy who had cited an interest in EUS. RESULTS: Responses were received from 56 of 138 institutions where EUS was carried out (41 %). A median of 325 EUS procedures had been carried out in the past year and a median of two endosonographers were employed who used an average of three echo endoscopes. Two-thirds of institutions trained fellows. A total of 225 repairs were reported for leaks (47 %), mechanical failures (33 %), images or optics difficulties (26 %), or other problems (1 %). Mechanical radial-scanning echo endoscopes tended to break, on average, after 68 procedures, while curved linear-array echo endoscopes failed after an average of 107 procedures. Echo endoscope failures led to rescheduling of procedures at three-quarters of institutions. Institutions paid an average of $ 10 534 over 12 months for echo endoscope repairs. The average repair cost per procedure was $ 41. There was an inverse relationship between quantity of procedures and the per-procedure repair rate ( P < 0.05). CONCLUSIONS: Direct and indirect costs of echo endoscope repairs are significant. Instrument failures are multifactorial; however instrument complexity, instrument age, and institutional inexperience may contribute to repair costs.

Cost-effectiveness of screening for hepatocellular carcinoma in patients with cirrhosis due to chronic hepatitis C.

BACKGROUND: Screening for hepatocellular carcinoma in cirrhotic patients using abdominal ultrasonography and alpha-foetoprotein levels is widely practiced. AIM: To evaluate its cost-effectiveness using a Markov decision model. METHODS: Several screening strategies with abdominal ultrasonography or computerized tomography and serum alpha-foetoprotein at 6-12-month intervals in 40-year-old patients with chronic hepatitis C and compensated cirrhosis were simulated from a societal perspective, resulting in discounted costs per quality-adjusted life-year saved. Extensive sensitivity analysis was performed. RESULTS: For the least efficacious strategy, annual alpha-foetoprotein/ultrasonography, the incremental cost-effectiveness ratio (vs. no screening) was $23 043/quality-adjusted life-year. Biannual alpha-foetoprotein/annual ultrasonography, the most commonly used strategy in the United States, was more efficacious, with a cost-effectiveness ratio of $33 083/quality-adjusted life-year vs. annual alpha-foetoprotein/ultrasonography. The most efficacious strategy, biannual alpha-foetoprotein/ultrasonography, resulted in a cost-effectiveness ratio of $73 789/quality-adjusted life-year vs. biannual alpha-foetoprotein/annual ultrasonography. Biannual alpha-foetoprotein/annual computerized tomography screening resulted in a cost-effectiveness ratio of $51 750/quality-adjusted life-year vs. biannual alpha-foetoprotein/annual ultrasonography screening. CONCLUSIONS: Screening for hepatocellular carcinoma is as cost-effective as other accepted screening protocols. Of the strategies evaluated, biannual alpha-foetoprotein/annual ultrasonography gives the most quality-adjusted life-year gain while still maintaining a cost-effectiveness ratio <$50 000/quality-adjusted life-year. Biannual alpha-foetoprotein/annual computerized tomography screening may be cost-effective.

Immunoproliferative small intestinal disease: prolonged 30-year course without development of lymphoma.

Immunoproliferative small intestinal disease (IPSID) is mostly found in young adults of low socioeconomic class in developing countries. This condition is characterized by a dense lymphoplasmacytic infiltrate beneath the epithelium in the duodenal and proximal jejunal mucosa and in the mesenteric lymph nodes. In two thirds of cases, the involved lymphocytes elaborate an anomalous alpha-heavy chain protein. The etiology of this disease is unclear, although various parasitic, genetic, and toxic mechanisms have been proposed. Half of all IPSID patients will be found at diagnosis to have a concurrent intestinal B-cell lymphoma, and most of the remaining patients develop frank lymphoma within a few years. Although most reports of IPSID are from developing nations or indigent immigrant populations within Western countries, four cases of an IPSID-like condition have been documented in white women. Furthermore, although many IPSID patients progress to high grade indeterminate-type lymphoma within a few years of initial presentation, there have been occasional reports of long term survival without lymphomatous conversion. Here, we present an atypical case of IPSID--a California native who, though of Mexican heritage, had resided in the United States his entire life and did not belong to an indigent population. This patient had biopsy-proven IPSID that progressed over 30 yr but never exhibited lymphomatous conversion despite end stage intestinal stasis and recurrent obstruction, culminating in death. Our case calls into question some current assumptions about the prelymphomatous nature of this disease.

Fine-needle aspiration of epithelioid sarcoma: cytology findings in nine cases.

BACKGROUND: Epithelioid sarcoma is a rare tumor with characteristic morphologic and immunohistochemical features. It can be confused histologically and cytologically with a variety of benign and malignant lesions, including a granulomatous process, synovial sarcoma, melanoma, squamous cell carcinoma, and adenocarcinoma. The objective of this study was to define the cytologic features of this rare tumor. METHODS: The cytologic features of nine histologically confirmed epithelioid sarcomas were analyzed. The criteria evaluated included cell size and shape, cell borders, cluster organization, cytoplasmic characteristics, nuclear and nucleolar features, and background characteristics. RESULTS: In most cases, single, dispersed cells represented the predominant pattern, with only a few small clusters present. The cells were mostly round with interspersed spindle cells and mild to moderate pleomorphism. The nuclei were large and eccentrically located, with a plasmacytoid appearance. A pale zone in the perinuclear area was evident in three of nine cases. Well-defined cell borders with intercellular spaces between malignant cells were observed in eight cases. In three cases, a granuloma-like structure was identified. In two cases, the cells were mostly spindle and showed greater cellular pleomorphism. CONCLUSION: Epithelioid sarcoma is an uncommon tumor with a wide range of differential diagnoses, especially in cytology specimens. Awareness of its existence and knowledge of its cytologic features are important for a correct diagnosis.

Ascitic fluid carcinoembryonic antigen and alkaline phosphatase levels for the differentiation of primary from secondary bacterial peritonitis with intestinal perforation.

BACKGROUND/AIMS: In cirrhotic patients, spontaneous bacterial peritonitis (SBP) may be difficult to distinguish from secondary peritonitis with occult intestinal perforation; Runyon's criteria (based on ascitic fluid glucose, protein and lactate dehydrogenase levels) are sensitive but not specific. Ascitic fluid carcinoembryonic antigen (CEA) and alkaline phosphatase (AP) are potential markers for secondary peritonitis. METHODS: Ascitic fluid CEA and AP levels were prospectively compared among three subject groups--cirrhotic patients with sterile ascites, cirrhotic patients with SBP, and patients (cirrhotic and non-cirrhotic) with perforation-related secondary peritonitis. RESULTS: The secondary peritonitis group (n = 38 including 11 cirrhotic patients) had significantly higher mean CEA and AP levels than the SBP (n = 34) and sterile ascites patients (n = 63). Of secondary peritonitis patients, 92% fulfilled predetermined criteria (either CEA >5 ng/ml or AP >240 units/l) versus only 12% of SBP patients; sensitivity was 92% and specificity 88% for differentiating secondary peritonitis from SBP. Runyon's criteria had a sensitivity of 97% and specificity of 56%. Stratification of secondary peritonitis patients by the presence or absence of cirrhosis did not alter our results. CONCLUSIONS: Ascitic fluid CEA or AP elevations appear to be sensitive and specific markers for perforation-related secondary peritonitis in cirrhotic as well as non-cirrhotic patients.

High incidence of positive peritoneal cytology in low-risk endometrial cancer treated by laparoscopically assisted vaginal hysterectomy.

OBJECTIVE: Laparoscopically assisted vaginal hysterectomy (LAVH) has evolved into an alternative form of surgical management in the treatment of low-risk endometrial cancer. The purpose of this study was to determine whether low-risk endometrial cancer patients are subject to a higher incidence of positive peritoneal cytology when treated with LAVH compared to total abdominal hysterectomy (TAH). METHODS: We retrospectively reviewed the medical records of patients with low-risk endometrial cancer (grade 1--2 endometrioid type with no evidence of extrauterine spread or grade 3 with <50% myometrial invasion (MI), no cervical or adnexal involvement, and negative lymph nodes when sampled) treated at Memorial Sloan-Kettering Cancer Center from January 1993 to September 1999. We compared 131 patients treated with LAVH to 246 controls who underwent TAH. The two groups were compared for known prognostic factors including grade, MI, vascular space involvement, and lower uterine segment extension. RESULTS: The mean age of patients who underwent LAVH (61 years) was similar to that of the controls (62 years). Fourteen (10.3%) of the patients treated with LAVH had positive peritoneal cytology compared to only 7 (2.8%) of the control population. Factors including FIGO grade, myometrial invasion, and preoperative hysteroscopy did not influence the final results. When stratifying for these factors, the odds ratios of having positive peritoneal washings in those patients treated by LAVH were 5.2, 5.2, and 3.7, respectively. CONCLUSION: Treatment of low-risk endometrial cancer by LAVH is associated with a significantly higher incidence of positive peritoneal cytology. This may be due to the retrograde dissemination of cancer cells into the peritoneal cavity during uterine manipulation. The clinical significance of these findings is yet to be determined.

Risk of endometrial carcinoma associated with BRCA mutation.

OBJECTIVE: Inherited mutations in the BRCA1 or BRCA2 genes are associated with a greatly increased lifetime risk of breast and ovarian cancers and a modestly increased risk of several other cancer types. Several case reports of endometrial carcinoma in women with a BRCA mutation have led to speculation regarding the effect of these genes on the risk of endometrial cancer. The purpose of this study was to test the hypothesis that germline mutation of a BRCA gene is associated with an increased risk of endometrial carcinoma. METHODS: A retrospective cohort of 199 consecutive Ashkenazi Jewish patients with endometrial carcinoma was identified from a 12-year period at this institution. All were genotyped for the three BRCA founder mutations (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2) that exist in this population, and the case frequency was compared to the known population frequency of these mutations. Additionally, endometrial carcinomas occurring in patients with BRCA mutations were assessed for somatic loss of the wild-type BRCA allele. RESULTS: Germline BRCA mutations were identified in 3 (1 in BRCA1 and two in BRCA2) of 199 (1.5%) patients, compared to a frequency of 2.0% in this population generally. A relative risk of endometrial carcinoma associated with BRCA mutation, as estimated by the odds ratio, was calculated as 0.75 (95% CI = 0.24--2.34; P = 0.6). Loss of the wild-type BRCA allele was observed in two of three tumors associated with a BRCA mutation. CONCLUSIONS: For individuals with a germline BRCA mutation, the lifetime risk of endometrial carcinoma is not increased.

Current treatment strategies for chronic hepatitis B and C.

For chronic hepatitis B, treatment with a 4-month course of interferon alfa-2b can achieve hepatitis B e antigen seroconversion, normalization of aminotransferase levels, reduced hepatic inflammation, and possibly reduced progression to cirrhosis and improvement in survival in 20%-30% of patients. Similar results can be achieved with a 12-month course of lamivudine, with response rates increasing to 40%-65% after 3 years of therapy. Interferon can also be used in early cirrhotic patients, and lamivudine can be used in advanced cirrhotics and immunosuppressed patients. Combination interferon and lamivudine therapy does not confer additional benefits. For chronic hepatitis C, the combination of interferon alfa-2b and ribavirin is the treatment of choice, offering superior sustained response rates (40%) compared with interferon alone (15%). Therapy should be administered for 12 months to patients with genotype 1 virus but for only 6 months to patients with genotypes 2 and 3. Patients experiencing relapse after 6 months of interferon monotherapy can be re-treated with interferon and ribavirin or high-dose interferon, with 45%-56% sustained response rates. However, relatively few patients who are prior nonresponders to interferon monotherapy will have sustained response to further interferon-based treatments, including combination therapy with ribavirin. Successful therapy not only leads to the eradication of viral RNA but also may delay progression to cirrhosis and hepatocellular carcinoma. Interferon combined with polyethylene glycol (PEG), shows promise as an improved formulation of interferon with yet higher sustained response rates.

Upright versus supine reflux in gastroesophageal reflux disease.

BACKGROUND: Postural measures are early recommendations in the management of heartburn, and are aimed at preventing acid reflux through an incompetent lower esophageal sphincter (LES). However, LES incompetence is found in only a minority of patients, and transient LES relaxations, primarily in the upright position, are currently recognized as the main pathophysiological abnormality in gastroesophageal reflux disease (GERD). We investigated the importance of supine acid reflux in patients with GERD. METHODS: Upon review of their clinical, manometric, pH monitoring and endoscopic characteristics, 85 patients with reflux symptoms were classified into three groups: Group A (n=22), consisting of symptomatic patients without esophagitis or pathological reflux; group B (n=38), symptomatic patients with reflux but no endoscopic esophagitis; and group C (n=25), symptomatic patients with both ulcerative or complicated esophagitis and pathological reflux. RESULTS: All groups were similar in age distribution. Groups B and C had a higher prevalence of hiatal hernia and reflux symptoms. Manometry revealed similar LES pressures in groups A and B, but lower LES pressure in group C (P < 0.005). In groups A and B, supine reflux, in terms of percentage of time with pH < 4, was less pronounced than upright reflux (P < 0.0001). In contrast, group C supine reflux was as pronounced as the upright reflux. CONCLUSIONS: The majority of patients reflux in the upright position. Only patients with complicated esophagitis have significant bipositional acid reflux. These findings suggest that unless the patient has severe reflux disease, postural measures may not be indicated.

Dietary habits and right-sided colonic diverticulosis.

PURPOSE: In Asian populations, there is a high prevalence of right-sided colonic diverticulosis, the cause of which is uncertain. It is suspected that dietary habits may interact with a congenital predilection to cause this condition. To evaluate the relationship between long-term dietary habits and the prevalence of right-sided diverticulosis in the general population, we performed a retrospective case-control study. METHODS: We reviewed the records of 3,105 screening colonoscopies performed on healthy, asymptomatic adults. All cases of right-sided diverticulosis were selected, and a similar number of gender-matched and age-matched controls with negative colonoscopies were randomly sampled from the same cohort. All case and control subjects were interviewed by a single-blinded nurse to establish their dietary habits during the past decade, in addition to other demographic characteristics. Based on consumption frequency, they were assigned to one of three diet classes for each of three food categories of interest: meat, vegetable, and fruit products. Staple foods such as rice were not included. Odds ratios were then calculated using multivariate conditional logistic regression and tests for trend were performed. RESULTS: A total of 86 cases of right-sided diverticulosis were included, whereas 106 controls were randomly selected. There was a marked association between meat consumption frequency and right-sided diverticulosis, with a trend P value of <0.01 and an odds ratio of 24.81 between the most and least frequent consumers of meat products. CONCLUSIONS: The prevalence of right-sided diverticulosis is strongly positively associated with past meat consumption frequency. There is no association with vegetable or fruit consumption frequency, laxative use, supplemental fiber intake, smoking, or family history.

Inflammatory fibroid polyp of the duodenum.

Duodenal inflammatory fibroid polyps (IFP) are extemely rare lesions indistinguishable from submucosal tumors by endoscopic inspection alone. Like gastric inflammatory fibroid polyps, they can be managed by endoscopic polypectomy or mucosectomy. However, preoperative diagnosis of this benign lesion is difficult. Here we present a case of duodenal IFP causing gastrointestinal bleeding that was evaluated by endoscopic ultrasound before surgical removal. On endosonography, the duodenal IFP appeared as a coarsely heterogeneous isoechoic and hypoechoic mass circumscribed by a distinct margin and arising from the third layer of the duodenal wall. The endosonographic appearance of this lesion was in marked contrast to that previously reported for gastric IFPs, which have tended to appear as hypoechoic homogeneous lesions with indistinct margins. Endosonographic evaluation of suspected IFPs before endoscopic or surgical treatment is useful. However, the endosonographic appearances of duodenal and gastric IFPs may be significantly different, possibly because of differences in the makeup of the duodenal and gastric walls.

Bacterial peritonitis after elective endoscopic variceal ligation: a prospective study.

OBJECTIVE: Endoscopic variceal ligation is becoming the therapy of choice for esophageal varices, replacing endoscopic variceal sclerotherapy. The latter is associated with a 5-53% incidence of port-procedural bacteremia and a 0.5-3% incidence of peritonitis, whereas the former carries a 3-6% risk of bacteremia. However, the incidence of peritonitis after variceal ligation has not been well studied. This prospective study is designed to investigate the risk of developing bacteremia and bacterial peritonitis after elective endoscopic variceal ligation. METHODS: Sixty-seven patients with esophageal varices and ascites secondary to liver cirrhosis underwent elective endoscopic variceal ligation. Before the procedure, ascitic fluid was drawn under ultrasound guidance and sent for cell counts, Gram stain, and cultures. Two to 4 days afterward, a repeat ascitic fluid sample was sent for the same studies whether or not the patient had symptoms or signs suggestive of infection. Blood cultures were drawn both immediately before and after the endoscopic ligation procedure. RESULTS: Of 67 subjects, 11 developed asymptomatic bacteremia with Gram-positive commensals. However, none of them progressed to peritonitis. Two patients who did not have bacteremia developed mild febrile peritonitis with Escherichia coli and were successfully treated with oral antibiotics. No other infectious complications were noted. CONCLUSIONS: There is a significant risk of asymptomatic bacteremia and bacterial peritonitis after elective variceal ligation. The peritonitis does not seem to be related to the bacteremia, as patients who had bacteremia did not develop peritonitis and vice versa. In addition, the involved organisms were quite different. Unlike the bacteremia, postligation peritonitis may be a consequence of severe liver cirrhosis rather than the procedure itself. The clinical significance of postligation bacteremia is doubtful. With regard to peritonitis, in our opinion the use of prophylactic antibiotics should be reserved for patients with Child's C class cirrhosis, a recent history of variceal bleeding, a past history of bacterial peritonitis, or a comorbid immunosuppressive condition.

Subcutaneous sparganosis--a case report and a review of human sparganosis in Taiwan.

Human sparganosis is a rare parasitic disease infected by plerocercoid larva (sparganum) of Spirometra species. It was usually diagnosed accidentally and has long been underestimated. In this report, we describe a 53-year-old woman presenting as an enlarging subcutaneous nodule in the right thigh for 3 months, which was excised in the belief that it was a lipoma. Characteristic sparganum accompanied by granulomatous inflammation, eosinophilic infiltrate and sinus tract in the subcutaneous tissue were discovered under microscopic examination of the excised tissue. Contaminated drinking water was presumed to be the infectious source. Complete excision is a curative treatment. We also review previously documented 19 human sparganosis in Taiwan to provide the clinical context for this report.