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A correction to the article "Lessons from human teratomas to guide development of safe stem cell therapies" that was published in the June 4, 2013 issue is presented.

The ability to predict cancer progression may help the clinical management of patients with penile squamous cell carcinoma. We studied 22 cases of squamous cell carcinoma of the penis diagnosed between 1989 and 1998. The depth of invasion was measured from the basement membrane of the squamous epithelium to the deepest invasive cancer cells. Cancer progression was defined as the development of lymph node metastasis or distant metastasis. The mean patient age was 63 years and the mean follow-up was 28 months. Ten patients developed cancer progression. The mean depth of invasion among patients with cancer progression was 9.8 mM, as compared to the mean depth of invasion of 4.0 mM among those patients without cancer progression (P =.02). Vascular invasion was also predictive of cancer progression (P =.02). Metastases developed in the majority (6 out of 7) of cases invading more than 6 mM, but developed only in a minority (4 out of 15) of cases invading 6 mM or less. We conclude that depth of invasion and vascular invasion are significant predictors of cancer progression for penile squamous cell carcinoma.

Background: Molecular data suggest that peritoneal tumors in women with advanced-stage ovarian papillary serous adenocarcinoma are monoclonal in origin. Whether the same is true for ovarian tumors of low malignant potential is not known. We compared peritoneal and ovarian tumors from women with advanced-stage ovarian papillary serous tumors of low malignant potential to determine whether the peritoneal tumors arose from the same clone as the ovarian tumors., Methods: We studied the clonality of 73 peritoneal and ovarian tumors from 18 women with advanced-stage ovarian papillary serous tumors of low malignant potential. Formalin-fixed, paraffin-embedded tumors and representative normal tissues were sectioned and stained with hematoxylin-eosin, representative sections from separate tumors were manually microdissected, genomic DNA was extracted from the microdissected tumors, and the polymerase chain reaction was used to amplify a CAG polymorphic site in the human androgen receptor locus on the X chromosome to determine the inactivation pattern of the X chromosome and the clonality of the tumors., Results: The pattern of X-chromosome inactivation could be determined from the tumors of 13 of 18 patients. Of the 13 patients, seven (54%) had nonrandom inactivation of the X chromosome, and six of the seven had different inactivation patterns in the peritoneal and ovarian tumors. Three of these patients also had different patterns of nonrandom X-chromosome inactivation in tumors from each ovary. The remaining six patients had random patterns of X-chromosome inactivation in the peritoneal and ovarian tumors., Conclusions: Our data suggest that peritoneal and ovarian tumors of low malignant potential arise independently.

Background: -Cytokeratin 7 (CK7) and cytokeratin 20 (CK20) are 2 types of intermediate filament protein. Expression of CK7 is seen in the majority of primary urinary bladder carcinomas. CK20 is restricted to superficial and occasional intermediate cells of the normal urothelium of the bladder. Aberrant CK20 expression has been documented in urothelial carcinoma and has proved useful as an ancillary diagnostic aid for urinary bladder tumor. Our hypothesis is that the pattern of CK7 and CK20 expression in metastatic urothelial carcinoma duplicates the expression of the same markers in the primary tumors. Therefore, immunohistochemical staining of metastatic tumors for these 2 markers may be helpful for differential diagnosis in ambiguous metastatic tumor deposits., Objective: -To determine the concordance of CK7 and CK20 expression in primary bladder urothelial carcinoma and the matched lymph node metastasis., Design: -We studied 26 patients with lymph node metastases who underwent radical cystectomy and bilateral lymphadenectomy for bladder carcinoma. Immunohistochemical staining for CK7 and CK20 was performed on formalin-fixed paraffin-embedded tissues containing primary cancers and lymph node metastases., Results: -In all cases, there was a concordant expression of CK20 in the primary cancer and its matched lymph node metastasis. Twelve cases (46%) showed positive CK20 immunoreactivity in the primary tumor and its matched lymph node metastases, whereas 14 cases (54%) were negative for CK20 in both the primary tumor and lymph node metastasis. All cases showed positive CK7 immunoreactivity in the primary cancers and matched lymph node metastases., Conclusions: -CK20 immunoreactivity is reliably observed in metastases from bladder cancer when the primary tumor expresses CK20.

The human AP endonuclease (Ape1 or ref-1) DNA base excision repair (BER) enzyme is a multifunctional protein that has an impact on a wide variety of important cellular functions including oxidative signaling, transcription factor regulation, and cell cycle control. It acts on mutagenic AP (baseless) sites in DNA as a critical member of the DNA BER repair pathway. Moreover, Ape1/ref-1 stimulates the DNA-binding activity of transcription factors (Fos-Jun, nuclear factor-kappaB, Myb, ATF/cyclic AMP-responsive element binding protein family, HIF-1alpha, HLF, PAX, and p53) through a redox mechanism and thus represents a novel component of signal transduction processes that regulate eukaryotic gene expression. Ape1/ref-1 has also been shown to be closely linked to apoptosis associated with thioredoxin, and altered levels of Ape1/ref-1 have been found in some cancers. In a pilot study, we have examined Ape1/ref-1 expression by immunohistochemistry in sections of germ cell tumors (GCTs) from 10 patients with testicular cancer of various histologies including seminomas, yolk sac tumors, and malignant teratomas. Ape1/ref-1 was expressed at relatively high levels in the tumor cells of nearly all sections. We hypothesized that elevated expression of Ape1/ref-1 is responsible in part for the resistance to therapeutic agents. To answer this hypothesis, we overexpressed the Ape1/ref-1 cDNA in the GCT cell line NT2/D1 using retroviral gene transduction with the vector LAPESN. Using an oligonucleotide cleavage assay and immunohistochemistry to assess Ape1/ref-1 repair activity and expression, respectively, we found that the repair activity and relative Ape1/ref-1 expression in GCT cell lines are directly related. NT2/D1 cells transduced with Ape1/ref-1 exhibited 2-fold higher AP endonuclease activity in the oligonucleotide cleavage assay, and this was reflected in a 2-3-fold increase in protection against bleomycin. Lesser protection was observed with gamma-irradiation. We conclude that: (a) Ape1/ref-1 is expressed at relatively high levels in some GCTs; (b) elevated expression of Ape1/ref-1 in testicular cancer cell lines results in resistance to certain therapeutic agents; and (c) Ape1/ref-1 expression in GCT cell lines determined by immunohistochemistry and repair activity assays parallels the level of protection from bleomycin. We further hypothesize that elevated Ape1/ref-1 levels observed in human testicular cancer may be related to their relative resistance to therapy and may serve as a diagnostic marker for refractory disease. To our knowledge, this is the first example of overexpressing Ape1/ref-1 in a mammalian system resulting in enhanced protection to DNA-damaging agents.

Background/aims: The American Cancer Society recommends that asymptomatic persons aged > or = 50 years undergo sigmoidoscopy every 3-5 years. However, the yield of a second examination 3 years later in persons who are initially negative is unknown. The aim of this study was to determine the yield of a second flexible sigmoidoscopy in average-risk persons aged > or = 50 years after an initial negative examination., Methods: Two hundred fifty-nine asymptomatic, average-risk persons who had undergone a negative screening flexible sigmoidoscopy examination at age > or = 50 years underwent a second examination at least 2 years later (mean, 3.4 years)., Results: The second examination found adenomas in 15 (6%) screenees, but no cancers or large (> 1 cm) or severely dysplastic adenomas were detected. Persons aged > or = 60 years at the time of the second examination were more likely (10%) to have adenomas than those < 60 years (3%) (odds ratio, 3.76; 95% confidence interval, 1.17-12.2), but no advanced lesions were found in persons aged > or = 60 years., Conclusions: These data suggest that the American Cancer Society should consider changing its recommendation for screening flexible sigmoidoscopy in asymptomatic, average-risk persons to 5-year intervals after a negative examination.

The significance of distal colonic hyperplastic polyps was investigated in 482 asymptomatic average-risk subjects, aged 50-75 years, in whom fecal occult blood test results were negative and who underwent screening colonoscopy. The incidence of adenomas in the colon proximal to the sigmoid-descending colon junction in subjects with hyperplastic polyps distal to that point was 18% and was similar to the incidence of proximal colonic adenomas in subjects with no distal colonic polyps (15%). The incidence of proximal colonic adenomas in subjects with no distal colonic adenomas was 38% and was significantly greater than the incidence found in individuals with no distal colonic polyps or only hyperplastic polyps. Our data do not support distal colonic hyperplastic polyps as markers for proximal colonic adenomas in asymptomatic average-risk subjects.

Colonoscopy was performed on 210 asymptomatic average-risk persons, aged 50-75 years, who had negative fecal occult blood test results. Colonoscopy was complete to the cecum in 209 subjects. Fifty-three subjects (25%) had adenomas and two had cancer. All of the adenomas greater than or equal to 1 cm in size and both cancers occurred in subjects aged greater than or equal to 60 years. Fifty-one percent of subjects with adenomas and one with cancer had no neoplasms distal to the sigmoid-descending colon junction. One subject had a major postpolypectomy hemorrhage that stopped spontaneously. Screening colonoscopy, therefore, has a high yield for detection of neoplasms in asymptomatic average-risk persons aged greater than or equal to 60 years with negative fecal occult blood test results. The yield is low in persons aged 50-54 years and intermediate in persons aged 55-59 years.

A single, 1.3-cm, intraocular tumor, composed of interlacing, spindle-shaped astrocytes, involved the retina and optic disc of a 13-month-old girl. Neither the patient nor her family had stigmas of a phakomatosis. We found 42 previous cases of histologically documented astrocytic tumors of the retina. Twenty-four patients (57%) had tuberous sclerosis, six patients (14%) had neurofibromatosis, and 12 patients (29%) were otherwise normal. Patients with tuberous sclerosis usually had multiple, peripheral, retinal tumors containing giant "astrocytes." Patients with neurofibromatosis and otherwise normal patients more frequently had disc-based tumors. However, three patients (50%) with neurofibromatosis had multiple tumors, whereas multiplicity occurred in only one of the patients in the sporadic group. We conclude that if the tumor is single, is disc based, and lacks giant cells, the patient is not at great risk of tuberous sclerosis.

Clinical and morphologic observations from two patients undergoing percutaneous transluminal angioplasty of stenotic aortocoronary saphenous vein bypass grafts early (3 months) and late (56 months) after graft insertion are described. Each patient had one or more clinically successful graft dilations resulting in an angiographic increase in luminal diameter and a decrease in mean trans-stenotic gradient, and each had restenosis of the graft at the site of previous angioplasty within 2 months of dilation. Both operatively excised grafts had diffuse but variable amounts of intimal fibrous thickening and severe narrowing at the previous angioplasty site. The early graft had no evidence of dilation injury, and the intimal thickening consisted solely of fibrocollagenous tissue free of calcific deposits. In contrast, the late graft had a healing intimal dissection at the angioplasty site, and the intimal thickening consisted of atherosclerotic plaque with calcific deposits. Angiographic and morphologic correlations suggest that the mechanism of saphenous vein angioplasty early (less than or equal to 1 year) after insertion is by graft "stretching," while late (greater than 1 year) after insertion it is by atherosclerotic plaque "fracture" similar to that observed in atherosclerotic coronary arteries subjected to angioplasty procedures.

Seven pathologists independently classified 50 slides of ovarian tumors using category I of the World Health Organization classification (WHO I), each case being seen twice under different random code numbers. Intraobserver reproducibility and interobserver reproducibility, based on consistent interpretations, were both suboptimal. However, scrutiny suggested that no pathologist was a source of excessive variability, nor was suboptimal interobserver reproducibility simply due to intraobserver variability. Neither could excessive variability be attributed to skewing of results by a subgroup of unclassifiable cases. However, clearcut sources of variability were identified among the categories of WHO I, namely, mixed epithelial, unclassified epithelial, and undifferentiated carcinoma. There was also considerable variability in distinguishing serous and endometrioid neoplasms, and in identifying tumors of low malignant potential. These findings should not be misconstrued as implying that pathologists in routine practice cannot diagnose common ovarian cancers reproducibly for patient care purposes. Availability of clinical and macroscopic data, extensive sampling, histochemistry, and consultation combine, in an uncontrolled and highly individualistic fashion, to render routine service work very different from this highly controlled formal exercise. Furthermore, at the current state of the therapeutic art, many of the taxonomic problems identified in this study may have little clinical significance. Nonetheless, this study has strengthened the evidence that there may be important problems in classifying common ovarian cancers reproducibly using WHO I, and that WHO I may require greater clarity to enhance reproducibility. Current emphasis on quality assurance dictates reconsideration of the literature on reproducibility of histopathologic taxonomy, which has tended to inculpate pathologists as sources of variability. Virtually all of this literature is subject to some degree of skepticism due to deficiencies in methodology. Consideration of the question of how to measure reproducibility in anatomic pathology leads us to suggest that the community of pathologists should address the need to decrease ambiguity in classification systems as an important step toward optimizing reproducibility.

Germ cell neoplasms were reviewed for the investigation of a mesenchyme-like component of yolk sac tumor (YST) characterized by spindle cells with few mitoses in a myxoid, vascular background. Nineteen YSTs with this pattern were identified. The mesenchyme-like component of these YSTs appeared to derive from the epithelial elements of YST, since cytokeratin as well as vimentin positivity occurred in the spindle cells of the mesenchyme-like areas and foci of epithelial-spindle cell transition were present. In some cases the mesenchyme-like component showed differentiated mesenchymal elements (usually skeletal muscle). Similar features were identified in 13 chemotherapy-treated cases of YST that consisted only of this mesenchyme-like component. The mesenchyme-like component of YST appears to represent a chemoresistant, pluripotential cell population arising from metaplasia of YST epithelium; it may give rise to sarcomas occurring in some patients with treated germ cell tumors.