Cytogenetic analysis of pancreatic carcinomas: intratumor heterogeneity and nonrandom pattern of chromosome aberrations

Twenty-nine nonendocrine pancreatic carcinomas (20 primary tumors and nine metastases) were studied by chromosome banding after short-term culture. Acquired clonal aberrations were found in 25 tumors and a detailed analysis of these revealed extensive cytogenetic intratumor heterogeneity. Apart from six carcinomas with one clone only, 19 tumors displayed from two to 58 clones, bringing the total number of clones to 230. Karyotypically related clones, signifying evolutionary variation, were found in 16 tumors, whereas unrelated clones were present in nine, the latter finding probably reflecting a distinct pathogenetic mechanism. The cytogenetic profile of pancreatic carcinoma was characterized by multiple numerical and structural changes. In total, more than 500 abnormal chromosomes, including rings, markers, homogeneously stained regions, and double minutes, altogether displaying 608 breakpoints, were detected. This complexity and heterogeneity notwithstanding, a nonrandom karyotypic pattern can be discerned in pancreatic cancer. Chromosomes 1, 3, 6, 7, 8, 11, 12, 17, and 19 and bands 1q12, 1q21, 3q11, 6p21, 6q21, 7q11, 7q22, 7q32, 11q13, 13cen, 14cen, 17q11, 17q21, and 19q13 were most frequently involved in structural rearrangements. A total of 19 recurrent unbalanced structural changes were identified, 11 of which were not reported previously: del(1)(q11), del(3)(p11), i(3)(q10), del(4)(q25), del(11)(p13), dup(11)(q13q23), i(12)(p10), der(13;15)(q10;q10), del(18)(q12), del(18)(q21), and i(19)(q10). The main karyotypic imbalances were entire-copy losses of chromosomes 18, Y, and 21, gains of chromosomes 7, 2, and 20, partial or whole-arm losses of 1p, 3p, 6q, 8p, 9p, 15q, 17p, 18q, 19p, and 20p, and partial or whole-arm gains of 1q, 3q, 5p, 6p, 7q, 8q, 11q, 12p, 17q, 19q, and 20q. In general, the karyotypic pattern of pancreatic carcinoma fits the multistep carcinogenesis concept. The observed cytogenetic heterogeneity appears to reflect a multitude of interchangeable but oncogenetically equivalent events, and the nonrandomness of the chromosomal alterations underscores the preferential pathways involved in tumor initiation and progression.     

In vivo correlation of Doppler waveform analysis with arterial input impedance parameters

Previous studies have confirmed that Doppler waveform analysis (DWA) offers a valid reflection of changes in peripheral vascular resistance. However, the ability of the pulsatility index (PI), a parameter of DWA, to reflect the dynamic components of the circulation, as assessed by arterial input parameters, remains uncertain. In addition, the state of the central circulation is considered an important factor influencing the accuracy of this technique. This study evaluated the ability of the aortic PI to reflect alterations of input impedance in a chronically instrumented lamb model that was subjected to pharmacologic alteration of the circulation. Pressure, volumetric flow and continuous-wave Doppler frequency shift measurements were recorded from the infrarenal abdominal aorta. The parameters of input impedance, peripheral vascular resistance (Zpr), characteristic impedance (Zo) and reflection coefficient (Rc), were determined and then correlated with changes in the aortic PI. Initially, perturbations of the circulatory state were created with a vasodilator, hydralazine (HY) and a vasoconstrictor, phenylephrine (PE). During a second set of experiments, the effect of the reflex heart rate (HR) responses on the PI was evaluated. This was accomplished by inhibiting reflex HR responses to these vasoactive agents with either trimethophan (TM) or atropine methyl bromide (AMB). In response to HY and HY with TM, significant decreases in the PI and impedance parameters occurred. Administration of PE and PE with AMB resulted in significant increases in PI and each of the impedance parameters. HY and PE induced changes in PI correlated significantly with changes in volumetric flow (r = 0.82, 0.80; p < 0.001), mean arterial blood pressure (r = 0.64, 0.70; p < 0.001) and Zpr (r = 0.77, 0.80; p < 0.001), but not with Zo (r = 0.34, 0.36) and Rc (r = 0.26, 0.31). However, when reflex HR responses were inhibited during the administration of the vasoactive agents, HY with TM and PE with AMB, induced changes in PI correlated significantly with Zo (r = 0.93, 0.89; p < 0.001) and Rc (r = 0.84, 0.83; p < 0.001), and the correlation with mean arterial pressure (r = 0.78, 0.87; p < 0.05) and Zpr (r = 0.92, 0.91; p < 0.05) was significantly greater. These findings indicate that the PI accurately assesses pharmacologically induced changes in the downstream arterial input impedance. The accuracy of this assessment is enhanced further when central circulatory factors such as changes in HR are considered.     

Cardiac angiomyolipoma: radiologic and pathologic correlation

Primary tumors of the heart are rare. We report a case of large cardiac angiomyolipoma (hamartoma) that presented as a fat-containing tumor mass on imaging studies, diagnosed radiographically as teratoma. The patient was admitted through the emergency room at Tainan Municipal Hospital because of severe dyspnea. A chest radiograph revealed marked widening of the mediastinum. Echocardiography and computed tomographic scanning of the thorax showed a mass of mixed density with calcification. A teratoma with intrapericardial invasion was suspected. Sternotomy disclosed a large intrapericardial lobulated mass (34 x 30 x 12 cm, 3,150 g) arising from the right atrium, with severe adhesion to the origin of the inferior vena cava. Histopathologic examination demonstrated an angiomyolipoma of the heart. To our knowledge, this is the largest cardiac angiomyolipoma reported. We report this case to emphasize that a differential diagnosis of angiomyolipoma must be included in a patient with a fat-containing cardiac tumor.     

Significant correlation of telomerase activity in lung adenocarcinomas with cell differentiation and chromosome aberration

OBJECTIVE: To assess the long-term safety of adjunctive corticosteroids in the treatment of Pneumocystis carinii pneumonia (PCP). DESIGN: Analysis of data from a large prospective observational database. SETTING: HIV clinic at a large urban teaching hospital. PATIENTS: One hundred seventy-four patients who developed PCP after being enrolled in the database. RESULTS: Fifty-three patients (30%) received adjunctive corticosteroids and 121 (70%) did not. Survival did not differ between groups after adjusting for CD4 count (relative risk for adjunctive corticosteroids = 0.74, p = 0.13). There were no differences in the incidence of cytomegalovirus disease (adjunctive corticosteroids: 18.5 cases per 100 person-years vs no adjunctive corticosteroids: 15.7, p = 0.22), Mycobacterium avium complex (23.4 vs 27.0, p = 0.73), cryptococcal meningitis (1.8 vs 4.1, p = 0.58), toxoplasmosis (3.6 vs 11.0, p = 0.28), Kaposi's sarcoma (1.8 vs 2.2, p = 0.92), herpes simplex (27.1 vs 42.7, p = 0.66), herpes zoster (3.8 vs 6.9, p = 0.71), oropharyngeal candidiasis (18.9 vs 10.9, p = 0.09), or non-Hodgkin's lymphoma (3.5 vs 4.2, p = 0.92). Esophageal candidiasis was more common among adjunctive corticosteroid recipients (45.1 vs 26.6, p = 0.01). Results were similar for time to development of opportunistic conditions. CONCLUSIONS: Adjunctive corticosteroids do not increase mortality or the risk of most common HIV-associated complications.     

Fryns syndrome: prenatal diagnosis and pathologic correlation

From 1988 to 1995, 96 patients (161 feet) underwent a modified Mitchell distal metatarsal osteotomy performed for mild-to-moderate hallux valgus. On AP x-rays of the standing foot, the average intermetatarsal angle was corrected from 15 degrees to 9 degrees, and the first metatarsophalangeal angles were corrected from an average of 41 degrees to 15 degrees. Criteria for evaluation of clinical results included relief of pain, appearance of foot, and shoe wear. After an average follow-up of 38 months, the overall satisfaction rate was 92.5%. Complications included 13 pin tract infections, two delayed unions, and two correction losses. The most common late sequela was transfer metatarsalgia of the lesser toes, which occurred in 20 feet (12.4%), leading to some dissatisfaction. The Mitchell osteotomy can be used on cases with less than 20 degrees of intermetatarsal angle, offering a stable construct with easy postoperative care.     

Metaplastic carcinoma of the breast: mammographic appearance with pathologic correlation

OBJECTIVE: The objective of this study was to describe the mammographic appearance with pathologic correlation of metaplastic carcinoma of the breast. CONCLUSION: Metaplastic carcinomas of the breast are masses with mammographic characteristics of low suspicion because of their histologic appearance. Metaplastic carcinoma should be included in the differential assessment of predominately circumscribed, noncalcified masses revealed on mammography. One salient feature that may distinguish metaplastic carcinomas is the occurrence of a circumscribed portion with a spiculated portion, which is seen in carcinomas that have a significant mixture of metaplastic and invasive carcinoma growth patterns.     

Fibromyxoma of the retropharyngeal space: MR appearance with pathologic correlation

A 19-year-old woman reported difficulties in swallowing and breathing. A submucosal mass, shown by MR imaging in the retropharyngeal space, was the cause of her symptoms. Histologically, the mass proved to be a fibromyxoma. The oval well-delineated lesion appeared hypointense relative to muscle and strongly enhanced after injection of contrast material on T1-weighted images; on T2-weighted images, it appeared hyperintense, and was seen to contain fibrous septa, which were hypointense on all sequences. This case delineates the characteristic MR features of a fibrous component within a rare benign tumor of the retropharyngeal space.     

Cytogenetic profile of lymphoma of follicle mantle lineage: correlation with clinicobiologic features

Conventional chromosome analysis (CCA) and interphase fluorescence in situ hybridization (FISH) was performed in 42 patients with mantle-cell lymphoma (MCL), with BCL1 rearrangement. The t(11;14)(q13;q32) or 11q abnormalities were detected by CCA in 34 cases, 20 of which had additional aberrations. A normal karyotype was observed in 8 cases. Probes detecting the chromosome aberrations that were observed in at least 3 cases by CCA, ie, +12, 13q14 deletion, and 17p deletion, were used for interphase FISH analysis. FISH detected total or partial +12, 13q14 deletion and 17p- in 28.5%, 52.4%, and 26% of the cases, respectively. The presence of these anomalies was not a function of karyotype complexity. Based on the results of CCA/FISH, three groups of increasing karyotype complexity were recognized: group 1, including 11 patients without detectable aberrations in addition to BCL1 rearrangement; group 2, including 14 patients with 1 to 2 additional anomalies; and group 3, including 17 patients with three or more additional anomalies. Clinical parameters associated with shorter survival were male sex (P =.006) and primary lymph-node involvement compared with primary bone marrow involvement (P =.015). Trisomy 12 was the only single cytogenetic parameter predictive of a poor prognosis (P =.006) and the best prognostic indicator was the derived measure of karyotype complexity (P <.0001), which maintained statistical significance in multivariate analysis (P<.0001). We arrived at the following conclusions: 13q14 deletion occurs at a high incidence in MCL; 17p deletion and total/partial +12 are relatively frequent events in MCL, the latter aberration being associated with a shorter survival; and the degree of karyotype complexity has a strong impact on prognosis in this neoplasia.     

Numerical aberration of chromosome 17 is correlated with multiple primary cancer in colorectal carcinoma

In order to test the hypothesis that attention deficit hyperactivity disorder (ADHD) is related to deficits in somatosensory processing, 49 ADHD male children and 49 matched controls were tested on a wide range of tactile tasks, and somatosensory evoked potentials (SEP) were also recorded. In addition, parents' and teachers' ratings on the children's typical responses to tactile stimuli were obtained. The results show that the ADHD children were less skilled on suprathreshold, but not on threshold tasks than were the controls. Further, a larger percentage of ADHD children were 'tactile defensive'. Finally, the ADHD children showed larger-than-normal amplitudes of late, but not early components of the SEP. These data suggest that some aspects of somatosensory processing by ADHD children are deficient.     

Cavernous hemangioma of the liver: pathologic correlation with dynamic CT findings

Malignant mixed mesodermal tumors (MMMT) are the most malignant neoplasms known to occur in the uterus. The most important prognostic factors are the extent of tumor at diagnosis, depth of myometrial invasion, and, as regarded by some authors, the sarcomatous component. We report on a retrospective analysis in 83 patients with MMMT. By univariate analysis survival was dependent on stage, depth of myometrial invasion, kind of therapy, age at menopause, and parity. However, the sarcomatous component did not significantly influence survival. Using the multivariate Cox regression analysis stage and parity or depth of myometrial invasion and parity were found to independently predict prognosis. Despite an interval of more than 20 years from the last childbirth to tumor appearance a beneficial influence of parity on the prognosis of MMMT was identified. This is unique in oncology. Especially patients with more than three children formed a subgroup of long-term survivors. It is interesting to note that parity was found by means of a Cox regression analysis to be statistically independent, and no correlation with other classical prognostic factors was detected.     

Thrombosis of the deep cerebral veins: CT and MRI findings with pathologic correlation

Deep cerebral vein thrombosis can present with acute, severe neurological symptoms and may be rapidly fatal as in the 20-year-old woman reported here. Although MRI is superior for establishing the diagnosis, CT is usually the first examination performed in the clinical setting. It is therefore important to recognise certain indicators such as extensive bithalamic low density. These and certain other less specific signs are correlated with the MRI and autopsy findings.     

Early advanced hepatocellular carcinoma: evaluation of CT and MR appearance with pathologic correlation

PURPOSE: To determine the computed tomographic (CT) and magnetic resonance (MR) imaging appearances of early advanced hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Twenty-seven surgically resected cases of early advanced HCC were studied with CT, CT during arterial portography, CT arteriography, and MR imaging. RESULTS: The sensitivity of standard CT (unenhanced, early, and late CT combined) for the detection of early advanced HCC was 81%, while that of standard MR imaging (T1- and T2-weighted MR imaging combined) was 83%. A nodule-in-nodule appearance was identified in approximately one-third to one-half of cases. Signal behavior of early and advanced components of early advanced HCC followed the expected behaviors of isolated early HCC and isolated advanced HCC, respectively. Tumor size was accurately estimated with standard CT and standard MR imaging. CONCLUSION: More research must be performed to ascertain whether any relationship exists between the different types of HCC and the clinical outcome.     

Autoradiographic analysis of [14C]deoxy-D-glucose in thyroid cancer xenografts: a comparative study with pathologic correlation

Plants have evolved the ability to regulate flowering in response to environmental signals such as temperature and photoperiod. The physiology and genetics of floral induction have been studied extensively, but the molecular mechanisms that underlie this process are poorly understood. To study this process, we isolated a gene, LUMINIDEPENDENS (LD), that is involved in the timing of flowering in Arabidopsis. Mutations in this gene render Arabidopsis late flowering and appear to affect light perception. The late-flowering phenotype of the ld mutation was partially suppressed by vernalization. Genomic and cDNA clones of the LD gene were characterized. The predicted amino acid sequence of the LD protein contains 953 residues and includes two putative bipartite nuclear localization signals and a glutamine-rich region.     

Quantitative analysis of CEA expression in colorectal adenocarcinoma and serum: lack of correlation

Tissues and sera from 110 patients diagnosed with colorectal primary carcinoma, 20 patients with benign colorectal diseases and 31 healthy donors were subjected to quantitative CEA analysis. Multiple samples from tumor lesions and autologous histologically normal mucosa (10 cm from the tumor) were obtained at the time of surgery (cancer patients) or endoscopy (benign patients and healthy volunteers). CEA content was measured in protein extracts obtained from these tissues using a quantitative RIA method. A limit of normality for CEA content was established as 300 ng/mg of protein. When this was taken as cut-off, 104 of 110 (94.5%) tumor lesions and 51 of 110 (46.4%) autologous histologically normal colonic mucosa from cancer patients had elevated CEA levels. No correlation with stage of disease was found, while a correlation was observed with degree of tumor differentiation. A statistically significant difference between CEA content in tumor lesions and in histologically normal mucosa from cancer patients was observed (p = -0.001). Moreover, CEA content was statistically higher in the normal mucosa from cancer patients than in that from healthy donors (p = 0.005). CEA content in tissue specimens from benign lesions differed significantly from that in tissue from healthy donors (p = 0.005) and in carcinoma lesions (p < 0.001). The highest CEA content was observed in benign lesions with severe dysplasia. No statistical correlation between CEA content in carcinoma tissues and serum CEA levels (r = 0.195, p = .13) was found. Therefore, in considering diagnosis or therapy with anti-CEA MAbs for colorectal-carcinoma patients, or potential therapies with anti-CEA recombinant vaccines, serum CEA levels should not be taken as indicating CEA expression in tumor lesions.     

Cytogenetic and ploidy analysis of prostatic adenocarcinoma

The cytogenetic evaluation of prostatic adenocarcinoma has shown no consistent cytogenetic abnormalities. Despite manipulation of culture conditions, the majority of low-stage, untreated prostatic adenocarcinomas show a normal karyotype. We have performed cytogenetic analysis on eight primary prostate adenocarcinomas, using several control measures to increase the probability that any normal karyotype was derived from neoplastic cells rather than accompanying normal cells. Tumors were grown in media that encourages epithelial growth; DNA ploidy studies were performed before and after tissue culture; and immunohistochemical confirmation of the prostatic and epithelial nature of the cells was done following culture. Percentage of tumor on tissue sections adjacent to those submitted for culture was > 75% in all cases. Seven of eight cases were evaluable, and six cases showed no clonal abnormalities and were diploid. One tumor showed a population of tetraploid cells, without structural abnormalities. Three additional tumors showed evidence of tetraploidy by DNA analysis. One case showed nonclonal marker chromosomes and was aneuploid. This patient was pathologic Stage D. We conclude that the majority of prostatic adenocarcinomas at their inception may not show routinely detectable cytogenetic abnormalities. However, tetraploidy may play a role in the evolution of prostatic adenocarcinoma.     

Deep benign fibrous histiocytoma of the knee: CT and MR features with pathologic correlation

Magnetic resonance imaging and pathologic findings in a 28-year-old patient with a giant deep benign fibrous histiocytoma in the popliteal fossa of the right knee are described. The MR imaging findings include a well-delineated oval mass with low signal intensity on T1-, and high signal intensity on T2-weighted, images, and marked peripheral contrast enhancement. To the best of our knowledge, this is the first report on the MR findings in this entity.     

Cytogenetic and molecular analysis of dynamic mutation associated with fragile X syndrome

The gate control theory of pain (Melzack and Wall, 1965) suggests that tactile stimuli can decrease the perception of pain. We have found the reverse effect: Heat at levels that induce pain can substantially suppress tactile sensitivity, independently of shifts in attention or arousal. Ten human observers were stimulated by a tonic, pain-producing heat stimulus and vibrotactile stimuli (1, 10, and 100 Hz) coincidentally presented to the right thenar eminence. Vibrotactile thresholds were assessed with the skin at a normative temperature of 31 degrees C and at higher temperatures producing pain. Increases in vibrotactile thresholds (mean change = 7.3 dB) occurred at skin temperatures just below and above those that induced pain. Furthermore, absolute-magnitude estimates of suprathreshold vibrotactile stimuli determined during the same experiments showed decreased sensitivity and psychophysical recruitment. The changes are not attributable to attentional or arousal shifts, since they were not associated with changes in auditory thresholds. Furthermore, the changes occurred just below the subjects' pain thresholds (where nociceptors are presumably activated). This over-twofold diminution of vibrotactile sensitivity suggests that heat stimuli capable of inducing pain can significantly diminish taction, perhaps through a "touch gate" in a manner similar to the gate control theory proposed for pain.     

Mediastinal lymph node metastasis from esophageal carcinoma: CT assessment with pathologic correlation

Computed tomographic (CT) scans were performed in 179 patients with esophageal carcinoma to evaluate mediastinal lymph node metastasis. Histopathologic findings were compared with CT findings in a total of 7,218 resected lymph nodes. First, the criterion for lymph node metastasis on CT scans was 10 mm or more in long transverse diameter. The overall sensitivity and positive predictive value (PPV) were 19% (60 of 317 nodes) and 33% (60 of 180 nodes), respectively. Analysis of each of the eight subgroups of mediastinal nodes revealed that the PPV was more than 70% in node Nos. 105, 108, 110, and 112. In other subgroups, however, the PPV was less than 60%. Sensitivity was less than 50% in all eight subgroups. Second, the criterion for metastasis was 10 mm or more in short transverse diameter. The overall sensitivity and PPV were 8% (26 of 317 nodes) and 63% (26 of 41 nodes), respectively. Analysis of subgroups showed that the PPV in No. 106 nodes increased to 92%. In No. 106 nodes, use of a 5 mm criterion in long transverse diameter increased sensitivity to only 55%. Of the 317 histopathologically proven metastatic lymph nodes, 90 nodes (28%) were 10 mm or more in size, 112 (35%) were 5-10 mm, and 115 (36%) were less than 5 mm. Of the 6,901 non-metastatic lymph nodes, 473 nodes (7%) were 10 mm or more in size. Small (less than 5 mm in size) metastatic nodes were present in all eight subgroups. Among No. 107 and 109 nodes, large (10 mm or more in size) nonmetastatic nodes were prominent, resulting in low sensitivity and PPV. We conclude that CT does not provide an accurate assessment of metastatic versus non-metastatic mediastinal lymph nodes in patients with esophageal carcinoma.     

Differential nuclear matrix protein expression in prostate cancers: correlation with pathologic stage

PURPOSE: Nuclear Matrix Proteins (NMP) have been shown to be tissue and cell-type specific. Several unique NMPs have been investigated in various cancerous tissues, including prostate, bladder and kidney, and some are presently utilized as tumor markers. This study was aimed at characterizing the differential NMP expression in the pathologically more aggressive prostate cancers. METHODS: High resolution two-dimensional gel electrophoresis and silver staining was used to elucidate the NMP distribution of fresh prostate cancer nuclei, obtained from 39 radical prostatectomy specimens, surgically removed from men with clinically localized prostate cancer. Based on the final pathological grading, specimens were grouped according to predicted prognosis: poor--with seminal vesicle (SV) or lymph node (LN) involvement or established capsular penetration (ECP) with gleason score >7; intermediate--organ confined (OC) or focal capsular penetration (FCP) with gleason score 7 or ECP with gleason score 6; and good--with OC or FCP and gleason score <7. RESULTS: A specific charged protein (YL-1) of molecular weight 76 kD and isoelectric range 6.0-6.6 was found to be consistently present in 19 of 19 aggressive cancers. It was present only in 1 of 10 in the group with good prognosis and weakly positive in 9 of 10 in the intermediate group. CONCLUSIONS: Within this preliminary study, the expression of YL-1 appears to be related to aggressive prostate cancer, suggesting a potential marker of poor prognosis for clinically localized prostate cancer. Further characterization of the identity and function of this NMP is needed to fully ascertain its clinical potential.