BREAST CANCER

Breast cancer is a cancer that starts in the cells of the breast. Worldwide, breast cancer is the second most common type of cancer (10.4%; after lung cancer) and the fifth most common cause of cancer death (after lung cancer, stomach cancer, liver cancer, and colon cancer). Among women worldwide, breast cancer is the most common cause of cancer death. In 2005, breast cancer caused 502,000 deaths worldwide (7% of cancer deaths; almost 1% of all deaths). The number of cases worldwide has significantly increased since the 1970s, a phenomenon partly blamed on modern lifestyles in the Western world.

North American women have the highest incidence of breast cancer in the world. Among women in the U.S., breast cancer is the most common cancer and the second-most common cause of cancer death (after lung cancer). Women in the U.S. have a 1 in 8 (12.5%) lifetime chance of developing invasive breast cancer and a 1 in 35 (3%) chance of breast cancer causing their death. In 2007, breast cancer was expected to cause 40,910 deaths in the U.S. (7% of cancer deaths; almost 2% of all deaths).

In the U.S., both incidence and death rates for breast cancer have been declining in the last few years. Nevertheless, a U.S. study conducted in 2005 by the Society for Women's Health Research indicated that breast cancer remains the most feared disease, even though heart disease is a much more common cause of death among women.

Because the breast is composed of identical tissues in males and females, breast cancer also occurs in males. Incidences of breast cancer in men are approximately 100 times less common than in women, but men with breast cancer are considered to have the same statistical survival rates as women.

Breast cancers are described along four different classification schemes, or groups, each based on different criteria and serving a different purpose :

* Pathology - A pathologist will categorize each tumor based on its histological (microscopic anatomy) appearance and other criteria. The most common pathologic types of breast cancer are invasive ductal carcinoma, malignant cancer in the breast's ducts, and invasive lobular carcinoma, malignant cancer in the breast's lobules.
* Grade of tumor - The histological grade of a tumor is determined by a pathologist under a microscope. A well-differentiated (low grade) tumor resembles normal tissue. A poorly differentiated (high grade) tumor is composed of disorganized cells and, therefore, does not look like normal tissue. Moderately differentiated (intermediate grade) tumors are somewhere in between.
* Protein & gene expression status - Currently, all breast cancers should be tested for expression, or detectable effect, of the estrogen receptor (ER), progesterone receptor (PR) and HER2/neu proteins. These tests are usually done by immunohistochemistry and are presented in a pathologist's report. The profile of expression of a given tumor helps predict its prognosis, or outlook, and helps an oncologist choose the most appropriate treatment. More genes and/or proteins may be tested in the future.
* Stage of a tumour - The currently accepted staging scheme for breast cancer is the TNM classification :
o Tumor - There are five tumor classification values (Tis, T1, T2, T3 or T4) which depend on the presence or absence of invasive cancer, the dimensions of the invasive cancer, and the presence or absence of invasion outside of the breast (e.g. to the skin of the breast, to the muscle or to the rib cage underneath).
o Lymph Node - There are four lymph node classification values (N0, N1, N2 or N3) which depend on the number, size and location of breast cancer cell deposits in lymph nodes.
o Metastases - There are two metastatic classification values (M0 or M1) which depend on the presence or absence of breast cancer cells in locations other than the breast and lymph nodes (so-called distant metastases, e.g. to bone, brain, lung).

Early breast cancer can in some cases present as breast pain (mastodynia) or a painful lump. Since the advent of breast mammography, breast cancer is most frequently discovered as an asymptomatic nodule on a mammogram, before any symptoms are present. A lump under the arm or above the collarbone that does not go away may be present.

When breast cancer has invaded the dermal lymphatics - small lymph vessels of the skin, its presentation can resemble skin inflammation and thus is known as inflammatory breast cancer. In inflammatory breast cancer, the breast cancer is blocking lymphatic vessels and this can cause pain, swelling, warmth, and redness throughout the breast, as well as an orange peel texture to the skin referred to as peau d'orange. Although there may have been no previous signs of breast cancer and the cancer might be missed in screening mamograms, Inflammatory Breast Cancer is at least locally advanced at presentation (LABC) and Stage IIIB. Immediate staging tests are required to rule out distant metastes which might already be present making it Stage IV.

Changes in the appearance or shape of the breast can raise suspicions of breast cancer.

Another reported symptom complex of breast cancer is Paget's disease of the breast. This syndrome presents as eczematoid skin changes at the nipple, and is a late manifestation of an underlying breast cancer.

Most breast symptoms do not turn out to represent underlying breast cancer. Benign breast diseases such as fibrocystic mastopathy, mastitis, functional mastodynia, and fibroadenoma of the breast are more common causes of breast symptoms. The appearance of a new breast symptom should be taken seriously by both patients and their doctors, because of the possibility of an underlying breast cancer at almost any age.

Occasionally, breast cancer presents as metastatic disease, that is, cancer that has spread beyond the original organ. Metastatic breast cancer will cause symptoms that depend on the location of metastasis. More common sites of metastasis include bone, liver, lung, and brain. Unexplained weight loss can occasionally herald an occult breast cancer, as can symptoms of fevers or chills. Bone or joint pains can sometimes be manifestations of metastatic breast cancer, as can jaundice or neurological symptoms. Pleural effusions are not uncommon with metastatic breast cancer. Obviously, these symptoms are "non-specific," meaning they can also be manifestations of many other illnesses.

Epidemiological risk factors for a disease can provide important clues as to the etiology of a disease. The first work on breast cancer epidemiology was done by Janet Lane-Claypon, who published a comparative study in 1926 of 500 breast cancer cases and 500 control patients of the same background and lifestyle for the British Ministry of Health.

Today, breast cancer, like other forms of cancer, is considered to be the final outcome of multiple environmental and hereditary factors.

1. Lesions to DNA such as genetic mutations. Exposure to estrogen has been experimentally linked to the mutations that cause breast cancer. Beyond the contribution of estrogen, research has implicated viral oncogenesis and the contribution of ionizing radiation.
2. Failure of immune surveillance, which usually removes malignancies at early phases of their natural history.
3. Abnormal growth factor signaling in the interaction between stromal cells and epithelial cells, for example in the angiogenesis necessary to promote new blood vessel growth near new cancers.
4. Inherited defects in DNA repair genes, such as BRCA1, BRCA2 and p53.

Although many epidemiological risk factors have been identified, the cause of any individual breast cancer is often unknowable. In other words, epidemiological research informs the patterns of breast cancer incidence across certain populations, but not in a given individual. The primary risk factors that have been identified are sex, age, childbearing, hormones, a high-fat diet, alcohol intake, obesity, and environmental factors such as tobacco use and radiation.

No etiology is known for 95% of breast cancer cases, while approximately 5% of new breast cancers are attributable to hereditary syndromes. In particular, carriers of the breast cancer susceptibility genes, BRCA1 and BRCA2, are at a 30-40% increased risk for breast and ovarian cancer, depending on in which portion of the protein the mutation occurs.

Studies have found that "folate intake counteracts breast cancer risk associated with alcohol consumption" and "women who drink alcohol and have a high folate intake are not at increased risk of cancer." A prospective study of over 17,000 women found that those who consume 40 grams of alcohol (about 3-4 drinks) per day have a higher risk of breast cancer. However, in women who take 200 micrograms of folate (folic acid or Vitamin B9) every day, the risk of breast cancer drops below that of alcohol abstainers.

Folate is involved in the synthesis, repair, and functioning of DNA, the body’s genetic map, and a deficiency of folate may result in damage to DNA that may lead to cancer. In addition to breast cancer, studies have also associated diets low in folate with increased risk of pancreatic, and colon cancer.

Foods rich in folate include citrus fruits, citrus juices, dark green leafy vegetables (such as spinach), dried beans, and peas. Vitamin B9 can also be taken in a multivitamin pill.

Breast cancer is diagnosed by the examination of surgically removed breast tissue. A number of procedures can obtain tissue or cells prior to definitive treatment for histological or cytological examination. Such procedures include fine-needle aspiration, nipple aspirates, ductal lavage, core needle biopsy, and local surgical excision. These diagnostic steps, when coupled with radiographic imaging, are usually accurate in diagnosing a breast lesion as cancer. Occasionally, pre-surgical procedures such as fine needle aspirate may not yield enough tissue to make a diagnosis, or may miss the cancer entirely. Imaging tests are sometimes used to detect metastasis and include chest X-ray, bone scan, Cat scan, MRI, and PET scanning. While imaging studies are useful in determining the presence of metastatic disease, they are not in and of themselves diagnostic of cancer. Only microscopic evaluation of a biopsy specimen can yield a cancer diagnosis. Ca 15.3 (carbohydrate antigen 15.3, epithelial mucin) is a tumor marker determined in blood which can be used to follow disease activity over time after definitive treatment. Blood tumor marker testing is not routinely performed for the screening of breast cancer, and has poor performance characteristics for this purpose.

Breast cancer is staged according to the TNM system, updated in the AJCC Staging Manual, now on its sixth edition. Prognosis is closely linked to results of staging, and staging is also used to allocate patients to treatments both in clinical trials and clinical practice. The information for staging is as follows:

TX: Primary tumor cannot be assessed. T0: No evidence of tumor. Tis: Carcinoma in situ, no invasion T1: Tumor is 2 cm or less T2: Tumor is more than 2 cm but not more than 5 cm T3: Tumor is more than 5 cm T4: Tumor of any size growing into the chest wall or skin, or inflammatory breast cancer

NX: Nearby lymph nodes cannot be assessed N0: Cancer has not spread to regional lymph nodes. N1: Cancer has spread to 1 to 3 axillary or one internal mammary lymph node N2: Cancer has spread to 4 to 9 axillary lymph nodes or multiple internal mammary lymph nodes N3: One of the following applies:

Cancer has spread to 10 or more axillary lymph nodes, or Cancer has spread to the lymph nodes under the clavicle (collar bone), or Cancer has spread to the lymph nodes above the clavicle, or Cancer involves axillary lymph nodes and has enlarged the internal mammary lymph nodes, or Cancer involves 4 or more axillary lymph nodes, and tiny amounts of cancer are found in internal mammary lymph nodes on sentinel lymph node biopsy.

MX: Presence of distant spread (metastasis) cannot be assessed. M0: No distant spread. M1: Spread to distant organs, not including the supraclavicular lymph node, has occurred

Summary of stages:

* Stage 0 - Carcinoma in situ
* Stage I - Tumor (T) does not involve axillary lymph nodes (N).
* Stage IIA – T 2-5 cm, N negative, or T <2 cm and N positive.
* Stage IIB – T > 5 cm, N negative, or T 2-5 cm and N positive (< 4 axillary nodes).
* Stage IIIA – T > 5 cm, N positive, or T 2-5 cm with 4 or more axillary nodes
* Stage IIIB – T has penetrated chest wall or skin, and may have spread to < 10 axillary N
* Stage IIIC – T has > 10 axillary N, 1 or more supraclavicular or infraclavicular N, or internal mammary N.
* Stage IV – Distant metastasis (M)

Breast lesions are examined for certain markers, notably sex steroid hormone receptors. About two thirds of postmenopausal breast cancers are estrogen receptor positive (ER+) and progesterone receptor positive (PR+).[74] Receptor status modifies the treatment as, for instance, only ER-positive tumors, not ER-negative tumors, are sensitive to hormonal therapy.

The breast cancer is also usually tested for the presence of human epidermal growth factor receptor 2, a protein also known as HER2, neu or erbB2. HER2 is a cell-surface protein involved in cell development. In normal cells, HER2 controls aspects of cell growth and division. When activated in cancer cells, HER2 accelerates tumor formation. About 20-30% of breast cancers overexpress HER2. Those patients may be candidates for the drug trastuzumab, both in the postsurgical setting (so-called "adjuvant" therapy), and in the metastatic setting.

The mainstay of breast cancer treatment is surgery when the tumor is localized, with possible adjuvant hormonal therapy (with tamoxifen or an aromatase inhibitor), chemotherapy, and/or radiotherapy. At present, the treatment recommendations after surgery (adjuvant therapy) follow a pattern. This pattern is subject to change, as every two years, a worldwide conference takes place in St. Gallen, Switzerland, to discuss the actual results of worldwide multi-center studies. Depending on clinical criteria (age, type of cancer, size, metastasis) patients are roughly divided to high risk and low risk cases, with each risk category following different rules for therapy. Treatment possibilities include radiation therapy, chemotherapy, hormone therapy, and immune therapy.

In planning treatment, doctors can also use PCR tests like Oncotype DX or microarray tests like MammaPrint that predict breast cancer recurrence risk based on gene expression. In February 2007, the MammaPrint test became the first breast cancer predictor to win formal approval from the Food and Drug Administration. This is a new gene test to help predict whether women with early-stage breast cancer will relapse in 5 or 10 years, this could help influence how aggressively the initial tumor is treated.

A prognosis is the medical team's "best guess" in how cancer will affect a patient. There are many prognostic factors associated with breast cancer: staging, tumour size and location, grade, whether disease is systemic (has metastasized, or traveled to other parts of the body), recurrence of the disease, and age of patient.

Stage is the most important, as it takes into consideration size, local involvement, lymph node status and whether metastatic disease is present. The higher the stage at diagnosis, the worse the prognosis. Larger tumours, invasiveness of disease to lymph nodes, chest wall, skin or beyond, and aggressiveness of the cancer cells raise the stage, while smaller tumours, cancer-free zones, and close to normal cell behaviour (grading) lower it.

Grading is based on how cultured biopsied cells behave. The closer to normal cancer cells are, the slower their growth and a better prognosis. If cells are not well differentiated, they appear immature, divide more rapidly, and tend to spread. Well differentiated is given a grade of 1, moderate is grade 2, while poor or undifferentiated is given a higher grade of 3 or 4 (depending upon the scale used).

Younger women tend to have a poorer prognosis than post-menopausal women due to several factors. Their breasts are active with their cycles, they may be nursing infants, and may be unaware of changes in their breasts. Therefore, younger women are usually at a more advanced stage when diagnosed.

The presence of estrogen and progesterone receptors in the cancer cell, while not prognostic, is important in guiding treatment. Those who do not test positive for these specific receptors will not respond to hormone therapy.

Likewise, HER2/neu status directs the course of treatment. Patients whose cancer cells are positive for HER2/neu have more aggressive disease and may be treated with trastuzumab, a monoclonal antibody that targets this protein.

Breast cancer may be one of the oldest known forms of cancer tumors in humans. The oldest description of cancer was discovered in Egypt and dates back to approximately 1600 BC. The Edwin Smith Papyrus describes 8 cases of tumors or ulcers of the breast that were treated by cauterization.The writing says about the disease, "There is no treatment." For centuries, physicians described similar cases in their practises, with the same sad conclusion. It wasn't until doctors achieved greater understanding of the circulatory system in the 17th century that they could establish a link between breast cancer and the lymph nodes in the armpit. The French surgeon Jean Louis Petit (1674-1750) and later the Scottish surgeon Benjamin Bell (1749-1806) were the first to remove the lymph nodes, breast tissue, and underlying chest muscle. Their successful work was carried on by William Stewart Halsted who started performing mastectomies in 1882. He became known for his Halsted radical mastectomy, a surgical procedure that remained popular up to the 1970s.

ATOMIC BOMB - A STRIKE FROM A FAR

The atomic bombings of Hiroshima and Nagasaki were nuclear attacks during World War II against the Empire of Japan by the United States of America at the order of U.S. President Harry S. Truman. After six months of intense firebombing of 67 other Japanese cities, the nuclear weapon "Little Boy" was dropped on the city of Hiroshima on August 6, 1945, followed on August 9, 1945 by the detonation of the "Fat Man" nuclear bomb over Nagasaki. These are to date the only attacks with nuclear weapons in the history of warfare.

The bombs killed as many as 140,000 people in Hiroshima and 80,000 in Nagasaki by the end of 1945, roughly half on the days of the bombings. Since then, thousands more have died from injuries or illness attributed to exposure to radiation released by the bombs. In both cities, the overwhelming majority of the dead were civilians.

Six days after the detonation over Nagasaki, on August 15, Japan announced its surrender to the Allied Powers, signing the Instrument of Surrender on September 2, officially ending the Pacific War and therefore World War II. (Germany had signed its Instrument of Surrender on May 7, 1945, ending the war in Europe.) The bombings led post-war Japan to adopt Three Non-Nuclear Principles, forbidding that nation from nuclear armament.

The United States, with assistance from the United Kingdom and Canada,[4] designed and built the first atomic bombs under what was called the Manhattan Project. The scientific research was directed by the American physicist, J. Robert Oppenheimer. The Hiroshima bomb, a gun-type bomb called "Little Boy", was made with uranium-235, a rare isotope of uranium. The engineers were confident in the design, so it was not tested. The atomic bomb was first tested at Trinity Site, on July 16, 1945, near Alamogordo, New Mexico. The test weapon, "the gadget," and the Nagasaki bomb, "Fat Man", were both implosion-type devices made primarily of plutonium-239, a synthetic element.

The Target Committee at Los Alamos on May 10–11, 1945, recommended Kyoto, Hiroshima, Yokohama, and the arsenal at Kokura as possible targets. The committee rejected the use of the weapon against a strictly military objective because of the chance of missing a small target not surrounded by a larger urban area. The psychological effects on Japan were of great importance to the committee members. They also agreed that the initial use of the weapon should be sufficiently spectacular for its importance to be internationally recognized. The committee felt Kyoto, as an intellectual center of Japan, had a population "better able to appreciate the significance of the weapon." Hiroshima was chosen because of its large size, its being "an important army depot" and the potential that the bomb would cause greater destruction because the city was surrounded by hills which would have a "focusing effect".

Secretary of War Henry L. Stimson struck Kyoto from the list because of its cultural significance, over the objections of General Leslie Groves, head of the Manhattan Project. According to Professor Edwin O. Reischauer, Stimson "had known and admired Kyoto ever since his honeymoon there several decades earlier." On July 25 General Carl Spaatz was ordered to bomb one of the targets: Hiroshima, Kokura, Niigata, or Nagasaki as soon after August 3 as weather permitted and the remaining cities as additional weapons became available.

On July 26, Truman and other allied leaders issued The Potsdam Declaration outlining terms of surrender for Japan. It was presented as an ultimatum and stated that without a surrender, the Allies would attack Japan, resulting in "the inevitable and complete destruction of the Japanese armed forces and just as inevitably the utter devastation of the Japanese homeland" but the atomic bomb was not mentioned. On July 28, Japanese papers reported that the declaration had been rejected by the Japanese government. That afternoon, Prime Minister Kantaro Suzuki declared at a press conference that the Potsdam Declaration was no more than a rehash (yakinaoshi) of the Cairo Declaration and that the government intended to ignore it (mokusatsu).[8] The statement was taken by both Japanese and foreign papers as a clear rejection of the declaration. Emperor Hirohito, who was waiting for a Soviet reply to noncommittal Japanese peace feelers, made no move to change the government position. On July 31, he made clear to Kido that the Imperial Regalia of Japan had to be defended at all costs.

In early July, on his way to Potsdam, Truman had re-examined the decision to use the bomb. In the end, Truman made the decision to drop the atomic bombs on Japan. His stated intention in ordering the bombings was to bring about a quick resolution of the war by inflicting destruction, and instilling fear of further destruction, that was sufficient to cause Japan to surrender.

At the time of its bombing, Hiroshima was a city of some industrial and military significance. A number of military camps were located nearby, including the headquarters of the Fifth Division and Field Marshal Shunroku Hata's 2nd General Army Headquarters, which commanded the defense of all of southern Japan. Hiroshima was a minor supply and logistics base for the Japanese military. The city was a communications center, a storage point, and an assembly area for troops. It was one of several Japanese cities left deliberately untouched by American bombing, allowing a pristine environment to measure the damage caused by the atomic bomb. Another account stresses that after General Spaatz reported that Hiroshima was the only targeted city without prisoner of war (POW) camps, Washington decided to assign it highest priority.

The center of the city contained several reinforced concrete buildings and lighter structures. Outside the center, the area was congested by a dense collection of small wooden workshops set among Japanese houses. A few larger industrial plants lay near the outskirts of the city. The houses were of wooden construction with tile roofs, and many of the industrial buildings also were of wood frame construction. The city as a whole was highly susceptible to fire damage.

The population of Hiroshima had reached a peak of over 381,000 earlier in the war, but prior to the atomic bombing the population had steadily decreased because of a systematic evacuation ordered by the Japanese government. At the time of the attack the population was approximately 255,000. This figure is based on the registered population used by the Japanese in computing ration quantities, and the estimates of additional workers and troops who were brought into the city may be inaccurate.

Hiroshima was the primary target of the first nuclear bombing mission on August 6, with Kokura and Nagasaki being alternative targets. August 6 was chosen because there had previously been cloud cover over the target. The B-29 Enola Gay, piloted and commanded by 509th Composite Group commander Colonel Paul Tibbets, was launched from North Field airbase on Tinian in the West Pacific, about six hours flight time from Japan. The Enola Gay (named after Colonel Tibbets' mother) was accompanied by two other B29s, The Great Artiste which carried instrumentation, commanded by Major Charles W. Sweeney, and a then-nameless aircraft later called Necessary Evil commanded by Captain George Marquardt.

After leaving Tinian the aircraft made their way separately to Iwo Jima where they rendezvoused at 2440 m (8000 ft) and set course for Japan. The aircraft arrived over the target in clear visibility at 9855 m (32,000 ft). On the journey, Navy Captain William Parsons had armed the bomb, which had been left unarmed to minimize the risks during takeoff. His assistant, 2nd Lt. Morris Jeppson, removed the safety devices 30 minutes before reaching the target area.

The release at 08:15 (Hiroshima time) was uneventful, and the gravity bomb known as "Little Boy", a gun-type fission weapon with 60 kg (130 pounds) of uranium-235, took 57 seconds to fall from the aircraft to the predetermined detonation height about 600 meters (1,900 ft) above the city. It created a blast equivalent to about 13 kilotons of TNT. (The U-235 weapon was considered very inefficient, with only 1.38% of its material fissioning.) The radius of total destruction was about 1.6 km (1 mile), with resulting fires across 11.4 km² (4.4 square miles). Infrastructure damage was estimated at 90 percent of Hiroshima's buildings being either damaged or completely destroyed.

About an hour before the bombing, Japanese early warning radar detected the approach of some American aircraft headed for the southern part of Japan. An alert was given and radio broadcasting stopped in many cities, among them Hiroshima. At nearly 08:00, the radar operator in Hiroshima determined that the number of planes coming in was very small—probably not more than three—and the air raid alert was lifted. To conserve fuel and aircraft, the Japanese had decided not to intercept small formations. The normal radio broadcast warning was given to the people that it might be advisable to go to air-raid shelters if B-29s were actually sighted, but no raid was expected beyond some sort of reconnaissance.

The Tokyo control operator of the Japanese Broadcasting Corporation noticed that the Hiroshima station had gone off the air. He tried to re-establish his program by using another telephone line, but it too had failed. About twenty minutes later the Tokyo railroad telegraph center realized that the main line telegraph had stopped working just north of Hiroshima. From some small railway stops within 16 kilometers (10 mi) of the city came unofficial and confused reports of a terrible explosion in Hiroshima. All these reports were transmitted to the headquarters of the Japanese General Staff.

Military bases repeatedly tried to call the Army Control Station in Hiroshima. The complete silence from that city puzzled the men at headquarters; they knew that no large enemy raid had occurred and that no sizable store of explosives was in Hiroshima at that time. A young officer of the Japanese General Staff was instructed to fly immediately to Hiroshima, to land, survey the damage, and return to Tokyo with reliable information for the staff. It was generally felt at headquarters that nothing serious had taken place and that it was all a rumor.

The staff officer went to the airport and took off for the southwest. After flying for about three hours, while still nearly 100 miles (160 km) from Hiroshima, he and his pilot saw a great cloud of smoke from the bomb. In the bright afternoon, the remains of Hiroshima were burning. Their plane soon reached the city, around which they circled in disbelief. A great scar on the land still burning and covered by a heavy cloud of smoke was all that was left. They landed south of the city, and the staff officer, after reporting to Tokyo, immediately began to organize relief measures.

Tokyo's first knowledge of what had really caused the disaster came from the White House public announcement in Washington, D.C., sixteen hours after the nuclear attack on Hiroshima.

By August 8, 1945, newspapers in the US were reporting that broadcasts from Radio Tokyo had described the destruction observed in Hiroshima. "Practically all living things, human and animal, were literally seared to death," Japanese radio announcers said in a broadcast captured by Allied sources.

According to most estimates, the bombing of Hiroshima killed approximately 70,000 people due to immediate effects of the blast. Estimates of total deaths by the end of 1945 range from 90,000 to 140,000, due to burns, radiation and related disease, aggravated by lack of medical resources. Some estimates state up to 200,000 had died by 1950, due to cancer and other long-term effects. From 1950 to 1990, roughly 9% of the cancer and leukemia deaths among bomb survivors was due to radiation from the bombs. At least eleven known prisoners of war died from the bombing.

Some of the reinforced concrete buildings in Hiroshima were very strongly constructed because of the earthquake danger in Japan, and their framework did not collapse even though they were fairly close to the center of damage in the city. Akiko Takakura was among the closest survivors to the hypocenter of the blast. She had been in the strongly built Bank of Hiroshima only 300m from ground-zero at the time of the attack. Since the bomb detonated in the air, the blast was more downward than sideways, which was largely responsible for the survival of the Prefectural Industrial Promotional Hall, now commonly known as the Genbaku, or A-bomb Dome designed and built by the Czech architect Jan Letzel, which was only 150 meters (490 feet) from ground zero (the hypocenter). The ruin was named Hiroshima Peace Memorial and made a UNESCO World Heritage site in 1996 over the objections of the U.S. and China.

After the Hiroshima bombing, President Truman announced, "If they do not not accept our terms, they may expect a rain of ruin from the air the likes of which has never been seen on this earth." On August 8, 1945, leaflets were dropped and warnings were given to Japan by Radio Saipan. (The area of Nagasaki did not receive warning leaflets until August 10, though the leaflet campaign covering the whole country was over a month into its operations.)

The Japanese government still did not react to the Potsdam Declaration. Emperor Hirohito, the government and the War council were considering four conditions for surrender: the preservation of the kokutai (Imperial institution and national polity), assumption by the Imperial Headquarters of responsibility for disarmament and demobilization, no occupation, and delegation to the Japanese government of the punishment of war criminals.

The Soviet Foreign Minister Molotov informed Tokyo of the Soviet Union's unilateral abrogation of the Soviet-Japanese Neutrality Pact on April 5. At two minutes past midnight on August 9, Tokyo time, Soviet infantry, armor, and air forces launched an invasion of Manchuria. Four hours later, word reached Tokyo that the Soviet Union had declared war on Japan. The senior leadership of the Japanese Army began preparations to impose martial law on the nation, with the support of Minister of War Korechika Anami, in order to stop anyone attempting to make peace.

Responsibility for the timing of the second bombing was delegated to Colonel Tibbets as commander of the 509th Composite Group on Tinian. Scheduled for August 11 against Kokura, the raid was moved forward to avoid a five day period of bad weather forecast to begin on August 10. Three bomb pre-assemblies had been transported to Tinian, labeled F-31, F-32, and F-33 on their exteriors. On August 8 a dress rehearsal was conducted off Tinian by Maj. Charles Sweeney using Bockscar as the drop airplane. Assembly F-33 was expended testing the components and F-31 was designated for the mission August 9.

The city of Nagasaki had been one of the largest sea ports in southern Japan and was of great wartime importance because of its wide-ranging industrial activity, including the production of ordnance, ships, military equipment, and other war materials.

In contrast to many modern aspects of Hiroshima, the bulk of the residences were of old-fashioned Japanese construction, consisting of wood or wood-frame buildings, with wood walls (with or without plaster), and tile roofs. Many of the smaller industries and business establishments were also housed in buildings of wood or other materials not designed to withstand explosions. Nagasaki had been permitted to grow for many years without conforming to any definite city zoning plan; residences were erected adjacent to factory buildings and to each other almost as closely as possible throughout the entire industrial valley.

Nagasaki had never been subjected to large-scale bombing prior to the explosion of a nuclear weapon there. On August 1, 1945, however, a number of conventional high-explosive bombs were dropped on the city. A few hit in the shipyards and dock areas in the southwest portion of the city, several hit the Mitsubishi Steel and Arms Works and six bombs landed at the Nagasaki Medical School and Hospital, with three direct hits on buildings there. While the damage from these bombs was relatively small, it created considerable concern in Nagasaki and many people—principally school children—were evacuated to rural areas for safety, thus reducing the population in the city at the time of the nuclear attack.

To the north of Nagasaki there was a camp holding British Commonwealth prisoners of war, some of whom were working in the coal mines and only found out about the bombing when they came to the surface. At least eight known POWs died from the bombing.

On the morning of August 9, 1945, the U.S. B-29 Superfortress Bockscar, flown by the crew of 393rd Squadron commander Major Charles W. Sweeney, carried the nuclear bomb code-named "Fat Man", with Kokura as the primary target and Nagasaki the secondary target. The mission plan for the second attack was nearly identical to that of the Hiroshima mission, with two B-29's flying an hour ahead as weather scouts and two additional B-29's in Sweeney's flight for instrumentation and photographic support of the mission. Sweeney took off with his weapon already armed but with the electrical safety plugs still engaged.

Observers aboard the weather planes reported both targets clear. When Sweeney's aircraft arrived at the assembly point for his flight off the coast of Japan, the third plane, Big Stink, flown by the group's Operations Officer, Lt. Col. James I. Hopkins, Jr. failed to make the rendezvous. Bockscar and the instrumentation plane circled for forty minutes without locating Hopkins. Already thirty minutes behind schedule, Sweeney decided to fly on without Hopkins.

By the time they reached Kokura a half hour later, a 7/10 cloud cover had obscured the city, prohibiting the visual attack required by orders. After three runs over the city, and with fuel running low because a transfer pump on a reserve tank had failed before take-off, they headed for their secondary target, Nagasaki. Fuel consumption calculations made en route indicated that Bockscar had insufficient fuel to reach Iwo Jima and they would be forced to divert to Okinawa. After initially deciding that if Nagasaki were obscured on their arrival they would carry the bomb to Okinawa and dispose of it in the ocean if necessary, the weaponeer Navy Commander Frederick Ashworth decided that a radar approach would be used if the target was obscured.

At about 07:50 Japanese time, an air raid alert was sounded in Nagasaki, but the "all clear" signal was given at 08:30. When only two B-29 Superfortresses were sighted at 10:53, the Japanese apparently assumed that the planes were only on reconnaissance and no further alarm was given.

A few minutes later, at 11:00, The Great Artiste, the support B-29 flown by Captain Frederick C. Bock dropped instruments attached to three parachutes. These instruments also contained an unsigned letter to Professor Ryokichi Sagane, a nuclear physicist at the University of Tokyo who studied with three of the scientists responsible for the atomic bomb at the University of California, Berkeley, urging him to tell the public about the danger involved with these weapons of mass destruction. The messages were found by military authorities but not turned over to Sagane until a month later. In 1949 one of the authors of the letter, Luis Alvarez, met with Sagane and signed the document.

At 11:01, a last minute break in the clouds over Nagasaki allowed Bockscar's bombardier, Captain Kermit Beahan, to visually sight the target as ordered. The "Fat Man" weapon, containing a core of ~6.4 kg (14.1 lbs.) of plutonium-239, was dropped over the city's industrial valley. Forty-three seconds later it exploded 469 meters (1,540 ft) above the ground exactly halfway between the Mitsubishi Steel and Arms Works in the south and the Mitsubishi-Urakami Ordnance Works (Torpedo Works) in the north. This was nearly 3 kilometers (2 mi) northwest of the planned hypocenter; the blast was confined to the Urakami Valley and a major portion of the city was protected by the intervening hills. The resulting explosion had a blast yield equivalent to 21 kilotons of TNT. The explosion generated heat estimated at 7000 degrees Fahrenheit and winds that were estimated at 624 mph.

Casualty estimates for immediate deaths range from 40,000 to 75,000. Total deaths by the end of 1945 may have reached 80,000. The radius of total destruction was about 1.6 km (1 mile), followed by fires across the northern portion of the city to 3.2 km (2 miles) south of the bomb.

An unknown number of survivors from the Hiroshima bombing had made their way to Nagasaki, where they were bombed again.

ETHANOL FUEL - ALTERNATIVE FUEL OF THE FUTURE

Ethanol fuel is ethanol (ethyl alcohol), the same type of alcohol found in alcoholic beverages. It can be used as a fuel, mainly as a biofuel alternative to gasoline, and is widely used in cars in Brazil. Because it is easy to manufacture and process, and can be made from very common materials, such as sugar cane, it is steadily becoming a promising alternative to gasoline throughout much of the world.

Anhydrous ethanol (ethanol with less than 1% water) can be blended with gasoline in varying quantities up to pure ethanol (E100), and most spark-ignited gasoline style engines will operate well with mixtures of 10% ethanol (E10). Most cars on the road today in the U.S. can run on blends of up to 10% ethanol, and the use of 10% ethanol gasoline is mandated in some cities where harmful levels of auto emissions are possible.

Ethanol can be mass-produced by fermentation of sugar or by hydration of ethylene from petroleum and other sources. Current interest in ethanol mainly lies in bio-ethanol, produced from the starch or sugar in a wide variety of crops, but there has been considerable debate about how useful bio-ethanol will be in replacing fossil fuels in vehicles. Concerns relate to the large amount of arable land required for crops, as well as the energy and pollution balance of the whole cycle of ethanol production. Recent developments with cellulosic ethanol production and commercialization may allay some of these concerns.

According to the International Energy Agency, cellulosic ethanol could allow ethanol fuels to play a much bigger role in the future than previously thought. Cellulosic ethanol offers promise as resistant cellulose fibers, a major component in plant cells walls, can be used to generate ethanol. Dedicated energy crops, such as switchgrass, are also promising cellulose sources that can be produced in many regions of the United States.

During ethanol fermentation, glucose is decomposed into ethanol and carbon dioxide.

C6H12O6 → 2C2H6O + 2CO2

During combustion ethanol reacts with oxygen to produce carbon dioxide, water, and heat: (other air pollutants are also produced when ethanol is burned in the atmosphere rather than in pure oxygen)

C2H6O + 3O2 → 2CO2 + 3H2O

Together, these two equations add up to the following:

C6H12O6 + 6O2 → 6CO2 + 6H2O + heat

This is the reverse of the photosynthesis reaction, which shows that the three reactions completely cancel each other out, only converting light into heat without leaving any byproducts:

6CO2 + 6H2O + light → C6H12O6 + 6O2

Ethanol is considered "renewable" because it is primarily the result of conversion of the sun's energy into usable energy. Creation of ethanol starts with photosynthesis causing the feedstocks such as switchgrass, sugar cane, or corn to grow. These feedstocks are processed into ethanol

About 5% of the ethanol produced in the world in 2003 was actually a petroleum product. It is made by the catalytic hydration of ethylene with sulfuric acid as the catalyst. It can also be obtained via ethylene or acetylene, from calcium carbide, coal, oil gas, and other sources. Two million tons of petroleum-derived ethanol are produced annually. The principal suppliers are plants in the United States, Europe, and South Africa. Petroleum derived ethanol (synthetic ethanol) is chemically identical to bio-ethanol and can be differentiated only by radiocarbon dating.

Bio-ethanol is obtained from the conversion of carbon based feedstock. Agricultural feedstocks are considered renewable because they get energy from the sun using photosynthesis, provided that all minerals required for growth (such as nitrogen and phosphorus) are returned to the land. Ethanol can be produced from a variety of feedstocks such as sugar cane, bagasse, miscanthus, sugar beet, sorghum, grain sorghum, switchgrass, barley, hemp, kenaf, potatoes, sweet potatoes, cassava, sunflower, fruit, molasses, corn, stover, grain, wheat, straw, cotton, other biomass, as well as many types of cellulose waste and harvestings, whichever has the best well-to-wheel assessment.

Current, first generation processes for the production of ethanol from corn use only a small part of the corn plant: the corn kernels are taken from the corn plant and only the starch, which represents about 50% of the dry kernel mass, is transformed into ethanol. Two types of second generation processes are under development. The first type uses enzymes to convert the plant cellulose into ethanol while the second type uses pyrolysis to convert the whole plant to either a liquid bio-oil or a syngas. Second generation processes can also be used with plants such as grasses, wood or agricultural waste material such as straw.

The basic steps for large scale production of ethanol are: microbial (yeast) fermentation of sugars, distillation, dehydration (requirements vary, see Ethanol fuel mixtures, below), and denaturing (optional). Prior to fermentation, some crops require saccharification or hydrolysis of carbohydrates such as cellulose and starch into sugars. Saccharification of cellulose is called cellulolysis. Enzymes are used to convert starch into sugar.

Ethanol is produced by microbial fermentation of the sugar. Production of ethanol from sugarcane (sugarcane requires a tropical climate to grow productively) returns about 8 units of energy for each unit expended compared to corn which only returns about 1.34 units of fuel energy for each unit of energy expended.

Carbon dioxide, a greenhouse gas, is emitted during fermentation and combustion. However, this is canceled out by the greater uptake of carbon dioxide by the plants as they grow to produce the biomass. When compared to gasoline, depending on the production method, ethanol releases less or even no greenhouse gases.

For the ethanol to be usable as a fuel, water must be removed. Most of the water is removed by distillation, but the purity is limited to 95-96% due to the formation of a low-boiling water-ethanol azeotrope. The 96% m/m (93% v/v) ethanol, 4% m/m (7% v/v) water mixture may be used as a fuel alone, but unlike anhydrous ethanol, is immiscible in gasoline, so the water fraction is typically removed in further treatment in order to burn with in combination with gasoline in gasoline engines.

Ethanol is most commonly used to power automobiles, though it may be used to power other vehicles, such as farm tractors and airplanes. Ethanol (E100) consumption in an engine is approximately 34% higher than that of gasoline (the energy per volume unit is 34% lower). However, higher compression ratios in an ethanol-only engine allow for increased power output and better fuel economy than would be obtained with the lower compression ratio. In general, ethanol-only engines are tuned to give slightly better power and torque output to gasoline-powered engines. In flexible fuel vehicles, the lower compression ratio requires tunings that give the same output when using either gasoline or hydrated ethanol. For maximum use of ethanol's benefits, a much higher compression ratio should be used, which would render that engine unsuitable for gasoline usage. When ethanol fuel availability allows high-compression ethanol-only vehicles to be practical, the fuel efficiency of such engines should be equal or greater than current gasoline engines. However, since the energy content (by volume) of ethanol fuel is less than gasoline, a larger volume of ethanol fuel (151%) would still be required to produce the same amount of energy.

A 2004 MIT study, and an earlier paper published by the Society of Automotive Engineers, describing tests, identify a method to exploit the characteristics of fuel ethanol that is substantially better than mixing it with gasoline. The method presents the possibility of leveraging the use of alcohol to even achieve definite improvement over the cost-effectiveness of hybrid electric. The improvement consists of using dual-fuel direct-injection of pure alcohol (or the azeotrope or E85) and gasoline, in any ratio up to 100% of either, in a turbocharged, high compression-ratio, small-displacement engine having performance similar to an engine having twice the displacement. Each fuel is carried separately, with a much smaller tank for alcohol. The high-compression (which increases efficiency) engine will run fine on ordinary gasoline under low-power cruise conditions. Alcohol is directly injected into the cylinders (and the gasoline injection simultaneously reduced) only when necessary to suppress ‘knock’ such as when significantly accelerating. Direct cylinder injection raises the already high octane rating of ethanol up to an effective 130. The calculated over-all reduction of gasoline use and CO2 emission is 30%. The consumer cost payback time shows a 4:1 improvement over turbo-diesel and a 5:1 improvement over hybrid. In addition, the problems of water absorption into pre-mixed gasoline (causing phase separation), supply issues of multiple mix ratios and cold-weather starting are avoided.

Ethanol's higher octane allows an increase of an engine's compression ratio for increased thermal efficiency. In one study, complex engine controls and increased exhaust gas recirculation allowed a compression ratio of 19.5 with fuels ranging from neat ethanol to E50. Thermal efficiency up to approximately that for a diesel was achieved. This would result in the MPG of a dedicated ethanol vehicle to be about the same as one burning gasoline.

Engines using fuel with from 30% to 100% ethanol also need a cold-starting system. For E85 fuel at temperatures below 11 °C (52 °F) a cold-starting system is required for reliable starting and to meet EPA emissions standards.