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Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous large-scale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.

OBJECTIVE: To study the feasibility of utilizing mRNA recovered from cytologic Papanicolaou (Pap) specimens as a resource for gene expression studies of normal and diseased cells. STUDY DESIGN: To assess the effects of fixation on mRNA recovery and analysis, fresh Pap samples were processed by three separate methods: (1) routine cytologic fixation, (2) 70% ethanol fixation, and (3) air drying without fixation. One-week-old, 1-month-old, 1-year-old and 10-year-old samples were studied to determine the quality of mRNA in archival samples, mRNA quality was analyzed by RT-PCR for the HPRT gene, and by complete transcript amplification. Both heterogeneous (whole slide scrapes) and microdissected cell populations were studied. RESULTS: Reverse transcriptase-polymerase chain reaction (RT-PCR) for the hypoxanthine guanine phosphoribosil transferase gene was positive in all fresh and archival samples and was not affected by fixative, processing methodology or microdissection. Complete transcript amplification followed by gel electrophoresis showed cDNA smears in all fresh samples with a maximum intensity between 1 and 2 kilobases (kb). Amplifi-cation of mRNA was not affected by fixation. Smaller cDNA smears were seen in archival specimens with a maximum intensity between 0.5 and 1.5 kb in both one-week-old and one-month-old samples. Smears of approximately 500 base pairs were observed in the 1-year-old and 10-year-old samples. Successful mRNA amplification was possible from microdissected cell populations. CONCLUSION: Messenger RNA recovery and analysis is possible from archival cytologic specimens, suggesting that they can serve as a useful template for RT-PCR analysis of individual genes as well as newly developing high-throughput gene expression methodologies, such as microarrays. Cytologic samples may be particularly useful for study or archival samples as well as diseases from which tissue samples amenable to mRNA-based studies are not available.

Objective: To identify the stage of placental development in which enalapril use in the pregnant rat is deleterious.Methods: Approximately 9 mg/rat/day of enalapril were given in the drinking water to Sprague-Dawley rats on days 1-7 (E1-7), 8-16 (E8-16) and 17-20 (E17-20) of pregnancy; rats drinking only water served as control. At day 20 of pregnancy, rats were sacrificed, fetuses and placentas weighed, and placentas examined double-blind by light microscopy.Main Outcome: Both placental morphology and fetal weights were altered in early, mid, and late pregnancy.Results: Placentas of enalapril-treated animals more frequently showed foci of parallel cords and hypocellular pattern than those of controls (66% vs. 28%). Fetal weights of all treated groups were smaller than control (P

The pathological differential diagnosis between primary and metastatic ovarian malignant tumors is usually difficult, specially for tumors originating in the gastrointestinal system or breast.To define an immunohistochemical flow chart to discriminate these tumor types.We performed a immunostaining analysis using a panel of six antibodies (CK 7, CA 125, CEA, CK20, BRST-2 and CA 15-3) in 3 tumor groups: 11 ovarian, 14 breast and 12 colonic primary tumors and in a study group of 38 ovarian tumors whose primary origin was unknown.We defined an ovarian immunohistochemical pattern (CEA-/CK20-, 45% in ovarian tumors, 0% in breast or colonic tumors, p0.001); an ovary/breast pattern (CEA+/CK20-, 0% in colonic tumors, p0.001): a breast pattern (CEA+/CK20-/BKST-2+, 64% in breast tumors and 0% in colonic and ovarian tumors, p0.001) and a colonic pattern (CEA+/CK20+/CK7-, 67% in colonic tumors and 0% in breast and ovarian tumors, p0.001).Employing a simple panel of antibodies, characteristic immunohistochemical patterns were defined for ovarian, breast and colonic tumors. These patterns allowed the identification of the origin of most tumors of the study group.

Background: The pathological differential diagnosis between primary and metastatic ovarian malignant tumors is usually difficult, specially for tumors originating in the gastrointestinal system or breast. Aim: To define an immunohistochemical flow chart to discriminate these tumor types. Material and methods: We performed a immunostaining analysis using a panel of six antibodies (CK 7, CA 125, CEA, CK20, BRST-2 and CA 15-3) in 3 tumor groups: 11 ovarian, 14 breast and 12 colonic primary tumors and in a study group of 38 ovarian tumors whose primary origin was unknown. Results: We defined an ovarian immunohistochemical pattern (CEA-/CK20-, 45% in ovarian tumors, 0% in breast or colonic tumors, p

Objective. Loss of heterozygosity (LOH) profiles and X chromosome inactivation patterns are analyzed in 42 patients with cervical intraepithelial neoplasias (CIN), including low-grade (CIN1) and high-grade (CIN2, CIN3) lesions, and 22 patients with invasive cervical carcinomas. Method. Laser capture microdissection was utilized to procure pure matched normal and lesional cells from each case. Sixteen microsatellite markers on four chromosomal arms, 6q21–q25.1, 8p21, 13q12.3–q13, and 17q12–q21, were amplified for LOH, as well as the HUMARA locus for X chromosome inactivation analysis. Eight additional markers spanning the long arm of chromosome 6 were utilized in all cases showing LOH on this arm and in which further tissue material was available for microdissection. Results. Fifty-five percent of carcinomas showed deletions on chromosome bands 6q21–q25.1, 43% on 13q12.3–q13, and 40% on 17q12–q21. Deletions on 6q were identified in CIN3 (40%), CIN2 (37%), and CIN1 (10%), on 13q in CIN3 (33%) and CIN2 (33%), and rarely on chromosomal arm 17q. Finer 6q mapping revealed that marker D6S310 (q22) represented the centromeric and marker D6S255 (q25–q16) the telomeric boundary of deletion. A second, telomeric area of deletion at marker D6S281 (q27) was also identified. Monoclonal X chromosome inactivation patterns were identified in 12/13 cancers, 13/14 CIN3, 5/10 CIN2, and 0/6 CIN1. Conclusions. Two areas of deletion on chromosome 6q were identified in cervical tumors, suggesting the presence of tumor suppressor gene(s) inactivated in this neoplasia. LOH on this arm were identified early during cervical tumor progression. LOH on 13q and 17q also occur in cervical cancers. X chromosome inactivation patterns suggest that CIN develops into a monoclonal lesion during progression from CIN1 to CIN3.

Papillary serous carcinoma with low malignant potential, similar to those described in the ovary, can also originate in the peritoneum. Characteristically they show peritoneal spread without involvement of the ovary and, if present, it corresponds to a superficial implant similar to those seen in the rest of the peritoneal cavity. Histologically they correspond to a low malignant potential tumor; they are slow growing and have good prognosis. They are common in young women, usually they present few symptoms and are frequently discovered during other surgical procedures. The treatment is surgical and it can be conservative in cases of women who want to preserve their fertility, without coadjuvant therapy. We report a 34 years old woman with a primary peritoneal serous carcinoma with low malignant potential and discuss its management.

The importance of inactivation of tumor suppressor genes in the development/progression of carcinomas of the uterine cervix is reviewed. It is well known that HPV-related oncogenes are strongly linked to cervical cancer. However, fewer studies have explored the occurrence of inactivation of tumor suppressor genes in this neoplasia. Genetic deletions affecting tumor suppressor genes are the most common mechanism of inactivation of these genes. Studies using conventional molecular techniques such as restriction fragment length polymorphism (RFLP) and Southern Blot showed low frequency of deletions in cervical carcinomas. Detection of deletions by using RFLP and Southern Blot presents several disadvantages, the most important being the difficulty in analyzing pure tumor cells. More sensitive approaches include tissue microdissection and PCR analysis of micro-satellites. Using these approaches, it has been shown that genetic deletions are, in fact, frequent events in cervical cancers, being detected in up to 95% of the cases. Multiple genetic loci are involved, including chromosomes 3p, 5p, 6p and 11q. Deletions are detected even in precursor lesions (cervical intraepithelial neoplasia, CIN). Some deletions have been correlated with prognostic parameters, such as stage, depth of invasion, and vascular space involvement. It is concluded that cervical carcinogenesis, like in other tumors, is a multistep process, characterized by the accumulation of events including activation of oncogenes, as well as inactivation of tumor suppressor genes.

Background: Adequate management and treatment of ovarian carcinoma requires a complete surgical staging supported by frozen-section examination. To achieve this goal it is necessary a high level of accuracy. Aim: To evaluate the accuracy of frozen-sections in ovarian carcinoma considering the influence of tumor diameter and weight. Patients and methods: Retrospective study of frozen-sections performed in patients with ovarian tumors who underwent surgery. Frozen- and permanent- sections were divided into three categories (benign, borderline and malignant) and stratified by diameter (20 cm) and weight (1400 g). The diagnostic correlation, sensitivity, specificity, predictive values and accuracy of each frozen-section diagnosis were determined. Results: Eight hundred forty two ovarian tumors that underwent frozen-sections between January 1988 and October 1998 were studied. Final diagnosis was 86,7% benign, 2,7% low malignant potential (LMP) and 10,6% malignant. The diagnosis correlation between frozen- and permanent-sections was 98,2%. Misdiagnosis was in epithelial ovarian tumors, particularly in LMP tumors. Sensitivity, specificity, positive- and negative- predictive values and accuracy of the four hundred eighty nine epithelial tumor were 92,6%, 99,2%, 96,7%, 98,2% and 97,9%, respectively. Diagnostic correlation was higher in epithelial ovarian tumors with diameter 10 cm or weight >700 g (particularly in LMP tumors) is difficult because of the extensive sampling required. Frozen-sections diagnoses are important to determine the type and extent of surgery performed at the initial operation.

To maintain ex vivo integral prostatic tissue including intact stromal and ductal elements using the NASA-designed Rotating Wall Vessel (RWV) which maintains colocalized cells in an environment that promotes both three-dimensional cellular interactions together with the uniform mass transfer of nutrients and metabolic wastes.Samples of normal prostate were obtained as a byproduct of transurethral prostatectomy or needle biopsy. Prostatic tissue dissected into small 1 x 1 mm. blocks was cultured in the Rotating Wall Vessel (RWV) Bioreactor for various time periods and analyzed using histological, immunochemical, and total cell RNA assays.We report the long term maintenance of benign explanted human prostate tissue grown in simple culture medium, under the simulated microgravity conditions afforded by the RWV bioreactor. Mesenchymal stromal elements including blood vessels and architecturally preserved tubuloglandular acini were maintained for a minimum of 28 days. Cytokeratins, vimentin and TGF-beta2 receptor and ligand were preserved through the entire culture period as revealed by immunocytochemistry. Prostatic acid phosphatase (PAP) was continuously expressed during the culture period, although somewhat decreased. Prostatic specific antigen (PSA) and its transcript were down regulated over time of culture. Prostatic carcinoma cells from the TSU cell line were able to invade RWV-cultured benign prostate tissue explants.The RWV bioreactor represents an additional new technology for culturing prostate tissue for further investigations concerning the basic physiology and pathobiology of this clinically important tissue.

In order to design a dating system based on the microscopic picture of brain infarcts of recent onset, we performed the histological examination of 31 infarcts covering the first 4 weeks of evolution in 30 autopsy cases. The date of the cerebral vascular accident was clinically established in every case. There were 13 men and 17 women with a mean age of 65 years. Hemorrhagic infarcts were found in 15 cases and anemic infarcts in 16 cases. Based on the histological features four periods were identified: the first period, from day 1 through day 4, was characterized by the predominance of eosinophilic neurons and necrotic oligodendrocytes; the second period, from day 5 through day 7, differed from the first by the appearance of macrophages and of newly formed blood vessels; the third period, from day 8 through day 14, showed neuronal ghosts, macrophages, astrocytic proliferation, gemistocytes, and absence of neutrophils; and in the fourth period, from day 15 through day 27, there were no eosinophilic neurons, and neither necrotic oligodendrocytes nor myelin in the central portion of the infarct were identified. By assessing the histological features and accurately correlating the findings with the corresponding clinical data, we have been able to describe four distinct microscopic patterns of the first month of evolution of brain infarcts. The present findings may be considered useful morphological clues to better characterize the early evolutional phase of brain infarcts in humans.

Enalapril (15 mg/kg/day p.o.) was given to 11 pregnant rats from day 1 to 9 (E1–9) and to 11 rats from day 10 to 20 (E10–20) of pregnancy; 12 rats were the control group. Fifteen animals were sacrificed on day 20 of pregnancy and 19 were allowed to progress into partum. Placentas were smaller in E10–20 rats (––15%, p < 0.05) and had a simple hypocellular cordonal structure; in E1–9 animals the predominant pattern was a combination of complex and simple structure. At day 20 the fetuses in the treated groups were smaller than the controls (––5% in E1–9 and ––16% in E10–20, p < 0.05); differences disappeared on the 13th day postpartum. Two fetuses from treated mothers presented incomplete skull ossification. We believe this report adds arguments to preclude converting enzyme inhibitors in pregnancy.

RESUMEN Se presentan los hallazgos ch'nicos, fonocar-diograficos, hemodinamicos y angiocardiografi-cos- de 8 ninos portadores de una aplasia devalvulas pulmonares. Todos con CIV asociada, 6con estenosis pulmonar infundibular. Ch'nica-mente destaca la existencia de un segundo ruidounico no acentuado, un soplo diastolico tardiocreciente-decreciente en el 2° y 3 er espaciointercostal izquierdo junto a una imagen radio-logica con sombras patologicas parahiliares,especialmente a derecha o gran dilatacion deltronco de arteria pulmonar. Los hallazgos angio-graficos son muy llamativos, no existiendo enninguna otra patologi'a dilataciones tan groserasdel tronco de la arteria pulmonar o sus ramas, asicomo la brusca transicion de calibre entre lostroncob pulmonares principales y sus ramas. Sediscute la etiologia de esta patologi'a y se anali-zan los resultados quirurgicos. REFERENCIAS1. Chevers, A'.: Recherches sur les maladies de 1'arterepulmonaire. Arch. Gen. Med. 15: 488, 1847.2. Kurtz, CM.; Sprague, H.B.; White, P.D.: CongenitaFheart disease: Intraventricular septal defect withassociated anomalies in serie of three cases exami-nated post mortem and living patient fifty eightyear old with cyanosis and clubbing of fingers. Am.Heart.J. 3: 77, 1927.3. Miller, R.A.; White, H,; Lev, M.: Congenital absenceof the pulmonary valve. Clinical and pathologicalsyndrome. Circulation (Abstr) 18: 759, 1958.4. Onesti, S.J., Harned, H.S.: Absence of the pulmona-ry valve associated with ventricular septal defect.Am. J.Cardiol. 2: 496, 1958.5. Lakier, J.B.; Stanger, P.; Heymann, M.A. et al:Tetralogy of Fallot with absent pulmonary valve:natural history and hemodynamic considerations.Circulation 50: 167, 1974.6. Emmanouilides, G.C.: Congenital absence of thepulmonary valve. IN: Moss A.J.; Adams F.H.;Emmanoulidies G.C. (ed.): Heart Disease in Infants,Children and Adolescents. 2