Gangliocytic paraganglioma of duodenum metastatic to lymph nodes and liver and extending into the retropancreatic space.

Gangliocytic paraganglioma (GP) is a rare benign neuroendocrine tumour found most often in the duodenum. To our knowledge, only a dozen cases of possibly malignant duodenal GP with local lymph node metastasis and only one case with liver metastasis have previously been published. Herein, we report an unusual case of GP of the duodenum spreading to the retropancreatic space and metastatic to the liver and lymph nodes. Additionally, the present tumour secreted pancreatic polypeptide (PP) which was detected in the serum during the follow-up period. We suggest that serum PP could be a valuable marker in the diagnosis and follow-up of patients with GP.

Association of the status of interstitial cells of Cajal and electrogastrogram parameters, gastric emptying and symptoms in patients with gastroparesis.

Our goal was to investigate associations between the status of interstitial cells of Cajal (ICC) and electrogastrogram (EGG) parameters, gastric emptying and symptoms in a large cohort of patients with gastroparesis. Forty-one patients with refractory gastroparesis who were referred for gastric electrical stimulation (GES) underwent full thickness gastric (antrum) biopsy during the surgery to place the GES device. The biopsy samples were stained with c-kit and scored for the presence of ICC based on criteria obtained from 10 controls. All patients underwent EGG recordings, a 4-h standardized scintigraphic gastric emptying study and symptom assessment prior to the surgery. Based on antral biopsy, 15 patients (36%) had almost no ICC (ICC- group) and 26 patients had adequate cell numbers (ICC+ group). EGG recordings in the ICC- group displayed significantly less normal slow waves than in the ICC+ group both in the fasting and fed states. Tachygastria in the ICC- group was significantly more than in the ICC+ group both in the fasting (32 +/- 8%vs 11 +/- 2%) and fed states (27 +/- 9%vs 12 +/- 2%). There was no statistical difference in gastric emptying, symptom severity of gastroparesis, aetiology, age and gender between the two groups. Severely depleted ICC occurs in up to 36% of gastroparetic patients and significantly correlates with an abnormal EGG. Severely depleted ICC does not correlate with the severity of gastroparesis as assessed by gastric emptying or symptom status but did result in a poorer symptomatic response to GES. These data suggest that the EGG may have a role for predicting ICC status during clinical evaluation of gastroparetic patients.

Embryonic stem (ES) cells and embryonal carcinoma (EC) cells: opposite sides of the same coin.

Embryonal carcinoma (EC) cells are the stem cells of teratocarcinomas, and the malignant counterparts of embryonic stem (ES) cells derived from the inner cell mass of blastocyst-stage embryos, whether human or mouse. On prolonged culture in vitro, human ES cells acquire karyotypic changes that are also seen in human EC cells. They also 'adapt', proliferating faster and becoming easier to maintain with time in culture. Furthermore, when cells from such an 'adapted' culture were inoculated into a SCID (severe combined immunodeficient) mouse, we obtained a teratocarcinoma containing histologically recognizable stem cells, which grew out when the tumour was explanted into culture and exhibited properties of the starting ES cells. In these features, the 'adapted' ES cells resembled malignant EC cells. The results suggest that ES cells may develop in culture in ways that mimic changes occurring in EC cells during tumour progression.

From stem cells to germ cell tumors and back.

Germ cell tumors originate from ovarian, testicular and extragonadal germ cells. Tumor stem cells can retain most of the features of germ cells and form seminomas or dysgerminomas or, transform into developmentally pluripotent embryonic stem cells and give rise to teratomas or teratocarcinomas. Similar tumors can be experimentally produced in mice from early mouse embryos transplanted to extrauterine sites. The malignant stem cells of teratocarcinomas, called in analogy with their human counterparts embryonal carcinoma (EC), can be isolated and grown in culture and or propagated indefinitely by isotransplantation in syngeneic inbred mice. When injected into the blastocyst, i.e., the embryonic environment from which they have been originally isolated, EC cells lose their malignancy and become benign, participating in the normal development of the injected blastocyst. Injection of EC cells into blastocysts has been used to generate transgenic mice. Developmentally pluripotent non-neoplastic embryonic stem (ES) cells can be produced from mouse blastocysts cultured in vitro. These cells are developmentally similar to EC cells. In contrast to EC cells, ES cells injected into adult mice do not produce teratocarcinomas but only teratomas. Similar ES cells were produced from human blastocysts cultured in vitro. Human ES injected into nude mice produce teratomas composed of various somatic tissues. Human ES cells resemble mouse ES cells, but differ from human EC cells. Like their mouse equivalents, human ES cells could be used for generating experimental models of various diseases and, hopefully, for cell therapy in not so distant future.

Expression and immune recognition of SV40 Tag in transgenic mice that develop metastatic osteosarcomas.

Mature adult mice of the C57BL/6-TgN(Amy1TAg)501Knw transgenic mouse lineage, 501, containing a liver alpha-amylase promoted-SV40 Tag hybrid gene, routinely develop SV40 Tag-induced metastatic osteosarcomas. This form of alpha-amylase was known to be expressed in the liver, salivary glands, pancreas, and fat. Cells in the normal rib adjacent to the periosteum also express alpha-amylase suggesting that transgene expression is correctly targeted to generate osteosarcomas. 501 mice express SV40 Tag in the salivary glands but do not develop abnormalities in these organs by the time of their death from SV40-induced osteosarcomas. Mice of the C57BL/6 strain make a strong and effective anti-tumor immune response to SV40 Tag immunization. However, immunization of 501 mice with SV40 Tag early in life does not alter or prevent SV40 Tag-induced osteosarcomagenesis. 501 mice mount a significantly less effective cytotoxic T-lymphocyte response following SV40 Tag immunization while 501 osteosarcoma-derived cells are fully susceptible to SV40 Tag-specific T-cell lysis. This suggests that partial tolerance, not loss of antigen presentation by tumor cells, characterizes this mouse model of endogenous bone tumor development. To determine whether the immune recognition of endogenous SV40 Tag could influence tumorigenesis, the metastatic potential and time of death from tumor was investigated in CD4-null mutant 501 mice and beta-2 microglobulin-null mutant 501 mice. The size and number of metastases in these strains and longevity of these strains varied. We suggest that components of both the innate and adaptive immune response control tumor appearance and progression.

Characteristics of medical students completing an honors program in pathology.

The Honors Program in pathology at Jefferson Medical College provides a voluntary enrichment opportunity for students who have demonstrated a superior ability to cope with the pathology curriculum and who rank in the upper fifth of their class. This study was performed to determine whether honor students possess cognitive and psychosocial attributes that distinguish them from their classmates. Students from five academic years (entering classes 1991 to 1995) were divided into 3 groups: (1) those who completed the Honors Program (n = 85), (2) those in the top 20% of the class who were offered the option but chose not to participate in the Honors Program (n = 128), and (3) students who did not qualify for the program (n = 953). Comparisons between these three groups were made on the basis of selected measures of academic achievement retrieved from the Jefferson Longitudinal Study database and psychosocial data obtained from a questionnaire completed during the first-year orientation. Students who completed the Honors Program in pathology had scored higher on the physical science section of the Medical College Admission Test (MCAT) and had obtained higher first-year grade point averages than students in both of the other groups. Subsequently, they attained higher second-year grade point averages and scored higher on Step 1 and Step 2 of the United States Medical Licensing Examination (USMLE), compared with their peers in the other groups. There were no significant differences in psychosocial measures between honor students and the rest of the cohort (group 3). However, students in the top 20% of the class who declined the invitation to participate in the Honors Program (group 2) showed higher scores on the Taylor Manifest Anxiety Scale and the Eysenck Emotional Instability (Neuroticism) Scale than did their classmates. Despite these differences, students who completed the Honors Program (group 1) and eligible students who declined participation (group 2) selected similar pathways of postgraduate residency training: both groups preferred internal medicine to family practice, and both were more likely than the rest of the cohort to begin residency training at a top-ranked academic/research medical center. Voluntary participation in an Honors Program is a self-selection system that identifies students who are most likely to succeed academically at the highest levels. Residency selection committees may wish to pay dose attention to student involvement in similar programs, because this information may provide insights into student personality and general aptitude.

Computer-based teaching of pathology at the Zagreb University School of Medicine.

AIM: To review the experience gained in transferring USA computer-based teaching system of medical school pathology to Croatia. METHODS: Computer-based teaching program of pathology developed at the University of Kansas School of Medicine, Kansas City, Kansas, USA, was transferred to the University of Zagreb School of Medicine, Zagreb, Croatia. The experimental group of 49 students was enrolled into this computer-based program. Their performance was compared with that of 195 classmates enrolled in the standard course. Objective (performance on the examinations) and subjective data (students' interviews and written evaluations of the course) were analyzed. RESULTS: The computer program was operational 5 months from the inception of the transfer. It was well received by the students, even though many initially complained that it required more effort and a continuous commitment. The major problems concerned scheduling, reflecting various requirements i mposed on students by other departments teaching in parallel with the Pathology course. Objective data gathered so far indicate that the students enrolled in the computer-based program took the first midterm examination at a significantly higher rate than the rest of the class (p<0.001), and passed the examination with significantly better grades (p<0.001). CONCLUSION: Computer-based teaching programs can be readily transferred to other countries. Full implementation of the program, however, may require significant changes in the existing curriculum in the medical school to which such a program has been transferred or considerable modifications in the program adopted for transfer. It appears that the students enrolled in the computer-based program perform better than students in the standard pathology course.

Mesotheliomas of tunica vaginalis testis of Fischer 344 (F344) rats treated with acrylamide: a light and electron microscopy study.

The incidence of spontaneous mesotheliomas of the tunica vaginalis testis, documented to be 1.3% in Fischer 344 rats can be increased by long term exposure to acrylamide. The light microscopic and electron microscopic features of tumors developing spontaneously in control animals were compared with those that developed in acrylamide treated animals to determine whether the tumors in the experimental group have any distinctive characteristics. The experimental group comprised three subgroups, i.e. animals exposed to acrylamide in three doses 0.1, 0.5 or 2.0 mg/kg/day over a period of 104 weeks. A total of 35 tumors were examined--7 in control group, 9 in low-dose group, 8 in mid-dose group and 11 in the high-dose group. Most tumors measured less than 1 cm in diameter in aggregate and approximately one-third of all tumors were of microscopic size, less than 5 mm in diameter. All tumors were classified as epithelial mesotheliomas. Three distinct microscopic patterns were recognized (papillary, tubular or solid). All tumors had papillary features, and focally showed some tubular or solid components. No ultrastructural differences were found between tumors of the four groups of animals. It was concluded that the tumors that developed in the tunica vaginalis testis of acrylamide treated animals do not differ morphologically from those that developed spontaneously in control animals. Cellular uniformity, small size of lesions and the absence of perotoneal seeding and metastasis suggests that the mesotheliomas of tunica vaginalis testis of Fischer 344 rats in this study were benign and equivalent to human benign mesothelioma of tunica vaginalis testis or adenomatoid tumors.

Differential expression of the zinc finger gene TCF17 in testicular tumors.

TCF17, the human homologue of the rat zinc finger gene Kid1, is highly expressed in neurons derived from the retinoic acid-treated human embryonal carcinoma (EC) cell line, NTERA-2. This differentiation-related up-regulation of TCF17 prompted us to investigate its expression during human spermatogenesis and in human testicular germ cell tumors considered to be precursors of EC. Expression of TCF17 increases as spermatogonia differentiate into spermatocytes, indicating that this gene is developmentally regulated during spermatogenesis. TCF17 mRNA levels are high in carcinoma in situ and in seminoma, a tumor derived from carcinoma in situ but still of low-grade malignancy. However, TCF17 expression is decreased in highly malignant EC. The differential regulation of TCF17 during neoplastic germ cell differentiation may be of predictive value in germ cell tumor diagnosis.

The 4th Copenhagen Workshop on Carcinoma in situ and Cancer of the Testis: concluding remarks.

The 4th Copenhagen Workshop "Carcinoma in situ Germ Cell and Testicular Cancer: Molecular and Endocrine Aspects" was held in Copenhagen, Denmark, May 18-21, 1997. This paper discusses the major themes that emerged during the workshop and summarises the most important contributions.

Relationship of students' perceptions of faculty to scholastic achievement: are popular instructors better educators?

Student evaluation of the faculty is a standard practice in most medical schools. Implied in these evaluations is the motion that popular instructors (ie, those considered outstanding by the students) are better educators, whose teaching translates into higher scores for their students on examinations. We tested this hypothesis by comparing students' evaluations of the faculty with levels of academic achievement in a second-year pathology course. Objective measures of academic achievement included scores on final comprehensive examinations, final course grade, and performance on the United States Medical Licensing Examination (USMLE). During the 4 years studied (1990 to 1995), students belonging to groups with the highest ratings for their instruction performed no better than those with the poorest ratings. There was no correlation between students' perceptions of quality in teaching and their academic achievement. Our results indicate that students' evaluations of the faculty are subjective and do not correlate with objective results used in the assessment of student knowledge. Popular instructors are not necessarily better educators.

The virtues of extended matching and uncued tests as alternatives to multiple choice questions.

The objectives of this study were to compare the reliability and validity of written test formats that are widely used in medical education (multiple choice, uncued, extended matching, and true/false) and evaluate the effects of uncued examinations on long-term retention of medical knowledge. Uncued tests were introduced into a traditional course in general and systemic pathology (six interim tests). In the following year, students were given eight tests written in the four formats, each being used twice. The academic achievement of students in these 2 years was compared with that of students in 2 previous years, in which multiple choice tests were used. Measures of academic achievement included performance on a final comprehensive examination and the United States Medical Licensing Examination (USMLE). Student performance on uncued tests was consistent over time (i.e., there was no learning curve). Mean scores ranged from 77% to 84%, and coefficient alpha reliability estimates on 100-item tests were excellent (0.79 to 0.90). Extended matching tests were also reliable, with a mean coefficient alpha of 0.90. There was no significant relationship between test format and student performance on subsequent comprehensive examinations. Our results indicate that extended matching and uncued tests have considerable advantages over multiple choice and true/false examinations. They are more reliable, better able to discriminate the well-prepared from the marginal student, and well suited for tested core knowledge. Contrary to our expectation, extended matching questions with 20 choices presented to the student were as statistically reliable and valid as uncued queries with several hundred choices.

Comparative analysis of cell surface antigens expressed by cell lines derived from human germ cell tumours.

The pattern of cell surface antigen expression of a set of cell lines derived from human germ cell tumours and corresponding to various cell phenotypes found within these tumours was studied using immunofluorescence. Twenty-two different antibodies were used. Many of these antibodies have been noted to recognise epitopes that are either preferentially expressed by embryonal carcinoma (EC) cells, or by more differentiated cell types. Using scatter plots and rank correlations, 6 groups of antibodies were distinguished with respect to their staining patterns on the cell lines tested. Several antibodies showed a specific staining pattern in relation to the differentiation state of the cells. Two groups of antibodies included those recognising high m.w. glycoproteins (antibodies TRA-1-60, TRA-1-81, GCTM2, 3-177, K4 and K21) and the ganglioseries glycolipid antigens SSEA-3 and -4 (antibodies MC631 and MC813-70). These antibodies mostly stained EC cells but not other cell types, confirming previously published data. However, one of these groups, comprising antibodies K4 and MC631, was more exclusively associated with the EC cell phenotype than was the other group. Antibodies recognising the liver isozyme of alkaline phosphatase (TRA-2-49 and TRA-2-54) also reacted strongly with most EC cell lines, although they reacted significantly with a number of other cell lines as well, whereas antibodies to the placental isozyme tended to react only weakly with EC cells. The antibodies recognising the ganglioseries glycolipids GD2 and GD3 (VIN2PB22 and VINIS56) preferentially stained cells with neuroectodermal characteristics. Other antibodies showed a heterogeneous staining pattern for the cell lines with different phenotypes. The data obtained from the cell lines were, in general, similar to data obtained from immunohistochemical studies on tissue sections of primary germ cell tumours of the adult testis, including carcinoma in situ.

Expression of gamma-glutamyl transpeptidase in midgestation mouse yolk sac and mouse visceral yolk sac carcinoma cells.

gamma-Glutamyl transpeptidase (gamma GT) is a crucial enzyme for the metabolism of xenobiotics and endogenous mediators of biological functions (leukotrienes, prostaglandins, and hepoxillins). Yet little is known about its potential role during development. It is a single copy gene expressed from at least seven promoters. Using histochemistry and immunohistochemistry we demonstrate that gamma GT first appears in the midgestational yolk sacs of mouse embryos. Established cell lines with phenotypic features of yolk sac endoderm (JC-44) or embryonic stem cells were also assayed for the expression of gamma GT. Significant levels were detected in JC-44 cells and higher levels were found in JC-44-derived embryoid bodies. Because this cell line appears to be a good in vitro counterpart of yolk sac differentiation, we characterized the gamma GT mRNA types expressed in JC-44 cells. By ribonuclease protection analysis, gamma GT RNA types IV and VI represent about 80% of the total gamma GT RNA in JC-44 embryoid bodies. Reverse transcription-mediated polymerase chain reaction detected low amounts of gamma GT RNA types I, III, and V. Expression of gamma GT in yolk sac follows a pattern seen in many tissues in which one or two gamma GT RNA types dominate the expression profile; however, the reason for this tissue specificity is unknown.

Testing of medical students with open-ended, uncued questions.

A written examination based on material covered in the first year of medical school (anatomy, physiology, biochemistry, and neuroscience) was administered to medical students immediately before they began the pathology course to assess their knowledge of the basic science content that is important for the study of pathology. In alternate years the questions were presented in the standard multiple choice question (MCQ) format or in an open-ended, uncued question (Un-Q) format. The students' mean scores obtained by these two testing methods were comparable. The discrimination indices, which measure the ability of the test questions to distinguish between students of varying ability, were comparable. The Kuder-Richardson Formula 20 (KR-20), an estimate of the precision of the test given, was 0.53 for MCQ and 0.63 for Un-Q. We conclude that the Un-Q format is an acceptable alternative to the MCQ format and it has several advantages over MCQ. Because the answer sheets for Un-Q tests can be scanned optically and graded by computers, we recommend them as an alternative to MCQ tests.