Uncontrolled cell proliferation is the hallmark of cancer, and tumor cells have typically acquired damage to genes that directly regulate their cell cycles. Genetic alterations affecting p16(INK4a) and cyclin D1, proteins that govern phosphorylation of the retinoblastoma protein (RB) and control exit from the G1 phase of the cell cycle, are so frequent in human cancers that inactivation of this pathway may well be necessary for tumor development. Like the tumor suppressor protein p53, components of this "RB pathway," although not essential for the cell cycle per se, may participate in checkpoint functions that regulate homeostatic tissue renewal throughout life.

http://science.sciencemag.org/content/sci/274/5293/1672.full.pdf

Cancer Cell Cycles

Objective. —To identify and quantify the major external (nongenetic) factors that contribute to death in the United States. Data Sources. —Articles published between 1977 and 1993 were identified through MEDLINE searches, reference citations, and expert consultation. Government reports and compilations of vital statistics and surveillance data were also obtained. Study Selection. —Sources selected were those that were often cited and those that indicated a quantitative assessment of the relative contributions of various factors to mortality and morbidity. Data Extraction. —Data used were those for which specific methodological assumptions were stated. A table quantifying the contributions of leading factors was constructed using actual counts, generally accepted estimates, and calculated estimates that were developed by summing various individual estimates and correcting to avoid double counting. For the factors of greatest complexity and uncertainty (diet and activity patterns and toxic agents), a conservative approach was taken by choosing the lower boundaries of the various estimates. Data Synthesis. —The most prominent contributors to mortality in the United States in 1990 were tobacco (an estimated 400000 deaths), diet and activity patterns (300 000), alcohol (100 000), microbial agents (90 000), toxic agents (60 000), firearms (35 000), sexual behavior (30 000), motor vehicles (25 000), and illicit use of drugs (20 000). Socioeconomic status and access to medical care are also important contributors, but difficult to quantify independent of the other factors cited. Because the studies reviewed used different approaches to derive estimates, the stated numbers should be viewed as first approximations. Conclusions. —Approximately half of all deaths that occurred in 1990 could be attributed to the factors identified. Although no attempt was made to further quantify the impact of these factors on morbidity and quality of life, the public health burden they impose is considerable and offers guidance for shaping health policy priorities. (JAMA. 1993;270:2207-2212)

https://jamanetwork.com/journals/JAMA/articlepdf/409171/jama_270_18_038.pdf

Actual causes of death in the United States.

Endostatin: an endogenous inhibitor of angiogenesis and tumor growth.

NOTE The report of the Committee without its annexes appears as Official Records of the General Assembly, Sixty-third Session, Supplement No. 46. The designations employed and the presentation of material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the United Nations concerning the legal status of any country, territory, city or area, or of its authorities, or concerning the delimitation of its frontiers or boundaries. The country names used in this document are, in most cases, those that were in use at the time the data were collected or the text prepared. In other cases, however, the names have been updated, where this was possible and appropriate, to reflect political changes. Scientific Annexes Annex A. Medical radiation exposures Annex B. Exposures of the public and workers from various sources of radiation INTROdUCTION 1. In the course of the research and development for and the application of atomic energy and nuclear technologies, a number of radiation accidents have occurred. Some of these accidents have resulted in significant health effects and occasionally in fatal outcomes. The application of technologies that make use of radiation is increasingly widespread around the world. Millions of people have occupations related to the use of radiation, and hundreds of millions of individuals benefit from these uses. Facilities using intense radiation sources for energy production and for purposes such as radiotherapy, sterilization of products, preservation of foodstuffs and gamma radiography require special care in the design and operation of equipment to avoid radiation injury to workers or to the public. Experience has shown that such technology is generally used safely, but on occasion controls have been circumvented and serious radiation accidents have ensued. 2. Reviews of radiation exposures from accidents have been presented in previous UNSCEAR reports. The last report containing an exclusive chapter on exposures from accidents was the UNSCEAR 1993 Report [U6]. 3. This annex is aimed at providing a sound basis for conclusions regarding the number of significant radiation accidents that have occurred, the corresponding levels of radiation exposures and numbers of deaths and injuries, and the general trends for various practices. Its conclusions are to be seen in the context of the Committee's overall evaluations of the levels and effects of exposure to ionizing radiation. 4. The Committee's evaluations of public, occupational and medical diagnostic exposures are mostly concerned with chronic exposures of …

sources and effects of ionizing radiation

Background Cetuximab is effective in platinum-resistant recurrent or metastatic squamous-cell carcinoma of the head and neck. We investigated the efficacy of cetuximab plus platinum-based chemotherapy as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck. Methods We randomly assigned 220 of 442 eligible patients with untreated recurrent or metastatic squamous-cell carcinoma of the head and neck to receive cisplatin (at a dose of 100 mg per square meter of body-surface area on day 1) or carboplatin (at an area under the curve of 5 mg per milliliter per minute, as a 1-hour intravenous infusion on day 1) plus fluorouracil (at a dose of 1000 mg per square meter per day for 4 days) every 3 weeks for a maximum of 6 cycles and 222 patients to receive the same chemotherapy plus cetuximab (at a dose of 400 mg per square meter initially, as a 2-hour intravenous infusion, then 250 mg per square meter, as a 1-hour intravenous infusion per week) for a maximum of 6 cycles. Patients with stable disease who received chemotherapy plus cetuximab continued to receive cetuximab until disease progression or unacceptable toxic effects, whichever occurred first. Results

/pdf/platinum-based-chemotherapy-plus-cetuximab-in-head-and-neck-2c129qnqh9.pdf

Platinum-Based Chemotherapy plus Cetuximab in Head and Neck Cancer

PURPOSE Two clinical characteristics of the metastatic cancer phenotype are virulence-which reflects the pace of disease growth, clinical manifestation, and dissemination-and metastagenicity, the ultimate likelihood of distant metastasis. Molecular markers may allow distinguishing between these two cancer phenotypes. The purpose of this study is to determine whether proliferating cell nuclear antigen (PCNA) and tumor nuclear grade are markers of virulence or metastagenicity. PATIENTS AND METHODS PCNA and tumor nuclear grade were determined in patients with extensive follow-up, treated only with mastectomy, for whom archival paraffin-embedded tissue was available. RESULTS There is no significant difference in long-term disease-free survival (DFS) as a function of PCNA, but after only 5 years of analysis there are significant differences that gradually disappear with further follow-up, reflecting differences in virulence. While the likelihood of recurrence is the same, in patients with high PCNA 80% of disease recurrences become evident in the first 2 to 3 years, whereas in patients with low PCNA it takes more than 10 years for 80% of metastases to become clinically detectable. There was a significant difference in 20-year DFS for nuclear grade 1 compared with nuclear grade 2 and 3 tumors, indicating a difference in metastagenicity. The differences in DFS between nuclear grade 2 and 3 tumors decrease as the length of follow-up increases; thus, like PCNA, these grade differences are also a marker of virulence. Eighty percent of the metastasis became evident within 4 years in grade 3 tumors and within 12 years in grade 2 tumors. DISCUSSION PCNA and nuclear grade (2 vs 3) are markers of virulence. We have previously shown angiogenesis to be a marker of metastagenicity as is, in this study, the difference between nuclear grade 1 and nuclear grades 2 and 3. Both phenotypic characteristics, virulence and metastagenicity, are important to understanding the natural history of the tumors and may influence the nature of the therapy.

Breast cancer metastatic phenotype as predicted by histologic tumor markers.

BACKGROUND

Hormone therapy commonly is used to treat metastatic, locally advanced, and localized prostate carcinoma. The objective of the current investigation was to determine, using the number-needed-to-treat (NNT) method, the effect of using hormone therapy to treat locally advanced disease, with consideration given to both the complications and the known advantages associated with hormone therapy.



METHODS

A literature review was performed to determine 1) the absolute benefit, based on available clinical endpoints, associated with the addition of hormone therapy to external beam radiotherapy for locally advanced prostate carcinoma; 2) the incidence of side effects of short-term and long-term hormone therapy; and 3) the stepwise progression from biochemical failure to death. A model was constructed to estimate the complication/utility-adjusted survival detriment resulting from the side effects of short-term (≤ 6 months) and long-term (> 6 months) hormone therapy, and the absolute/unadjusted and complication-adjusted NNTs for the addition of short-term and long-term hormone therapy were computed. In all cases, the magnitudes and signs of the NNTs obtained were used to gauge the effect of hormone therapy.



RESULTS

The unadjusted NNTs were positive and in most cases had relatively small magnitudes (the greater the NNT, the smaller the benefit) for both short-term and long-term hormone therapy; these results were expected, and they suggested that there is a strong benefit associated with the use of hormones adjuvant to radiotherapy for locally advanced disease. Adjusted NNTs remained positive and had relatively small magnitudes even after the introduction into the analysis of complications of short-term and long-term hormone therapy. This finding, although weak with respect to the effect of short-term hormone therapy on cause-specific survival, remained robust over the range of values for utility impairment expected from short-term and long-term hormone therapy.



CONCLUSIONS

The benefits of short-term and long-term hormone therapy for locally advanced prostate carcinoma appear to be significant and to outweigh the associated side effects. Long-term therapy appears to be better than short-term therapy in terms of virtually all endpoints studied, even when the increased incidence of side effects is considered. The current investigation was successful in the use of the complication-adjusted NNT method for oncologic and radiotherapeutic scenarios in which the results of randomized trials could be summarized, adjusted for treatment toxicity, and individualized to a given patient. Cancer 2003. © 2003 American Cancer Society.

Hormone therapy adjuvant to external beam radiotherapy for locally advanced prostate carcinoma: a complication-adjusted number-needed-to-treat analysis.

Recent discoveries indicate that hematopoietic stem cells have limits on their proliferative capacity and are unable to divide indefinitely. There is great heterogeneity within the compartment as to the extent of this proliferative limitation. At any given time it appears that hematopoiesis is maintained by the progeny of only a few stem cells. When these are exhausted the progeny from other stem cells take their place. The observations of proliferative limitation, heterogeneity, and clonal succession must be incorporated into any model of stem cell organization. These new discoveries and the models incorporating them have important clinical implications. They may explain the inability of normal tissues to develop drug resistance and they also offer a mechanism by which cell renewal systems decrease the development of malignancies. In the selection of chemotherapeutic agents not only the effectiveness of the drug upon the tumor must be considered, but also how specific agents affect the stem cell compartment. These data have important implications in the use of bone marrow transplantation for both malignant and nonmalignant disease.

Functional organization of the hematopoietic stem cell compartment: implications for cancer and its therapy.

The success of bone marrow transplantation depends not only on the engraftment of adequate numbers of hematopoietic stem cells but also on their self-renewal capacity, which must be sufficient to provide lifetime hematopoiesis. The lectin peanut agglutinin (PNA), when exposed to bone marrow, causes separation into two distinct fractions. The agglutinated fraction not only is enriched with colony-forming units--spleen but also is devoid of graft-versus-host (GVH) activity when injected into allogeneic lethally irradiated recipients, and therefore, it is considered to be an ideal source for bone marrow transplantation. The absence of GVH activity is presumably due to the separation of mature thymocytes into the nonagglutinated fraction and functionally immature thymocytes into the agglutinated fraction. Although there has been speculation that immature hematopoietic stem cells also selectively bind to PNA, other evidence suggests that the relationship of lectin binding specificity to level of maturity varies in different tissues. This study was performed to assess the self-renewal capacity of lectin-separated bone marrow stem cells. Results indicate that the self-renewal of the agglutinated fraction is significantly lower than that of the unfractionated bone marrow; such self-renewal of the nonagglutinated fraction is higher. This is further evidence for the heterogeneity of the stem cell pool. Stem cell enrichment should not be the goal in bone marrow transplantation; rather, the goal should be utilization of stem cells with the greatest self-renewal potential.

Samuel Hellman

Papers

Breast cancer metastatic phenotype as predicted by histologic tumor markers.

Hormone therapy adjuvant to external beam radiotherapy for locally advanced prostate carcinoma: a complication-adjusted number-needed-to-treat analysis.

Functional organization of the hematopoietic stem cell compartment: implications for cancer and its therapy.

Differing Stem Cell Self-Renewal of Lectin-Separated Murine Bone Marrow Fractions

Important Advances in Oncology: 1994