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

Distant metastases are the major cause of morbidity and mortality in women with breast cancer. The prediction of this metastatic proclivity is essential in determining prognosis and should allow an appropriate choice of therapy. A critical look at the metastatic process and its phenotypic expression offers an opportunity to identify some of the important events in the process that may relate to prognosis, with the goal of identifying those patients with occult metastases and also sparing systemic treatment in those patients whose tumors have not developed the capacity for distant spread. To evaluate the significance of nm23 and angiogenesis in the metastatic cascade, we used archival material from 163 node-negative breast cancer patients who had a median follow-up of 14 years. All patients underwent mastectomy and received no adjuvant chemotherapy or hormone or radiation therapy. Immunohistochemistry was used to detect nm23-H1 expression, whereas angiogenesis was determined by microvessel count (MVC). We found the 15-year disease-free survival (DFS) to be significantly better in patients with high nm23 compared with low nm23 (91% compared with 70%, P = 0.008). Low MVC is associated with excellent (92%) long-term DFS. In those patients with high MVC, high nm23 allows the identification of a subgroup with significantly higher DFS (90% compared with 66%, P = 0.02). Among high nuclear grade tumors, if nm23 is high, the DFS is significantly better (89% compared with 68%, P = 0.03). Thus, nm23 is still associated with excellent survival, even when there is unfavorable angiogenesis or nuclear grade. Multivariate analysis confirms that nm23 and MVC are important prognostic factors. High MVC appears necessary but not sufficient for metastasis to occur, whereas low nm23 may further contribute to metastatic progression. Both nm23 and MVC contribute valuable information in characterizing the malignant phenotype.

/pdf/the-relationship-between-nm23-angiogenesis-and-the-3wgwgojiop.pdf

The Relationship between nm23, Angiogenesis, and the Metastatic Proclivity of Node-negative Breast Cancer

The role of radiation therapy in the primary treatment of carcinoma of the breast.

The clinical significance of anatomic substage was reassessed in a previously reported series of 130 patients with Hodgkin's disease in pathologic stage IIIA. For 100 patients, followup was greater than 8 years. By definition, stage III1 disease includes involvement of spleen or splenic, celiac, or portal nodes, or any combination of these; stage III2 disease includes involvement of para-aortic, iliac, or mesenteric nodes, with or without upper abdominal involvement. Both 8-year relapse-free survival (71% versus 40%) and 8-year overall survival (80% versus 54%) were better in stage III1A than in III2A patients (P less than 0.001). For stage III1A, relapse-free survival was better in patients receiving radiotherapy alone as initial treatment (92% versus 60%, P less than 0.002). However, 8 year overall survival rates in these two treatment groups were not significantly different (88% versus 76%, P = 0.20). For stage III2A, both relapse-free survival at 8 years (84% versus 19%, P less than 0.001) and overall survival at 8 years (84% versus 41%, P less than 0.01) were superior in patients receiving combined modality therapy. Anatomic substage is a critical prognostic variable, especially if standard total nodal radiotherapy is considered as one of the therapeutic options.

Anatomic substages of stage IIIA Hodgkin's disease: followup of a collaborative study.

Diagnostic improvements and earlier detection of tumors have resulted in the emergence of a shift from Halsted paradigm, which has encouraged the use of systemic adjuvant therapy. With these changes in tumor paradigm, the rationale for local treatment as a curative treatment strategy has been challenged. This Viewpoint emphasizes the importance of local control in this scenario.

Importance of local control in an era of systemic therapy.

The presence of large mediastinal involvement in patients with pathologically staged supradiaphragmatic Hodgkin’s disease has been associated with an increased risk of relapse as compared to patients with lesser or no mediastinal disease. In one study 50’5 of such patients have relapsed following initial treatment with radiation therapy compared with a relapse free survival of 92% in patients with lesser or no mediastinal disease.’ Characteristically, the majority of relapses have been intrathoracic and three separate patterns of relapse have been described: mediastinal recurrences within the treated voIume,7,‘J recurrences at the margin of the treated field,h and diffuse pulmonary rclapses.4~9 In addition there arc other special problems that must be considered in devising initial evaluation and treatment of patients with large mediastinal disease. There are potential risks associated with the use of radiation therapy and with the use of MOPP chemotherapy.” ” There may be a significant anesthesia risk in patients with large diameter intrathoracic involvement who undergo initial surgical staging.” The potential side clfects of each treatment modality. the risk of relapse with the USC of that modality, and the survival of patients once relapse occurs must be considered in proposing initial trcatmcnt for these patients. Whcthcr the risk of true infield mediastinal recurrence following radiation therapy is related to the initial dose to the mcdiastinum is unknown. However, Carmel and Kaplan have rcportcd that patients with large mediastinal disease whose mantle treatments were prolonged over 34 days had a higher risk of intrathoracic relapse than patients with Icss prolonged treatment.’ As mantle irradiation in such patients is often prolonged to allow for shrinkage of nodes and blockage of normal heart and lung. perhaps additional irradiation to the anterior mcdiastinum through angled lields following completion of the full mantle treatment would help in preventing

Samuel Hellman

Papers

The Relationship between nm23, Angiogenesis, and the Metastatic Proclivity of Node-negative Breast Cancer

The role of radiation therapy in the primary treatment of carcinoma of the breast.

Anatomic substages of stage IIIA Hodgkin's disease: followup of a collaborative study.

Importance of local control in an era of systemic therapy.

Supradiaphragmatic Hodgkin's disease: is there a role for MOPP chemotherapy in patients with bulky mediastinal disease?