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Hedgehog signaling pathway and gastrointestinal stem cell signaling network (review).

Hedgehog, BMP/TGFbeta, FGF, WNT and Notch signaling pathways constitute the stem cell signaling network, which plays a key role in a variety of processes, such as embryogenesis, maintenance of adult tissue homeostasis, tissue repair during chronic persistent inflammation, and carcinogenesis. Sonic hedgehog (SHH), Indian hedgehog (IHH) and Desert hedgehog (DHH) bind to PTCH1/PTCH or PTCH2 receptor to release Smoothened (SMO) signal transducer from Patched-dependent suppression. SMO then activates STK36 serine/threonine kinase to stabilize GLI family members and to phosphorylate SUFU for nuclear accumulation of GLI. Hedgehog signaling activation leads to GLI-dependent transcriptional activation of target genes, such as GLI1, PTCH1, CCND2, FOXL1, JAG2 and SFRP1. GLI1-dependent positive feedback loop combined with PTCH1-dependent negative feedback loop gives rise to transient proliferation of Hedgehog target cells. Iguana homologs (DZIP1 and DZIP1L) and Costal-2 homologs (KIF7 and KIF27) are identified by comparative integromics. SHH-dependent parietal cell proliferation is implicated in gastric mucosal repair during chronic Helicobacter pylori infection. BMP-RUNX3 signaling induces IHH expression in surface differentiated epithelial cells of stomach and intestine. Hedgehog signals from epithelial cells then induces FOXL1-mediated BMP4 upregulation in mesenchymal cells. Hedgehog signaling is frequently activated in esophageal cancer, gastric cancer and pancreatic cancer due to transcriptional upregulation of Hedgehog ligands and epigenetic silencing of HHIP1/HHIP gene, encoding the Hedgehog inhibitor. However, Hedgehog signaling is rarely activated in colorectal cancer due to negative regulation by the canonical WNT signaling pathway. Hedgehog signaling molecules or targets, such as SHH, IHH, HHIP1, PTCH1 and GLI1, are applied as biomarkers for cancer diagnostics, prognostics and therapeutics. Small-molecule inhibitors for SMO or STK36 are suitable to be used for treatment of Hedgehog-dependent cancer.

Animals↗

Cervical cancer in women with comprehensive health care access: attributable factors in the screening process.

BACKGROUND: Invasive cervical cancer is highly preventable, yet it continues to occur, even among women who have access to cancer screening and treatment services. To reduce cervical cancer among such women, reasons for its occurrence must be better understood. We examined factors associated with the diagnosis of cervical cancer among women enrolled in health plans. METHODS: We identified all cases of invasive cervical cancer (n = 833) diagnosed from January 1, 1995, through December 31, 2000, among women who were long-term members of seven prepaid comprehensive health plans and reviewed each woman's medical records for the 3 years prior to her cancer diagnosis. Women were classified into one of three categories based on Pap test histories 4-36 months before diagnosis: failure to screen with a Pap test, failure in detection by a Pap test, or failure in follow-up of an abnormal test result. RESULTS: The majority of cases (n = 464; 56%) were in women who had no Pap tests during the period 4-36 months prior to diagnosis. Of the remaining cases, 263 (32%) were attributed to Pap test detection failure and 106 (13%) to follow-up failure. Being older (odds ratio [OR] = 6.48, 95% confidence interval [CI] = 3.89 to 10.79) or living in an area of higher poverty (OR = 1.72, 95% CI = 1.11 to 2.67) or having a lower education level (OR= 1.52; 95% CI = 1.07 to 2.16) was associated with the likelihood of being assigned to the failure to screen category versus either of the other two categories. A total of 375 (81%) of the 464 patients who had not had Pap screening had had at least one outpatient visit 4-36 months prior to cancer diagnosis. The cancer diagnostic process was triggered by a routine screening examination in 44% of patients, whereas 53% of the patients presented with symptoms consistent with cervical cancer; the remaining 3% were identified fortuitously during the course of receiving noncervical care. CONCLUSIONS: To reduce the incidence of invasive cervical cancer among women with access to screening and treatment, Pap screening adherence should be increased. In addition, strategies to improve the accuracy of Pap screening could afford earlier detection of cervical cancer.

Adult↗

UPM3: review of a new molecular diagnostic urine test for prostate cancer.

PSA elevation is the most common indication for urologic referral to rule out the presence of prostate cancer. Recently PSA screening and its usefulness in suggesting the presence of clinically significant prostate cancer has been put into doubt. PSA has limitations in detecting significant cancers even when elevated and on the other hand significant cancers are found in the presence of low PSA levels. In order to better predict patients at risk of harboring prostate cancer new diagnostic tests are required. A promising novel approach is based on the molecular detection of prostate cancer cells in urine. The uPM3 assay is based on the amplification of specific target RNA using the nucleic acid sequence-based amplification (NASBA) technology. In a large multi-center study of 517 cases the overall sensitivity was 66% with a specificity of 89%. The positive (PPV) predictive values for the uPM3 test were 75% compared to 38% for a serum PSA cutoff of 4. The negative predictive value (NPV) was equivalent between the tests, but due to the higher PPV for uPM3, the accuracy of uPM3 was nearly two-fold greater than PSA (81% versus 43% and 47% for PSA cutoffs of 2.5 and 4 ng/ml, respectively). This test may become one of the first molecular diagnostic tools to aid in prostate cancer detection.

Adult↗

Emerging use of nanoparticles in diagnosis and treatment of breast cancer.

The biological application of nanoparticles is a rapidly developing area of nanotechnology that raises new possibilities in the diagnosis and treatment of human cancers. In cancer diagnostics, fluorescent nanoparticles can be used for multiplex simultaneous profiling of tumour biomarkers and for detection of multiple genes and matrix RNA with fluorescent in-situ hybridisation. In breast cancer, three crucial biomarkers can be detected and accurately quantified in single tumour sections by use of nanoparticles conjugated to antibodies. In the near future, the use of conjugated nanoparticles will allow at least ten cancer-related proteins to be detected on tiny tumour sections, providing a new method of analysing the proteome of an individual tumour. Supermagnetic nanoparticles have exciting possibilities as contrast agents for cancer detection in vivo, and for monitoring the response to treatment. Several chemotherapy agents are available as nanoparticle formulations, and have at least equivalent efficacy and fewer toxic effects compared with conventional formulations. Ultimately, the use of nanoparticles will allow simultaneous tumour targeting and drug delivery in a unique manner. In this review, we give an overview of the use of clinically applicable nanoparticles in oncology, with particular focus on the diagnosis and treatment of breast cancer.

Animals↗

Determinants of papillary cancer of the thyroid.

Determinants of papillary thyroid cancer were evaluated in a questionnaire-based case-control study from southeastern Sweden. A total of 104 cases, diagnosed from 1977 to 1987, and 387 randomly selected controls were included in the analyses. Female subjects with papillary cancer reported a work history as dentists/dental assistants, telephone operators, teachers, and day nursery personnel, and an occupational contact with chemicals and video display terminals more often than did controls. The 11 male cases more often reported working as mechanics and metal workers and having occupational contact with solvents. Other factors associated with increased risk for female papillary cancer were having private well water at the birth address; leisure time exposure to combustion smoke; low intake of cruciferous vegetables and seafood; and a family history of goiter, heart disease, biliary disorder, or female genital cancer. Diagnostic radiographic examinations, especially to the head, neck, or upper back/chest area, or repeated dental examinations, were also found to be associated with this form of cancer. With regard to the possible influence from hormonal factors among women less than age 50 years at time of diagnosis, an increased risk was found for a pregnancy soon after puberty. Tendencies toward a decreasing risk with increasing age at first pregnancy as well as an increasing risk with increasing number of pregnancies were found as well. Multiparity seemed to potentiate the effect from prior radiographic examinations.

Adult↗

Cancer survivorship and agency model: implications for patient choice, decision making, and influence.

Relative to other types of health communication research (acute care physician patient communication, communication campaigns, compliance episodes, etc.), investigations of patient communication following the diagnosis of cancer are infrequent. Theoretically driven, empirical research is desperately needed in such postdiagnostic communication processes as survivorship, quality of life, palliative and hospice care, and loss, bereavement, and grief for those millions of people who have been diagnosed with the second leading cause of death in our nation. An organizational model of patient communication is needed that identifies and describes salient issues and processes involved when cancer patients attempt to negotiate the difficult courses of action following the diagnosis of cancer. The cancer survivorship and agency model (CSAM) proposes both general and specific strategies that serve as options for patients seeking to take greater control of the decision-making process related to their treatment and care of cancer. Although seemingly practical in its offering, CSAM is intended to serve as a heuristic springboard for theoretically based, applied communication research focusing exclusively on post diagnostic cancer processes.

Communication↗

The role of telomeres and telomerase in human cancer.

Human cancers/malignant transformation of normal cells occur from multiple independent genetic changes/mutations that can subvert the normal growth controls of cells, leading to distinct phenotypic changes and immortalization. Normal human somatic cells have limited proliferative capacity both in vitro and in vivo and undergo senescence. Recent studies have implicated telomeres and telomerase in the regulation of lifespan of cells. Telomeres are the stretches of DNA consisting of tandem repeats of nucleotide sequences that cap chromosomes and prevent its degradation and play a role, both in normal control of cell proliferation and abnormal growth of cancers. They are highly conserved during evolution. Telomerase, the novel reverse transcriptase enzyme that synthesizes telomeric DNA is repressed in most human somatic cells, it results in telomere shortening with each cell division, leading to a process thought to contribute to senescence. Recent research proposes that activation of telomerase is important for cells to proliferate indefinitely and that all human cancer cells require activation of this enzyme to maintain telomeric DNA, to overcome cellular senescence and to attain immortality. Thus telomeres and telomerase offer potential for diagnostics, cancer therapy as well as for understanding the process of aging.

Humans↗

[Diagnostic imaging in cancer therapy: the genito-urinary system].

Diagnostic approach of the tumors of the genitourinary system with multiple imaging modalities was described. The way of staging of the diseases was emphasized. Angiography has been used for diagnosis of renal and renal pelvic tumors, but CT and ultrasonography are more useful than angiography for evaluation of the extension of the disease into the perirenal or pararenal space as well as detection of lymph-node metastasis. Invasion into the renal vein or the interior vena cava is also demonstrated by those new modalities. They are also useful for post-operative follow up. For the staging of the bladder tumor, transurethral ultrasonography or CT are useful, as they can detect the extravesical infiltration of the diseases. Bone scintigraphy is more effective in detection of bony metastasis, which is essential for staging of prostatic carcinoma. Although transurethral ultrasonography is more useful in the evaluation of the extension of the prostatic carcinoma, when the extension is advanced CT is better than ultrasonography. CT is also effective for diagnosis of bony metastasis.

Adrenal Gland Neoplasms↗

Rapid diagnostic imaging of cancer using radiolabeled liposomes.

A novel tumor diagnostic imaging method was developed that allows tumor localization soon after administration of radiolabeled liposomes. Although previous studies showed that radiolabeled liposomes can reach various tumors in a short time, their blood clearance is slow, and the high blood background hinders early imaging. Therefore, we attempted to remove actively the liposomes from the circulation using the strong affinity between avidin and biotin. Liposomes that had biotin bound to their surface and were labeled with 111In, 67Ga, or 99mTc were administered to mice bearing sarcoma 180, followed by administration of avidin 2 or 4 h later. Avidin initiated liposomal aggregation, resulting in their rapid removal by the reticuloendothelial system. Consequently, their blood level was markedly reduced without any changes in tumor levels. The tumor-to-blood ratio reached about 13 at only 2.5 h after administration of 99mTc-labeled liposomes, versus 1.0 or less without postadministration of avidin. Increased liver accumulation was also observed, but it decreased gradually with time.

Animals↗

A computerised cancer registry data and validation system in India--its implications for developing countries.

The cancer registration system in India, and an appropriate computer program to validate the cancer patient data it generates, are described, with the resource inputs, and outputs of research, training, awareness creation and cancer control, in the context of local health care systems. Computer packages already available mostly address the type of data obtainable from western health care systems. The same factors that limit health care systems in India, and probably most other developing countries--inadequate health care facilities, skeletal medical records systems, meagre and unavailable vital statistics, few trained staff, funding and computer facilities--also limit the data sent to the National Cancer Registry Programme. The computer program we developed checks for the reliability and validity of various cancer diagnostic, spread, therapeutic and outcome variables. The program is in HIBASIC for a CPM operating system with a minimum of 64 kB memory, adaptable to MS-DOS systems, population-based cancer registry data, and perhaps to other types of chronic disease registries, with relevant modifications. Since reliable cancer registry data are needed for effective cancer control measures, this program may help in such efforts in developing countries.

Computers↗

Parathyroid cancer, a continued diagnostic and therapeutic dilemma: report of four cases and review of the literature.

Parathyroid cancer presents a diagnostic challenge as a rare endocrine malignancy usually not recognized preoperatively and often not conclusively identified intraoperatively. We examined a cluster of parathyroid cancers treated at University of Louisville-affiliated hospitals during a 5-year interval. Clinical and histologic data from patient records at University Surgical Associates, the University of Louisville Hospital, Norton Hospital, and the Louisville Veterans Administration Medical Center in Louisville, KY were retrospectively reviewed. During the study interval surgical exploration of the neck was undertaken on 175 patients with primary hyperparathyroidism; four parathyroid malignancies (2%) were identified. Three of the four patients exhibited symptomatic hyperparathyroidism with very high diagnostic calcium and parathormone levels. All patients had multiple coexisting diseases and two had undergone previous parathyroid surgery. Sestamibi scan localized the lesion in two patients, ultrasound was used in one patient, and a positron emission tomography scan was needed to identify the lesion in the fourth. Intraoperative findings varied from multiple nodules involving the thyroid and paratracheal nodules to otherwise normal-appearing enlarged parathyroid gland. External pathologic review was needed to conclusively establish the diagnosis in all cases, even though initial histologic analysis was suggestive of malignancy. All patients are alive, well, and free of disease. This rarely occurring malignancy may be suggested by very high preoperative calcium parathormone levels. Intraoperative and histologic findings are often inconclusive resulting in therapeutic decisions made by the operating surgeon on the basis of limited or incomplete information.

Frozen Sections↗

Biological markers of human tumors and monitoring of cancer treatment.

The development of human tumors is accompanied very often by tumor-associated phenomena such as production of tumor-derived substances, production of certian substances in response to the tumor or immunological reactions. Up to now no of these phenomena can be used as a diagnostic cancer test but biological markers are increasingly used for monitoring progression and regression of human tumors. Basing on a number of own studies the value of the determination of CEA-serum level and urinary excretion of hydroxyprolin, spermidin and putrescin for monitoring the tumor behaviour particularly during cancer chemotherapy is demonstrated.

Alkaline Phosphatase↗

Evaluation of institutional cancer registries in Colombia.

The four primary objectives of this descriptive study were to: 1) design a quality-measurement instrument for institutional cancer registries (ICRs), 2) evaluate the existing ICRs in Colombia with the designed instrument, 3) categorize the different registries according to their quality and prioritize efforts that will efficiently promote better registries with the limited resources available, and 4) determine the institution with the greatest likelihood of successfully establishing Colombia's second population-based cancer registry. In 1990 the National Cancer Institute of Colombia developed 13 institution-based cancer registries in different Colombian cities in order to promote the collection of data from a large group of cancer diagnostic and treatment centers. During the first half of 1997, this evaluation reviewed 12 registries; one of the original 13 no longer existed. All of the Colombian institutions (hospitals) that maintain institution-based cancer registries were included in the study. At each institution, a brief survey was administered to the hospital director, the registry coordinator, and the registrar (data manager). Researchers investigated the institutions by looking at six domains that are in standard use internationally. Within each domain, questions were developed and selected through the Delphi method. Each domain and each question were assigned weights through a consensus process. In most cases, two interviewers went to each site to collect the information. The university hospitals in Cali, Pereira, and Medellín had substantially higher scores, reflecting a good level of performance. Four of the 12 institutions had almost no cancer registry work going on. Five of the 12 hospital directors considered that the information provided by the cancer registries influenced their administrative decisions. Three of the registries had patient survival data. Four of the institutions allocated specific resources to operate their cancer registries; in the other 8 hospitals there was no clear budget allocation. Seven of the hospital directors could not identify five or more objectives of a cancer registry. Data management was usually poor and resources insufficient at most of the institutions. In summary, the cancer registry system in Colombia varies greatly from institution to institution. A few of the hospitals do a good job while others have neglected the registries. The high, identical total scores for Pereira and Medellín suggest they would be good locations to establish new population-based cancer registries similar to the existing one in Cali. However, the overall characteristics in Pereira may provide a more appropriate environment for the second registry, with Medellín as an alternative.

Colombia↗

Diagnostic tests for lung cancer.

The goals of diagnostic testing in patients with suspected lung cancer are to establish the diagnosis and to determine the stage of the disease so that appropriate therapy can be initiated. Unless a patient has hemoptysis, fever, or a change in cough as an initial manifestation, resectable lung cancer will seldom be diagnosed on the basis of the history. Screening tests--particularly chest roentgenography--have usually identified the abnormality. The managing physician should then select diagnostic procedures that are associated with low risk and that will provide further diagnostic and staging information. A biopsy will almost always be necessary before definitive therapy can be planned. In many cases, a single procedure--for example, a needle biopsy of a hepatic lesion or biopsy of a supraclavicular lymph node--will provide a definitive diagnosis and establish the stage of the disease. The roles of cytology, histopathologic examination, radiologic studies, and various types of biopsy in the diagnosis of lung cancer are reviewed in this report.

Biopsy, Needle↗