title: Ovarian cancer

text: Chemotherapy has been a general standard of care for ovarian cancer for decades, although with variable protocols. Chemotherapy is used after surgery to treat any residual disease, if appropriate. In some cases, there may be reason to perform chemotherapy first, followed by surgery. This is called "neoadjuvant chemotherapy", and is common when a tumor cannot be completely removed or optimally debulked via surgery. Though it has not been shown to increase survival, it can reduce the risk of complications after surgery. If a unilateral salpingo-oophorectomy or other surgery is performed, additional chemotherapy, called "adjuvant chemotherapy", can be given. Adjuvant chemotherapy is used in stage 1 cancer typically if the tumor is of a high histologic grade (grade 3) or the highest substage (stage 1c), provided the cancer has been optimally staged during surgery. Bevacizumab may be used as an adjuvant chemotherapy if the tumor is not completely removed during surgery or if the cancer is stage IV; it can extend progression-free survival but has not been shown to extend overall survival. Chemotherapy is curative in approximately 20% of advanced ovarian cancers; it is more often curative with malignant germ cell tumors than epithelial tumors. Adjuvant chemotherapy has been found to improve survival and reduce the risk of ovarian cancer recurring compared to no adjuvant therapy in women with early stage epithelial ovarian cancer.


title: Ovarian cancer

text: Chemotherapy in ovarian cancer typically consists of platins, a group of platinum-based drugs, combined with non-platins. Platinum-based drugs have been used since 1980. Common therapies can include paclitaxel, cisplatin, topotecan, doxorubicin, epirubicin, and gemcitabine. Carboplatin is typically given in combination with either paclitaxel or docetaxel; the typical combination is carboplatin with paclitaxel. Carboplatin is superior to cisplatin in that it is less toxic and has fewer side effects, generally allowing for an improved quality of life in comparison, though both are similarly effective. Three-drug regimens have not been found to be more effective, and platins alone or nonplatins alone are less effective than platins and nonplatins in combination. There is a small benefit in platinum‐based chemotherapy compared with non‐platinum therapy. Platinum combinations can offer improved survival over single platinum. In people with relapsed ovarian cancer, evidence suggests topotecan has a similar effect on overall survival as paclitaxel and topotecan plus thalidomide, whilst it is superior to treosulfan and not as effective as pegylated liposomal doxorubicin in platinum-sensitive people.


title: Ovarian cancer

text: Chemotherapy can be given intravenously or in the peritoneal cavity. Though intraperitoneal chemotherapy is associated with longer progression-free survival and overall survival, it also causes more adverse side effects than intravenous chemotherapy. It is mainly used when the cancer has been optimally debulked. Intraperitoneal chemotherapy can be highly effective because ovarian cancer mainly spreads inside the peritoneal cavity, and higher doses of the drugs can reach the tumors this way.


title: Ovarian cancer

text: Chemotherapy can cause anemia; intravenous iron has been found to be more effective than oral iron supplements in reducing the need for blood transfusions. Typical cycles of treatment involve one treatment every 3 weeks, repeated for 6 weeks or more. Fewer than 6 weeks (cycles) of treatment is less effective than 6 weeks or more. Germ-cell malignancies are treated differently than other ovarian cancers — a regimen of bleomycin, etoposide, and cisplatin (BEP) is used with 5 days of chemotherapy administered every 3 weeks for 3 to 4 cycles. Chemotherapy for germ cell tumors has not been shown to cause amenorrhea, infertility, birth defects, or miscarriage. Maintenance chemotherapy has not been shown to be effective.


title: Ovarian cancer

text: In people with "BRCA" mutations, platinum chemotherapy is more effective. Germ-cell tumors and malignant sex-cord/stromal tumors are treated with chemotherapy, though dysgerminomas and sex-cord tumors are not typically very responsive.


title: Ovarian cancer

text: If ovarian cancer recurs, it is considered partially platinum-sensitive or platinum-resistant, based on the time since the last recurrence treated with platins: partially platinum-sensitive cancers recurred 6–12 months after last treatment, and platinum-resistant cancers have an interval of less than 6 months. Second-line chemotherapy can be given after the cancer becomes symptomatic because no difference in survival is seen between treating asymptomatic (elevated CA-125) and symptomatic recurrences.


title: Ovarian cancer

text: For platinum-sensitive tumors, platins are the drugs of choice for second-line chemotherapy, in combination with other cytotoxic agents. Regimens include carboplatin combined with pegylated liposomal doxorubicin, gemcitabine, or paclitaxel. Carboplatin-doublet therapy can be combined with paclitaxel for increased efficacy in some cases. Another potential adjuvant therapy for platinum-sensitive recurrences is olaparib, which may improve progression-free survival but has not been shown to improve overall survival. (Olaparib, a PARP inhibitor, was approved by the US FDA for use in BRCA-associated ovarian cancer that had previously been treated with chemotherapy.) For recurrent germ cell tumors, an additional 4 cycles of BEP chemotherapy is the first-line treatment for those tho have been treated with surgery or platins.


title: Ovarian cancer

text: If the tumor is determined to be platinum-resistant, vincristine, dactinomycin, and cyclophosphamide (VAC) or some combination of paclitaxel, gemcitabine, and oxaliplatin may be used as a second-line therapy.


title: Ovarian cancer

text: For platinum-resistant tumors, there are no high-efficacy chemotherapy options. Single-drug regimens (doxorubicin or topotecan) do not have high response rates, but single-drug regimens of topotecan, pegylated liposomal doxorubicin, or gemcitabine are used in some cases. Topotecan cannot be used in people with an intestinal blockage. Paclitaxel used alone is another possible regimen, or it may be combined with liposomal doxorubicin, gemcitabine, cisplatin, topotecan, etoposide, or cyclophosphamide. ( See also Palliative care below.)


title: Ovarian cancer

text: Novel agents are being developed to inhibit the development of new blood vessels (angiogenesis) for women with ovarian cancer who develop resistance to chemotherapy drugs. As of 2011 only preliminary results are available.


title: Ovarian cancer

text: Novocure sponsored a phase-2 trial proving efficacy of tumor treating fields in recurrent platinum-resistant ovarian carcinoma, in conjunction with weekly paclitaxel chemotherapy.


title: Ovarian cancer

text: Dysgerminomas are most effectively treated with radiation, though this can cause infertility and is being phased out in favor of chemotherapy. Radiation therapy does not improve survival in people with well-differentiated tumors.


title: Ovarian cancer

text: In stage 1c and 2 cancers, radiation therapy is used after surgery if there is the possibility of residual disease in the pelvis but the abdomen is cancer-free. Radiotherapy can also be used in palliative care of advanced cancers. A typical course of radiotherapy for ovarian cancer is 5 days a week for 3–4 weeks. Common side effects of radiotherapy include diarrhea, constipation, and frequent urination.


title: Ovarian cancer

text: Despite the fact that 60% of ovarian tumors have estrogen receptors, ovarian cancer is only rarely responsive to hormonal treatments. A Cochrane review found a lack of evidence about the effects of tamoxifen in people with relapsed ovarian cancer. Estrogen alone does not have an effect on the cancer, and tamoxifen and letrozole are rarely effective. "Some women with borderline malignancy ovarian cancer and stromal ovarian cancer may receive hormonal therapy."


title: Ovarian cancer

text: Immunotherapy is a topic of current research in ovarian cancer. In some cases, the antibody drug bevacizumab, though still a topic of active research, is used to treat advanced cancer along with chemotherapy. It has been approved for this use in the European Union.


title: Ovarian cancer

text: Specific follow-up depends on, for example, the type and stage of ovarian cancer, the treatment, and the presence of any symptoms. Usually, a check-up appointment is made about every 2 to 3 months initially, followed by twice per year for up to 5 years. For epithelial ovarian cancers, the most common test upon follow-up is CA-125 level. However, treatment based only on elevated CA-125 levels and not any symptoms can increase side effects without any prolongation of life, so the implication of the outcome of a CA-125 test can be discussed before taking it. The recommendation as of 2014 is recurrent cancer may be present if the CA-125 level is twice normal. Treating a recurrence detected by CA-125 does not improve survival.


title: Ovarian cancer

text: For women with germ-cell tumors, follow-up tests generally include alpha-fetoprotein (AFP) and/or human chorionic gonadotropin. For women with stromal cancers, tests for hormones like estrogen, testosterone, and inhibin are sometimes helpful. Inhibin can also be useful for monitoring the progress of sex-cord tumors, along with mullerian inhibiting substance. AFP can also be used to monitor Sertoli-Leydig tumors. In dysgerminomas, lactate dehydrogenase and its two isozymes (LDH-1 and LDH-2) are used to test for recurrence.


title: Ovarian cancer

text: Women with ovarian cancer may not need routine surveillance imaging to monitor the cancer unless new symptoms appear or tumor markers begin rising. Imaging without these indications is discouraged because it is unlikely to detect a recurrence, improve survival, and because it has its own costs and side effects. However, CT imaging can be used if desired, though this is not common. If a tumor is easily imaged, imaging may be used to monitor the progress of treatment.


title: Ovarian cancer

text: Palliative care focuses on relieving symptoms and increasing or maintaining quality of life. This type of treatment's purpose is not to cure the cancer but to make the woman more comfortable while living with cancer that can not be cured. It has been recommended as part of the treatment plan for any person with advanced ovarian cancer or patients with significant symptoms. In platinum-refractory and platinum-resistant cases, other palliative chemotherapy is the main treatment.


title: Ovarian cancer

text: Palliative care can entail treatment of symptoms and complications of the cancer, including pain, nausea, constipation, ascites, bowel obstruction, edema, pleural effusion, and mucositis. Especially if the cancer advances and becomes incurable, treatment of symptoms becomes one of the main goals of therapy. Palliative care can also entail helping with decision-making such as if or when hospice care is appropriate, and the preferred place for the patient at end of life care.


title: Ovarian cancer

text: Bowel obstruction can be treated with palliative surgery (colostomy, ileostomy, or internal bypass) or medicine, but surgery has been shown to increase survival time. Palliative surgery may result in short bowel syndrome, enterocutaneous fistula, or re-obstruction; or may not be possible due to the extent of obstruction. Other treatments of complications can include total parenteral nutrition, a low-residue diet, palliative gastrostomy, and adequate pain control. Bowel obstruction can also be treated with octreotide when palliative surgery is not an option. Cancer can also block the ureters, which can be relieved by a nephrostomy or a ureteric stent. Ascites can be relieved by repeated paracentesis or placement of a drain to increase comfort. Pleural effusions can be treated in a similar manner, with repeated thoracentesis, pleurodesis, or placement of a drain.


title: Ovarian cancer

text: Radiation therapy can be used as part of the palliative care of advanced ovarian cancer, since it can help to shrink tumors that are causing symptoms. Palliative radiotherapy typically lasts for only a few treatments, a much shorter course of therapy than non-palliative radiotherapy. It is also used for palliation of chemotherapy-resistant germ cell tumors.


title: Ovarian cancer

text: Ovarian cancer has a significant effect on quality of life, psychological health and well-being. Interventions are available to help with the needs and social support. Many ovarian cancer survivors report a good quality of life and optimism. Others reported a "spiritual change" that helped them find meaning during their experience. Others have described their loss of faith after their diagnosis with ovarian cancer. Those who have gone through treatment sometimes experience social isolation but benefit from having relationships with other survivors. Frustration and guilt have been described by some who have expressed their inability to care for their family.


title: Ovarian cancer

text: Self-esteem and body image changes can occur due to hair loss, removal of ovaries and other reproductive structures, and scars. There is some improvement after hair grows in. Sexual issues can develop. The removal of ovaries results in surgically induced menopause that can result in painful intercourse, vaginal dryness, loss of sexual desire and being tired. Though prognosis is better for younger survivors, the impact on sexuality can still be substantial.


title: Ovarian cancer

text: Anxiety, depression and distress is present in those surviving ovarian cancer at higher rates than in the general population. The same psychosocial problems can develop in family members. Emotional effects can include a fear of death, sadness, memory problems and difficulty in concentrating. When optimism was adopted by those at the beginning of their treatment, they were less likely to develop distress. Those who have fear of the cancer recurring may have difficulty in expressing joy even when disease-free. The more treatments that a woman undergoes, the more likely the loss of hope is expressed. Women often can cope and reduce negative psychosocial effects by a number of strategies. Activities such as traveling, spending additional time with family and friends, ignoring statistics, journaling and increasing involvement in spiritually-based events are adaptive.


title: Ovarian cancer

text: Women with ovarian cancer may also experience difficulties with their diet and are at risk of malnutrition.


title: Ovarian cancer

text: Ovarian cancer usually has a relatively poor prognosis. It is disproportionately deadly because it lacks any clear early detection or screening test, meaning most cases are not diagnosed until they have reached advanced stages.


title: Ovarian cancer

text: Ovarian cancer metastasizes early in its development, often before it has been diagnosed. High-grade tumors metastasize more readily than low-grade tumors. Typically, tumor cells begin to metastasize by growing in the peritoneal cavity. More than 60% of women presenting with ovarian cancer have stage-III or stage-IV cancer, when it has already spread beyond the ovaries. Ovarian cancers shed cells into the naturally occurring fluid within the abdominal cavity. These cells can then implant on other abdominal (peritoneal) structures, including the uterus, urinary bladder, bowel, lining of the bowel wall, and omentum, forming new tumor growths before cancer is even suspected.


title: Ovarian cancer

text: The five-year survival rate for all stages of ovarian cancer is 46%; the one-year survival rate is 72% and the ten-year survival rate is 35%. For cases where a diagnosis is made early in the disease, when the cancer is still confined to the primary site, the five-year survival rate is 92.7%. About 70% of women with advanced disease respond to initial treatment, most of whom attain complete remission, but half of these women experience a recurrence 1–4 years after treatment. Brain metastasis is more common in stage III/IV cancer but can still occur in cancers staged at I/II. People with brain metastases survive a median of 8.2 months, though surgery, chemotherapy, and whole brain radiation therapy can improve survival.


title: Ovarian cancer

text: Ovarian cancer survival varies significantly with subtype. Dysgerminomas have a very favorable prognosis. In early stages, they have a five-year survival rate of 96.9%. Around two-thirds of dysgerminomas are diagnosed at stage I. Stage-III dysgerminomas have a five-year survival of 61%; when treated with BEP chemotherapy after incomplete surgical removal, dysgerminomas have a 95% two-year survival rate. Sex-cord-stromal malignancies also have a favorable prognosis; because they are slow-growing, even those with metastatic disease can survive a decade or more. Low malignant potential tumors usually only have a bad prognosis when there are invasive tumor implants found in the peritoneal cavity.


title: Ovarian cancer

text: Complications of ovarian cancer can include spread of the cancer to other organs, progressive function loss of various organs, ascites, and intestinal obstructions, which can be fatal. Intestinal obstructions in multiple sites are the most common proximate cause of death. Intestinal obstruction in ovarian cancer can either be a true obstruction, where tumor blocks the intestinal lumen, or a pseudo-obstruction, when tumor prevents normal peristalsis. Continuous accumulation of ascites can be treated by placing a drain that can be self-drained.


title: Ovarian cancer

text: There are a number of prognostic factors in ovarian cancer. Positive prognostic factors – those indicating better chances of survival – include no residual disease after surgery (stage III/IV), complete macroscopic resection (stage IV), BRCA2 mutations, young age (under 45 years), nonserous type, low histologic grade, early stage, co-occurrence with endometrial cancer, and low CA-125 levels. There is conflicting evidence for BRCA1 as a prognostic factor. Conversely, negative prognostic factors – those that indicate a worse chance of survival – include rupture of the ovarian capsule during surgery, older age (over 45 years), mucinous type, stage IV, high histologic grade, clear cell type, upper abdominal involvement, high CA-125 levels, the presence of tumor cells in the blood, and elevated cyclooxygenase-2.


title: Ovarian cancer

text: Expression of various mRNAs can also be prognostic for ovarian cancer. High levels of Drosha and Dicer are associated with improved survival, whereas high levels of let-7b, HIF1A, EphA1, and poly(ADP-ribose) polymerase are associated with worse survival. Cancers that are positive for WT1 carry a worse prognosis; estrogen-receptor positive cancers have a better prognosis.


title: Ovarian cancer

text: Overall five-year survival rates for all types of ovarian cancer are presented below by stage and histologic grade:


title: Ovarian cancer

text: The survival rates given below are for the different types of ovarian cancer, according to American Cancer Society. They come from the National Cancer Institute, SEER, and are based on patients diagnosed from 2004 to 2010.


title: Ovarian cancer

text: Ovarian cancer frequently recurs after treatment. Overall, in a 5-year period, 20% of stage I and II cancers recur. Most recurrences are in the abdomen. If a recurrence occurs in advanced disease, it typically occurs within 18 months of initial treatment (18 months progression-free survival). Recurrences can be treated, but the disease-free interval tends to shorten and chemoresistance increases with each recurrence. When a dysgerminoma recurs, it is most likely to recur within a year of diagnosis, and other malignant germ cell tumors recur within 2 years 90% of the time. Germ cell tumors other than dysgerminomas have a poor prognosis when they relapse, with a 10% long-term survival rate. Low malignant potential tumors rarely relapse, even when fertility-sparing surgery is the treatment of choice. 15% of LMP tumors relapse after unilateral surgery in the previously unaffected ovary, and they are typically easily treated with surgery. More advanced tumors may take up to 20 years to relapse, if they relapse at all, and are only treated with surgery unless the tumor has changed its histological characteristics or grown very quickly. In these cases, and when there is significant ascites, chemotherapy may also be used. Relapse is usually indicated by rising CA-125 levels and then progresses to symptomatic relapse within 2–6 months. Recurrent sex cord-stromal tumors are typically unresponsive to treatment but not aggressive.


title: Ovarian cancer

text: Globally, in 2018, the incidence of ovarian cancer was 6.6 per 100,000 and mortality was 3.9. Globally, about 160,000 people died from ovarian cancer in 2010. This was an increase from 113,000 in 1990. The number of new cases per year in Europe is approximately 5–15 per 100,000 women. In Europe, Lithuania, Latvia, Ireland, Slovakia, and the Czech Republic have the highest incidences of ovarian cancer, whereas Portugal and Cyprus have the lowest incidences. In 2008, the five-year survival rate was 44%. This has increased since 1977 when the survival rate was 36%.


title: Ovarian cancer

text: In 2022, in the United States, an estimated 19,880 new cases were diagnosed and 12,810 women died of ovarian cancer. The 5-year relative survival rate is 49.7%. Around 57% cases have metastasized at the time of diagnosis.


title: Ovarian cancer

text: In 2014, over 220,000 diagnoses of epithelial ovarian cancer were made yearly. The overall lifetime risk in the US is around 1.6% In the US, ovarian cancer affects 1.3–1.4% and is the cause of death of about 1% of women. In the United States, it is also the fifth-most common cancer in women but the fourth-most common cause of cancer death. This decrease made it the ninth-most common cancer in women.


title: Ovarian cancer

text: The risks from developing specific types of ovarian cancer varies. Germ cell tumors and sex cord-stromal tumors are less common than epithelial tumors. The number of new cases a year in the US is 0.4 per 100,000 women and 0.2 per 100,000 women, respectively. In young people, sex-cord stromal tumors and germ cell tumors total 1% of overall ovarian cancer. Ovarian cancer represents approximately 4% of cancers diagnosed in women.


title: Ovarian cancer

text: It is the 5th-most common cancer in UK women (around 7,100 were diagnosed in 2011) and the 5th-most common cause of cancer death in women (around 4,300 died in 2012). The incidence rate over the whole UK population is 21.6 per 100,000.


title: Ovarian cancer

text: As of 2014, the UK saw approximately 7,000–7,100 yearly diagnoses with 4,200 deaths. A 2022 article from "The Times" put the estimate at 7,500 new cases yearly in Britain. Early symptoms are often mistaken for common conditions such as cystitis or irritable bowel syndrome, and about 40 per cent of UK women wrongly believe that cervical screening detects ovarian cancer, an increase from 30 per cent in 2016. Ashkenazi Jewish women carry mutated "BRCA" alleles five times more often than the rest of the population, giving them a higher risk developing ovarian cancer.


title: Ovarian cancer

text: Black women have twice the risk for sex cord-stromal tumors compared to non-Black women. The highest prevalence is in Caucasian and Hispanic women, followed by African-American and Asian women. The highest mortality from ovarian cancer is in African-American women.


title: Ovarian cancer

text: In the US, the incidence rate in women over 50 is approximately 33 per 100,000. The rate of ovarian cancer between 1993 and 2008 decreased in women of the 40–49 age cohort and in the 50–64 age cohort. Ovarian cancer is most commonly diagnosed after menopause, between the ages of 60 and 64. Ninety percent of ovarian cancer occurs in women over the age of 45 and 80% in women over 50. Older women are more likely to present with advanced ovarian cancer.


title: Ovarian cancer

text: Malignant germ cell tumors are the type of ovarian cancer most likely to occur during pregnancy. They are typically diagnosed when an adnexal mass is found on examination (in 1–2% of all pregnancies), a tumor is seen on ultrasound, or the parent's level of alpha-fetoprotein is elevated. Dermoid cysts and dysgerminomas are the most common germ cell tumors during pregnancy. Germ cell tumors diagnosed during pregnancy are unlikely to have metastasized and can be treated by surgery and, in some cases, chemotherapy, which carries the risk of birth defects. Yolk sac tumors and immature teratomas grow particularly quickly and are usually treated with chemotherapy even during pregnancy; however, dysgerminomas that have been optimally debulked may be treated after childbirth.


title: Ovarian cancer

text: Ovarian tumors have been reported in equine mares. Reported tumor types include teratoma, cystadenocarcinoma, and particularly granulosa cell tumor.


title: Ovarian cancer

text: Screening by hysteroscopy to obtain cell samples obtained for histological examination is being developed. This is similar to the current pap smear that is used to detect cervical cancer. The UK Collaborative Trial of Ovarian Cancer Screening is testing a screening technique that combines CA-125 blood tests with transvaginal ultrasound. Other studies suggest that this screening procedure may be effective. Although results published in 2015 were not conclusive, there was some evidence that screening may save lives in the long-term. As a result, the trial has been extended and will publish definitive results at the end of 2019. One major problem with screening is no clear progression of the disease from stage I (noninvasive) to stage III (invasive) is seen, and it may not be possible to find cancers before they reach stage III. Another problem is that screening methods tend to find too many suspicious lesions, most of which are not cancer, but malignancy can only be assessed with surgery. The ROCA method combined with transvaginal ultrasonography is being researched in high-risk women to determine if it is a viable screening method. It is also being investigated in normal-risk women as it has shown promise in the wider population. Studies are also in progress to determine if screening helps detect cancer earlier in people with BRCA mutations.


title: Ovarian cancer

text: Research into various prognostic factors for ovarian cancer is also going on. Recent research shows that thrombocytosis predicts lower survival and higher stage cancer. Ongoing research is also investigating the benefits of surgery for recurrent ovarian cancer.


title: Ovarian cancer

text: While an active area of research, as of 2018 there is no good evidence that immunotherapy is effective for ovarian cancer. However, trials of the antibody and VEGF inhibitor bevacizumab, which can slow the growth of new blood vessels in the cancer, have shown promising results, especially in combination with pazopanib, which also slows the process of blood vessel growth. Bevacizumab has been particularly effective in preliminary studies on stage-III and -IV cancer and has been cited as having at least a 15% response rate. It is being investigated particularly in mucinous ovarian cancers.


title: Ovarian cancer

text: mTOR inhibitors were a highly investigated potential treatment in the 2000s and 2010s, but the side effects of these drugs (particularly hyperglycemia and hyperlipidemia) were not well tolerated and the survival benefit not confirmed. PI3 kinase inhibitors have been of interest, but they tend to be highly toxic and cause diarrhea. Another investigated drug is selumetinib, a MAPK inhibitor. It improved survival, but did not correlate with any mutations found in tumors.


title: Ovarian cancer

text: Bevacizumab can also be combined with platinum chemotherapy, a combination that has had positive preliminary results in PFS, but equivocal results regarding overall survival. One disadvantage to these treatments is the side effect profile, which includes high blood pressure and proteinuria. The drug can also exacerbate bowel disease, leading to fistulae or bowel perforation. Vintafolide, which consists of an antifolate conjugated with vinblastine, is also in clinical trials; it may prove beneficial because folate receptors are overexpressed in many ovarian cancers. Another potential immunotherapy is trastuzumab, which is active against tumors positive for Her2/neu mutations. Other angiogenesis inhibitors are also being investigated as potential ovarian cancer treatments. Combretastatin and pazopanib are being researched in combination for recurrent ovarian cancer. Trebananib and tasquinimod are other angiogenesis inhibitors being investigated. The monoclonal antibody farletuzumab is being researched as an adjuvant to traditional chemotherapy. Another type of immunotherapy involves vaccines, including TroVax.


title: Ovarian cancer

text: An alternative to BEP chemotherapy, a regimen of 3 cycles of carboplatin and etoposide, is a current topic of research for germ cell malignancies.


title: Ovarian cancer

text: Intraperitoneal chemotherapy has also been under investigation during the 2000s and 2010s for its potential to deliver higher doses of cytotoxic agent to tumors. Preliminary trials with cisplatin and paclitaxel have shown it is not well tolerated, but does improve survival, and more tolerable regimens are being researched. Cisplatin and paclitaxel are both being researched as intraperitoneal chemotherapy agents. A specific chemotherapy regimen for rare clear-cell cancers is also under investigation: irinotecan combined with cisplatin.


title: Ovarian cancer

text: PARP inhibitors have also shown promise in early trials, particularly in people with "BRCA" gene mutations, since the BRCA protein interacts with the PARP pathway. It is also being studied in recurrent ovarian cancer in general, where preliminary studies have shown longer PFS. Specifically, olaparib has shown greater survival compared to doxorubicin, though this treatment is still being investigated. It is not clear yet which biomarkers are predictive of responsiveness to PARP inhibitors. Rucaparib is another PARP inhibitor being researched in BRCA-positive and BRCA-negative recurrent advanced ovarian cancer. Niraparib is a PARP inhibitor being tested in BRCA-positive recurrent ovarian cancer.


title: Ovarian cancer

text: Tyrosine kinase inhibitors are another investigational drug class that may have applications in ovarian cancer. Angiogenesis inhibitors in the receptor tyrosine kinase inhibitor group, including pazopanib, cediranib, and nintedanib, have also been shown to increase progression free survival (PFS), but their benefit for overall survival has not been investigated as of 2015. Preliminary research showed that cediranib combined with platins in recurrent ovarian cancer increased the time to second recurrence by 3–4 months and increased survival by 3 months. MK-1775 is a tyrosine kinase inhibitor that is being used in combination with paclitaxel and carboplatin in platinum-sensitive cancers with p53 mutations. Nintedanib is being researched as a potential therapy in combination with cyclophosphamide for people with recurrences.


title: Ovarian cancer

text: Hormone therapies are a topic of current research in ovarian cancer, particularly, the value of certain medications used to treat breast cancer. These include tamoxifen, letrozole, and anastrozole. Preliminary studies have showed a benefit for tamoxifen in a small number of people with advanced ovarian cancer. Letrozole may help to slow or stop growth of estrogen receptor positive ovarian cancer. Anastrozole is being investigated in postmenopausal people with estrogen receptor-positive cancer.


title: Ovarian cancer

text: Research into mitigating side effects of ovarian cancer treatment is also ongoing. Radiation fibrosis, the formation of scar tissue in an area treated with radiation, may be relieved with hyperbaric oxygen therapy, but research has not been completed in this area. Treatment of ovarian cancer may also cause people to experience psychiatric difficulties, including depression. Research is ongoing to determine how counseling and psychotherapy can help people who have ovarian cancer during treatment.


title: Ovarian cancer

text: There are some indications that pelvic inflammatory disease may be associated with ovarian cancer, especially in non-western countries. It may be due to the inflammatory process present with pelvic inflammatory disease.


title: Ovarian cancer

text: Clinical trials are monitored and funded by US governmental organizations to test treatment options to see if they are safe and effective. These include NIH Clinical Research Trials and You (National Institutes of Health), Learn About Clinical Trials (National Cancer Institute), Search for Clinical Trials (National Cancer Institute), ClinicalTrials.gov (National Institutes of Health). Clinical trials are also conducted in Canada.


title: MOS Technology 6502

text: The MOS Technology 6502 (typically pronounced "sixty-five-oh-two" or "six-five-oh-two") is an 8-bit microprocessor that was designed by a small team led by Chuck Peddle for MOS Technology. The design team had formerly worked at Motorola on the Motorola 6800 project; the 6502 is essentially a simplified, less expensive and faster version of that design.


title: MOS Technology 6502

text: When it was introduced in 1975, the 6502 was the least expensive microprocessor on the market by a considerable margin. It initially sold for less than one-sixth the cost of competing designs from larger companies, such as the 6800 or Intel 8080. Its introduction caused rapid decreases in pricing across the entire processor market. Along with the Zilog Z80, it sparked a series of projects that resulted in the home computer revolution of the early 1980s.


title: MOS Technology 6502

text: Popular video game consoles and home computers of the 1980s and early 1990s, such as the Atari 2600, Atari 8-bit family, Apple II, Nintendo Entertainment System, Commodore 64, Atari Lynx, BBC Micro and others, use the 6502 or variations of the basic design. Soon after the 6502's introduction, MOS Technology was purchased outright by Commodore International, who continued to sell the microprocessor and licenses to other manufacturers. In the early days of the 6502, it was second-sourced by Rockwell and Synertek, and later licensed to other companies.


title: MOS Technology 6502

text: In 1981, the Western Design Center started development of a CMOS version, the 65C02. This continues to be widely used in embedded systems, with estimated production volumes in the hundreds of millions.


title: MOS Technology 6502

text: The 6502 was designed by many of the same engineers that had designed the Motorola 6800 microprocessor family. Motorola started the 6800 microprocessor project in 1971 with Tom Bennett as the main architect. The chip layout began in late 1972, the first 6800 chips were fabricated in February 1974 and the full family was officially released in November 1974. John Buchanan was the designer of the 6800 chip and Rod Orgill, who later did the 6501, assisted Buchanan with circuit analyses and chip layout. Bill Mensch joined Motorola in June 1971 after graduating from the University of Arizona (at age 26). His first assignment was helping define the peripheral ICs for the 6800 family and later he was the principal designer of the 6820 Peripheral Interface Adapter (PIA). Motorola's engineers could run analog and digital simulations on an IBM 370-165 mainframe computer. Bennett hired Chuck Peddle in 1973 to do architectural support work on the 6800 family products already in progress. He contributed in many areas, including the design of the 6850 ACIA (serial interface).


title: MOS Technology 6502

text: Motorola's target customers were established electronics companies such as Hewlett-Packard, Tektronix, TRW, and Chrysler. In May 1972, Motorola's engineers began visiting select customers and sharing the details of their proposed 8-bit microprocessor system with ROM, RAM, parallel and serial interfaces. In early 1974, they provided engineering samples of the chips so that customers could prototype their designs. Motorola's "total product family" strategy did not focus on the price of the microprocessor, but on reducing the customer's total design cost. They offered development software on a timeshare computer, the "EXORciser" debugging system, onsite training and field application engineer support. Both Intel and Motorola had initially announced a $360 price for a single microprocessor. The actual price for production quantities was much less. Motorola offered a design kit containing the 6800 with six support chips for $300.


title: MOS Technology 6502

text: Peddle, who would accompany the salespeople on customer visits, found that customers were put off by the high cost of the microprocessor chips. At the same time, these visits invariably resulted in the engineers he presented to producing lists of required instructions that were much smaller than "all these fancy instructions" that had been included in the 6800. Peddle and other team members started outlining the design of an improved feature, reduced size microprocessor. At that time, Motorola's new semiconductor fabrication facility in Austin, Texas, was having difficulty producing MOS chips, and mid-1974 was the beginning of a year-long recession in the semiconductor industry. Also, many of the Mesa, Arizona employees were displeased with the upcoming relocation to Austin, Texas.


title: MOS Technology 6502

text: Motorola's Semiconductor Products Division management was overwhelmed with problems and showed no interest in Peddle's low-cost microprocessor proposal. Eventually Peddle was given an official letter telling him to stop working on the system. Peddle responded to the order by informing Motorola that the letter represented an official declaration of "project abandonment", and as such, the intellectual property he had developed to that point was now his. In a November 1975 interview, Motorola's Chairman, Robert Galvin, ultimately agreed that Peddle's concept was a good one and that the division missed an opportunity, "We did not choose the right leaders in the Semiconductor Products division." The division was reorganized and the management replaced. The new group vice-president John Welty said, "The semiconductor sales organization lost its sensitivity to customer needs and couldn't make speedy decisions."


title: MOS Technology 6502

text: Peddle began looking outside Motorola for a source of funding for this new project. He initially approached Mostek CEO L. J. Sevin, but he declined. Sevin later admitted this was because he was afraid Motorola would sue them.


title: MOS Technology 6502

text: While Peddle was visiting Ford Motor Company on one of his sales trips, Bob Johnson, later head of Ford's engine automation division, mentioned that their former colleague John Paivinen had moved to General Instrument and taught himself semiconductor design. Paivinen then formed MOS Technology in Valley Forge, Pennsylvania in 1969 with two other executives from General Instrument, Mort Jaffe and Don McLaughlin. Allen-Bradley, a supplier of electronic components and industrial controls, acquired a majority interest in 1970. The company designed and fabricated custom ICs for customers and had developed a line of calculator chips.


title: MOS Technology 6502

text: After the Mostek efforts fell through, Peddle approached Paivinen, who "immediately got it". On 19 August 1974, Chuck Peddle, Bill Mensch, Rod Orgill, Harry Bawcom, Ray Hirt, Terry Holdt, and Wil Mathys left Motorola to join MOS. Mike Janes joined later. Of the seventeen chip designers and layout people on the 6800 team, eight left. The goal of the team was to design and produce a low-cost microprocessor for embedded applications and to target as wide as possible a customer base. This would be possible only if the microprocessor was low cost, and the team set the price goal at in volume. Mensch later stated the goal was not the processor price itself, but to create a set of chips that could sell at to compete with the recently-introduced Intel 4040 that sold for in a similar complete chipset.


title: MOS Technology 6502

text: Chips are produced by printing multiple copies of the chip design on the surface of a "wafer", a thin disk of highly pure silicon. Smaller chips can be printed in greater numbers on the same wafer, decreasing their relative price. Additionally, wafers always include some number of tiny physical defects that are scattered across the surface. Any chip printed in that location will fail and has to be discarded. Smaller chips mean any single copy is less likely to be printed on a defect. For both of these reasons, the cost of the final product is strongly dependent on the size of the chip design.


title: MOS Technology 6502

text: The original 6800 chips were intended to be , but layout was completed at , or an area of 29.0 mm. For the new design, the cost goal demanded a size goal of , or an area of . Several new techniques would be needed to hit this goal.


title: MOS Technology 6502

text: There were two significant advances that arrived in the market just as the 6502 was being designed that provided significant cost reductions. The first was the move to depletion-load NMOS. The 6800 used an early NMOS process that required three supply voltages, but one of the chip's features was an onboard voltage doubler that allowed a single +5 V supply be used for +5, −5 and +12 V internally, as opposed to other chips of the era like the Intel 8080 that required three separate supply pins. While this feature reduced the complexity of the power supply and pin layout, it still required separate power rails to the various gates on the chip, driving up complexity and size. By moving to the new depletion-load design, a single +5 V supply was all that was needed, eliminating all of this complexity.


title: MOS Technology 6502

text: A further practical advantage was that the clock signal for earlier CPUs had to be strong enough to survive all the dissipation as it traveled through the circuits, which almost always required a separate external chip that could supply a powerful signal. With the reduced power requirements of NMOS, the clock could be moved onto the chip, simplifying the overall computer design. These changes greatly reduced complexity and the cost of implementing a complete system.


title: MOS Technology 6502

text: Another change that was taking place was the introduction of projection masking. Previously, chips were patterned onto the surface of the wafer by placing a mask on the surface of the wafer and then shining a bright light on it. The masks often picked up tiny bits of dirt or photoresist as they were lifted off the chip, causing flaws in those locations on any subsequent masking. With complex designs like CPUs, 5 or 6 such masking steps would be used, and the chance that at least one of these steps would introduce a flaw was very high. In most cases, 90% of such designs were flawed, resulting in a 10% yield. The price of the working examples had to cover the production cost of the 90% that were thrown away.


title: MOS Technology 6502

text: In 1973, Perkin-Elmer introduced the Micralign system, which projected an image of the mask on the wafer instead of requiring direct contact. Masks no longer picked up dirt from the wafers and lasted on the order of 100,000 uses rather than 10. This eliminated step-to-step failures and the high flaw rates formerly seen on complex designs. Yields on CPUs immediately jumped from 10% to 60 or 70%. This meant the price of the CPU declined roughly the same amount and the microprocessor suddenly became a commodity device.


title: MOS Technology 6502

text: MOS Technology's existing fabrication lines were based on the older PMOS technology, they had not yet begun to work with NMOS when the team arrived. Paivinen promised to have an NMOS line up and running in time to begin the production of the new CPU. He delivered on the promise, the new line was ready by June 1975.


title: MOS Technology 6502

text: Chuck Peddle, Rod Orgill, and Wil Mathys designed the initial architecture of the new processors. A September 1975 article in EDN magazine gives this summary of the design:


title: MOS Technology 6502

text: The MOS Technology 650X family represents a conscious attempt of eight former Motorola employees who worked on the development of the 6800 system to put out a part that would replace and outperform the 6800, yet undersell it. With the benefit of hindsight gained on the 6800 project, the MOS Technology team headed by Chuck Peddle, made the following architectural changes in the Motorola CPU…


title: MOS Technology 6502

text: The main change in terms of chip size was the elimination of the tri-state drivers from the address bus outputs. This had been included in the 6800 to allow it to work with other chips in direct memory access (DMA) and co-processing roles, at the cost of significant die space. In practice, using such a system required the other devices to be similarly complex, and designers instead tended to use off-chip systems to coordinate such access. The 6502 simply removed this feature, in keeping with its design as an inexpensive controller being used for specific tasks and communicating with simple devices. Peddle suggested that anyone that actually required this style of access could implement it with a single 74158.


title: MOS Technology 6502

text: The next major difference was to simplify the registers. To start with, one of the two accumulators was removed. General-purpose registers like accumulators have to be accessed by many parts of the instruction decoder, and thus require significant amounts of wiring to move data to and from their storage. Two accumulators makes many coding tasks easier, but costs the chip design itself significant complexity. Further savings were made by reducing the stack register from 16 to 8 bits, meaning that the stack could only be 256 bytes long, which was enough for its intended role as a microcontroller.


title: MOS Technology 6502

text: The 16-bit IX index register was split in two, becoming X and Y. More importantly, the style of access changed; in the 6800, IX held a 16-bit address, which was offset by an 8-bit number supplied with the instruction, the two were added to produce the final address. In the 6502 (and most other designs), the 16-bit base address was stored in the instruction, and the X or Y was added to it.


title: MOS Technology 6502

text: Finally, the instruction set was simplified, freeing up room in the decoder and control logic. Of the original 72 instructions in the 6800, 56 were left. Among those removed were any instruction that moved data between the 6800's two accumulators, and several branch instructions inspired by the PDP-11, like the ability to directly compare two numeric values. The 6502 used a simpler system that handled comparisons by performing math on the accumulator and then examining result flags.


title: MOS Technology 6502

text: The chip's high-level design had to be turned into drawings of transistors and interconnects. At MOS Technology, the "layout" was a very manual process done with color pencils and vellum paper. The layout consisted of thousands of polygon shapes on six different drawings; one for each layer of the fabrication process. Given the size limits, the entire chip design had to be constantly considered. Mensch and Paivinen worked on the instruction decoder while Mensch, Peddle and Orgill worked on the ALU and registers. A further advance, developed at a party, was a way to share some of the internal wiring to allow the ALU to be reduced in size.


title: MOS Technology 6502

text: In spite of their best efforts, the final design ended up being 5 mils too wide. The first 6502 chips were , or an area of 19.8 mm. The rotate right instruction (ROR) did not work in the first silicon, so the instruction was temporarily omitted from the published documents, but the next iteration of the design shrank the chip and corrected the rotate right instruction, which was then included in revised documentation.


title: MOS Technology 6502

text: MOS would introduce two microprocessors based on the same underlying design: the 6501 would plug into the same socket as the Motorola 6800, while the 6502 re-arranged the pinout to support an on-chip clock oscillator. Both would work with other support chips designed for the 6800. They would not run 6800 software because they had a different instruction set, different registers, and mostly different addressing modes. Rod Orgill was responsible for the 6501 design; he had assisted John Buchanan at Motorola on the 6800. Bill Mensch did the 6502; he was the designer of the 6820 Peripheral Interface Adapter (PIA) at Motorola. Harry Bawcom, Mike Janes and Sydney-Anne Holt helped with the layout.


title: MOS Technology 6502

text: MOS Technology's microprocessor introduction was different from the traditional months-long product launch. The first run of a new integrated circuit is normally used for internal testing and shared with select customers as "engineering samples". These chips often have a minor design defect or two that will be corrected before production begins. Chuck Peddle's goal was to sell the first run 6501 and 6502 chips to the attendees at the Wescon trade show in San Francisco beginning on September 16, 1975. Peddle was a very effective spokesman and the MOS Technology microprocessors were extensively covered in the trade press. One of the earliest was a full-page story on the MCS6501 and MCS6502 microprocessors in the July 24, 1975 issue of "Electronics" magazine. Stories also ran in "EE Times" (August 24, 1975), "EDN" (September 20, 1975), "Electronic News" (November 3, 1975), "Byte" (November 1975) and "Microcomputer Digest" (November 1975). Advertisements for the 6501 appeared in several publications the first week of August 1975. The 6501 would be for sale at Wescon for each. In September 1975, the advertisements included both the 6501 and the 6502 microprocessors. The 6502 would cost only ().


title: MOS Technology 6502

text: When MOS Technology arrived at Wescon, they found that exhibitors were not permitted to sell anything on the show floor. They rented the MacArthur Suite at the St. Francis Hotel and directed customers there to purchase the processors. At the suite, the processors were stored in large jars to imply that the chips were in production and readily available. The customers did not know the bottom half of each jar contained non-functional chips. The chips were and while the documentation package was an additional . Users were encouraged to make photocopies of the documents, an inexpensive way for MOS Technology to distribute product information. The preliminary data sheets listed just 55 instructions excluding the Rotate Right (ROR) instruction which did not work correctly on these early chips. The reviews in "Byte" and "EDN" noted the lack of the ROR instruction. The next revision of the layout fixed this problem and the May 1976 datasheet listed 56 instructions. Peddle wanted every interested engineer and hobbyist to have access to the chips and documentation; other semiconductor companies only wanted to deal with "serious" customers. For example, Signetics was introducing the 2650 microprocessor and its advertisements asked readers to write for information on their company letterhead.


title: MOS Technology 6502

text: The 6501/6502 introduction in print and at Wescon was an enormous success. The downside was that the extensive press coverage got Motorola's attention. In October 1975, Motorola reduced the price of a single 6800 microprocessor from to . The system design kit was reduced to and it now came with a printed circuit board. On November 3, 1975, Motorola sought an injunction in Federal Court to stop MOS Technology from making and selling microprocessor products. They also filed a lawsuit claiming patent infringement and misappropriation of trade secrets. Motorola claimed that seven former employees joined MOS Technology to create that company's microprocessor products.


title: MOS Technology 6502

text: Motorola was a billion-dollar company with a plausible case and expensive lawyers. On October 30, 1974, Motorola had filed numerous patent applications on the microprocessor family and was granted twenty-five patents. The first was in June 1976 and the second was to Bill Mensch on July 6, 1976, for the 6820 PIA chip layout. These patents covered the 6800 bus and how the peripheral chips interfaced with the microprocessor. Motorola began making transistors in 1950 and had a portfolio of semiconductor patents. Allen-Bradley decided not to fight this case and sold their interest in MOS Technology back to the founders. Four of the former Motorola engineers were named in the suit: Chuck Peddle, Will Mathys, Bill Mensch and Rod Orgill. All were named inventors in the 6800 patent applications. During the discovery process, Motorola found that one engineer, Mike Janes, had ignored Peddle's instructions and brought his 6800 design documents to MOS Technology. In March 1976, the now independent MOS Technology was running out of money and had to settle the case. They agreed to drop the 6501 processor, pay Motorola ,000 and return the documents that Motorola contended were confidential. Both companies agreed to cross-license microprocessor patents. That May, Motorola dropped the price of a single 6800 microprocessor to . By November, Commodore had acquired MOS Technology.


title: MOS Technology 6502

text: With legal troubles behind them, MOS was still left with the problem of getting developers to try their processor, prompting Chuck Peddle to design the MDT-650 ("microcomputer development terminal") single-board computer. Another group inside the company designed the KIM-1, which was sold semi-complete and could be turned into a usable system with the addition of a 3rd party computer terminal and compact cassette drive. Much to their amazement, the KIM-1 sold well to hobbyists, tinkerers, and the engineers to which it had been targeted. The related Rockwell AIM-65 control, training, and development system also did well. The software in the AIM 65 was based on that in the MDT. Another roughly similar product was the Synertek SYM-1.


title: MOS Technology 6502

text: One of the first "public" uses for the design was the Apple I microcomputer, introduced in 1976. The 6502 was next used in the Commodore PET and the Apple II, both released in 1977. It was later used in the Atari 8-bit family and Acorn Atom home computers, the BBC Micro, VIC-20 and other designs both for home computers and business, such as Ohio Scientific and Oric. The 6510, a direct successor of the 6502 with a digital I/O port and a tri-state address bus, was the CPU utilized in the best-selling Commodore 64 home computer. 6502 or variants were used in all of Commodore's floppy disk drives for all of their 8-bit computers, from the PET line (some of which had two 6502-based CPUs) through the Commodore 128D, including the Commodore 64, and in all of Atari's disk drives for all of their 8-bit computer line, from the 400/800 through the XEGS.


title: MOS Technology 6502

text: Another important use of the 6500 family was in video games. The first to make use of the processor design was the Atari VCS, later renamed the Atari 2600. The VCS used a 6502 variant named the 6507, which had fewer pins, so it could address only 8 KB of memory. Millions of the Atari consoles would be sold, each with a MOS processor. Another significant use was by the Nintendo Entertainment System and Famicom. The 6502 used in the NES was a second source version by Ricoh, a partial system on a chip, that lacked the binary-coded decimal mode but added 22 memory-mapped registers and on-die hardware for sound generation, joypad reading, and sprite list DMA. Called 2A03 in NTSC consoles and 2A07 in PAL consoles (the difference being the memory divider ratio and a lookup table for audio sample rates), this processor was produced exclusively for Nintendo. The Atari Lynx used a 4 MHz version of the chip, the 65SC02.


title: MOS Technology 6502

text: In the 1980s, a popular electronics magazine Elektor/Elektuur used the processor in its microprocessor development board Junior Computer.


title: MOS Technology 6502

text: The 6502 is a little-endian 8-bit processor with a 16-bit address bus. The original versions were fabricated using an process technology chip with a die size of (advertised as ), for a total area of 16.6 mm.


title: MOS Technology 6502

text: The internal logic runs at the same speed as the external clock rate, but despite the low clock speeds (typically in the neighborhood of 1 to ), the 6502's performance was competitive with other contemporary CPUs using significantly faster clocks. This is partly due to a simple state machine implemented by combinational (clockless) logic to a greater extent than in many other designs; the two-phase clock (supplying two synchronizations per cycle) could thereby control the machine cycle directly. Typical instructions might take half as many cycles to complete on the 6502 as on contemporary designs. Like most simple CPUs of the era, the dynamic NMOS 6502 chip is not sequenced by a microcode ROM but uses a PLA (which occupied about 15% of the chip area) for instruction decoding and sequencing. As in most 8-bit microprocessors, the chip does some limited overlapping of fetching and execution.


title: MOS Technology 6502

text: The low clock frequency moderated the speed requirement of memory and peripherals attached to the CPU, as only about 50% of the clock cycle was available for memory access (due to the asynchronous design, this fraction varied strongly among chip versions). This was critical at a time when affordable memory had access times in the range .


title: MOS Technology 6502

text: Because the chip only accessed memory during certain parts of the clock cycle, and those cycles were indicated by the PHI2-low clock-out pin, other chips in a system could access memory during those times when the 6502 was off the bus. This was sometimes known as "hidden access". This technique was widely used by computer systems; they would use memory capable of access at 2 MHz, and then run the CPU at 1 MHz. This guaranteed that the CPU and video hardware could interleave their accesses, with a total performance matching that of the memory device. When faster memories became available in the 1980s, newer machines could run at higher clock rates, like the 2 MHz CPU in the BBC Micro, and still use the bus sharing techniques.


title: MOS Technology 6502

text: Like its precursor, the 6800, the 6502 has very few registers. The 6502's registers include one 8-bit accumulator register (A), two 8-bit index registers (X and Y), 7 processor status flag bits (P; from bit 7 to bit 0 these are the negative (N), overflow (V), "reserved", break (B), decimal (D), interrupt disable (I), zero (Z) and carry (C) flag), an 8-bit stack pointer (S), and a 16-bit program counter (PC). This compares to a typical design of the same era, the Z80, which has eight general-purpose 8-bit registers, which can be combined into four 16-bit ones. The Z80 also had a complete set of alternate registers, which made a total of sixteen general-purpose registers.


title: MOS Technology 6502

text: In order to make up somewhat for the lack of registers, the 6502 included a "zero-page" addressing mode that uses one address byte in the instruction instead of the two needed to address the full of memory. This provides fast access to the first of RAM by using shorter instructions. Chuck Peddle has said in interviews that the specific intention was to allow these first of RAM to be used like registers.


title: MOS Technology 6502

text: The stack address space is to memory page codice_1, i.e. the address range codice_2–codice_3 (codice_4–codice_5). Software access to the stack is done via four implied addressing mode instructions, whose functions are to push or pop (pull) the accumulator or the processor status register. The same stack is also used for subroutine calls via the JSR (jump to subroutine) and RTS (return from subroutine) instructions and for interrupt handling.


title: MOS Technology 6502

text: The chip uses the index and stack registers effectively with several addressing modes, including a fast "direct page" or "zero page" mode, similar to that found on the PDP-8, that accesses memory locations from addresses 0 to 255 with a single 8-bit address (saving the cycle normally required to fetch the high-order byte of the address)code for the 6502 uses the zero page much as code for other processors would use registers. On some 6502-based microcomputers with an operating system, the operating system uses most of zero page, leaving only a handful of locations for the user.


title: MOS Technology 6502

text: Addressing modes also include "implied" (1-byte instructions); "absolute" (3 bytes); "indexed absolute" (3 bytes); "indexed zero-page" (2 bytes); "relative" (2 bytes); "accumulator" (1); "indirect,x" and "indirect,y" (2); and "immediate" (2). Absolute mode is a general-purpose mode. Branch instructions use a signed 8-bit offset relative to the instruction after the branch; the numerical range −128..127 therefore translates to 128 bytes backward and 127 bytes forward from the instruction following the branch (which is 126 bytes backward and 129 bytes forward from the start of the branch instruction). Accumulator mode uses the accumulator as an effective address and does not need any operand data. Immediate mode uses an 8-bit literal operand.


title: MOS Technology 6502

text: The indirect modes are useful for array processing and other looping. With the 5/6 cycle "(indirect),y" mode, the 8-bit Y register is added to a 16-bit base address read from zero page, which is located by a single byte following the opcode. The Y register is therefore an "index" register in the sense that it is used to hold an actual "index" (as opposed to the X register in the 6800, where a base address was directly stored and to which an immediate offset could be added). Incrementing the index register to walk the array byte-wise takes only two additional cycles. With the less frequently used "(indirect,x)" mode the effective address for the operation is found at the zero page address formed by adding the second byte of the instruction to the contents of the X register. Using the indexed modes, the zero page effectively acts as a set of up to 128 additional (though very slow) address registers.


title: MOS Technology 6502

text: The 6502 is capable of performing addition and subtraction in binary or binary-coded decimal. Placing the CPU into BCD mode with the codice_6 (set D flag) instruction results in decimal arithmetic, in which codice_7 would result in $00 and the carry (C) flag being set. In binary mode (codice_8, clear D flag), the same operation would result in $9A and the carry flag being cleared. Other than Atari BASIC, BCD mode was seldom used in home-computer applications.


title: MOS Technology 6502

text: 6502 instruction operation codes ("opcodes") are 8 bits long and have the general form AAABBBCC, where AAA and CC define the opcode, and BBB defines the addressing mode.


title: MOS Technology 6502

text: For instance, consider the codice_9 instruction, which performs a bitwise OR on the bits in the accumulator with another value. The instruction opcode is of the form 000bbb01, where bbb may be 010 for an immediate mode value (constant), 001 for zero-page fixed address, 011 for an absolute address, and so on.


title: MOS Technology 6502

text: This pattern is not absolute, and there are a number of exceptions. However, where it does apply, it allows one to easily deconstruct opcode values back to assembly mnemonics for the majority of instructions, handling the edge cases with special-purpose code.


title: MOS Technology 6502

text: Of the 256 possible opcodes available using an 8-bit pattern, the original 6502 uses 151 of them, organized into 56 instructions with (possibly) multiple addressing modes. Depending on the instruction and addressing mode, the opcode may require zero, one or two additional bytes for operands. Hence 6502 machine instructions vary in length from one to three bytes. The operand is stored in the 6502's customary little-endian format.


title: MOS Technology 6502

text: The 65C816, the 16-bit CMOS descendant of the 6502, also supports 24-bit addressing, which results in instructions being assembled with three-byte operands, also arranged in little-endian format.


title: MOS Technology 6502

text: The remaining 105 opcodes are undefined. In the original design, instructions where the low-order 4 bits ("nibble") were 3, 7, B or F were not used, providing room for future expansion. Likewise, the $2x column had only a single entry, codice_10. The remaining 25 empty slots were distributed. Some of the empty slots were used in the 65C02 to provide both new instructions and variations on existing ones with new addressing modes. The $Fx instructions were initially left free to allow 3rd-party vendors to add their own instructions, but later versions of the 65C02 standardized a set of bit fiddling instructions developed by Rockwell Semiconductor.


title: MOS Technology 6502

text: A 6502 assembly language statement consists of a three-character instruction mnemonic, followed by any operands. Instructions that do not take a separate operand but target a single register based on the addressing mode combine the target register in the instruction mnemonic, so the assembler uses codice_11 as opposed to codice_12 to increment the X register.


title: MOS Technology 6502

text: The processor's non-maskable interrupt (NMI) input is edge sensitive, which means that the interrupt is triggered by the falling edge of the signal rather than its level. The implication of this feature is that a wired-OR interrupt circuit is not readily supported. However, this also prevents nested NMI interrupts from occurring until the hardware makes the NMI input inactive again, often under control of the NMI interrupt handler.


title: MOS Technology 6502

text: The simultaneous assertion of the NMI and IRQ (maskable) hardware interrupt lines causes IRQ to be ignored. However, if the IRQ line remains asserted after the servicing of the NMI, the processor will immediately respond to IRQ, as IRQ is level sensitive. Thus a sort of built-in interrupt priority was established in the 6502 design.


title: MOS Technology 6502

text: The B flag is set by the 6502's periodically sampling its NMI edge detector's output and its IRQ input. The IRQ signal being driven low is only recognized though if IRQs are allowed by the I flag. If in this way a NMI request or (maskable) IRQ is detected the B flag is set to zero and causes the processor to execute the BRK instruction next instead of executing the next instruction based on the program counter.


title: MOS Technology 6502

text: The BRK instruction then pushes the processor status onto the stack, with the B flag bit set to zero. At the end of its execution the BRK instruction resets the B flag's value to one. This is the only way the B flag can be modified. If an instruction other than the BRK instruction pushes the B flag onto the stack as part of the processor status the B flag always has the value one.


title: MOS Technology 6502

text: A high-to-low transition on the SO input pin will set the processor's overflow status bit. This can be used for fast response to external hardware. For example, a high-speed polling device driver can poll the hardware once in only three cycles using a Branch-on-oVerflow-Clear (codice_13) instruction that branches to itself until overflow is set by an SO falling transition. The Commodore 1541 and other Commodore floppy disk drives use this technique to detect when the serializer is ready to transfer another byte of disk data. The system hardware and software design must ensure that an SO will not occur during arithmetic processing and disrupt calculations.


title: MOS Technology 6502

text: The Western Design Center designed and currently produces the WDC 65C816S processor, a 16-bit, static-core successor to the 65C02. The W65C816S is a newer variant of the 65C816, which is the core of the Apple IIGS computer and is the basis of the Ricoh 5A22 processor that powers the Super Nintendo Entertainment System. The W65C816S incorporates minor improvements over the 65C816 that make the newer chip not an exact hardware-compatible replacement for the earlier one. Among these improvements was conversion to a static core, which makes it possible to stop the clock in either phase without the registers losing data. Available through electronics distributors, as of March 2020, the W65C816S is officially rated for 14 MHz operation.


title: MOS Technology 6502

text: The Western Design Center also designed and produced the 65C802, which was a 65C816 core with a 64-kilobyte address space in a 65(C)02 pin-compatible package. The 65C802 could be retrofitted to a 6502 board and would function as a 65C02 on power-up, operating in "emulation mode." As with the 65C816, a two-instruction sequence would switch the 65C802 to "native mode" operation, exposing its 16-bit accumulator and index registers, and other 65C816 features. The 65C802 was not widely used and production ended.


title: MOS Technology 6502

text: The following 6502 assembly language source code is for a subroutine named codice_14, which copies a null-terminated character string from one location to another, converting upper-case letter characters to lower-case letters. The string being copied is the "source", and the string into which the converted source is stored is the "destination".


title: Human–computer interaction

text: Human–computer interaction (HCI) is research in the design and the use of computer technology, which focuses on the interfaces between people (users) and computers. HCI researchers observe the ways humans interact with computers and design technologies that allow humans to interact with computers in novel ways. A device that allows interaction between human being and a computer is known as a "Human-computer Interface (HCI)".


title: Human–computer interaction

text: As a field of research, human–computer interaction is situated at the intersection of computer science, behavioral sciences, design, media studies, and several other fields of study. The term was popularized by Stuart K. Card, Allen Newell, and Thomas P. Moran in their 1983 book, "The Psychology of Human–Computer Interaction." The first known use was in 1975 by Carlisle. The term is intended to convey that, unlike other tools with specific and limited uses, computers have many uses which often involve an open-ended dialogue between the user and the computer. The notion of dialogue likens human–computer interaction to human-to-human interaction: an analogy that is crucial to theoretical considerations in the field.


title: Human–computer interaction

text: Humans interact with computers in many ways, and the interface between the two is crucial to facilitating this interaction. HCI is also sometimes termed "human–machine interaction" (HMI), "man-machine interaction" (MMI) or "computer-human interaction" (CHI). Desktop applications, internet browsers, handheld computers, and computer kiosks make use of the prevalent graphical user interfaces (GUI) of today. Voice user interfaces (VUI) are used for speech recognition and synthesizing systems, and the emerging multi-modal and Graphical user interfaces (GUI) allow humans to engage with embodied character agents in a way that cannot be achieved with other interface paradigms. The growth in human–computer interaction field has led to an increase in the quality of interaction, and resulted in many new areas of research beyond. Instead of designing regular interfaces, the different research branches focus on the concepts of multimodality over unimodality, intelligent adaptive interfaces over command/action based ones, and active interfaces over passive interfaces.


title: Human–computer interaction

text: The Association for Computing Machinery (ACM) defines human–computer interaction as "a discipline that is concerned with the design, evaluation, and implementation of interactive computing systems for human use and with the study of major phenomena surrounding them". An important facet of HCI is user satisfaction (or End-User Computing Satisfaction). It goes on to say:


title: Human–computer interaction

text: "Because human–computer interaction studies a human and a machine in communication, it draws from supporting knowledge on both the machine and the human side. On the machine side, techniques in computer graphics, operating systems, programming languages, and development environments are relevant. On the human side, communication theory, graphic and industrial design disciplines, linguistics, social sciences, cognitive psychology, social psychology, and human factors such as computer user satisfaction are relevant. And, of course, engineering and design methods are relevant."


title: Human–computer interaction

text: Due to the multidisciplinary nature of HCI, people with different backgrounds contribute to its success.


title: Human–computer interaction

text: Poorly designed human-machine interfaces can lead to many unexpected problems. A classic example is the Three Mile Island accident, a nuclear meltdown accident, where investigations concluded that the design of the human-machine interface was at least partly responsible for the disaster. Similarly, accidents in aviation have resulted from manufacturers' decisions to use non-standard flight instruments or throttle quadrant layouts: even though the new designs were proposed to be superior in basic human-machine interaction, pilots had already ingrained the "standard" layout. Thus, the conceptually good idea had unintended results.


title: Human–computer interaction

text: The human–computer interface can be described as the point of communication between the human user and the computer. The flow of information between the human and computer is defined as the "loop of interaction". The loop of interaction has several aspects to it, including:


title: Human–computer interaction

text: Human–computer interaction studies the ways in which humans make—or do not make—use of computational artifacts, systems, and infrastructures. Much of the research in this field seeks to "improve" the human–computer interaction by improving the "usability" of computer interfaces. How usability is to be precisely understood, how it relates to other social and cultural values, and when it is, and when it may not be a desirable property of computer interfaces is increasingly debated.


title: Human–computer interaction

text: Visions of what researchers in the field seek to achieve might vary. When pursuing a cognitivist perspective, researchers of HCI may seek to align computer interfaces with the mental model that humans have of their activities. When pursuing a post-cognitivist perspective, researchers of HCI may seek to align computer interfaces with existing social practices or existing sociocultural values.


title: Human–computer interaction

text: Researchers in HCI are interested in developing design methodologies, experimenting with devices, prototyping software and hardware systems, exploring interaction paradigms, and developing models and theories of interaction.


title: Human–computer interaction

text: The following experimental design principles are considered, when evaluating a current user interface, or designing a new user interface:


title: Human–computer interaction

text: Various strategies delineating methods for human–PC interaction design have developed since the conception of the field during the 1980s. Most plan philosophies come from a model for how clients, originators, and specialized frameworks interface. Early techniques treated clients' psychological procedures as unsurprising and quantifiable and urged plan specialists to look at subjective science to establish zones, (for example, memory and consideration) when structuring UIs. Present-day models, in general, center around a steady input and discussion between clients, creators, and specialists and push for specialized frameworks to be folded with the sorts of encounters clients need to have, as opposed to wrapping user experience around a finished framework.


title: Human–computer interaction

text: Displays are human-made artifacts designed to support the perception of relevant system variables and facilitate further processing of that information. Before a display is designed, the task that the display is intended to support must be defined (e.g., navigating, controlling, decision making, learning, entertaining, etc.). A user or operator must be able to process whatever information a system generates and displays; therefore, the information must be displayed according to principles to support perception, situation awareness, and understanding.


title: Human–computer interaction

text: Christopher Wickens et al. defined 13 principles of display design in their book "An Introduction to Human Factors Engineering".


title: Human–computer interaction

text: These principles of human perception and information processing can be utilized to create an effective display design. A reduction in errors, a reduction in required training time, an increase in efficiency, and an increase in user satisfaction are a few of the many potential benefits that can be achieved by utilizing these principles.


title: Human–computer interaction

text: Certain principles may not apply to different displays or situations. Some principles may also appear to be conflicting, and there is no simple solution to say that one principle is more important than another. The principles may be tailored to a specific design or situation. Striking a functional balance among the principles is critical for an effective design.


title: Human–computer interaction

text: "1. Make displays legible (or audible)". A display's legibility is critical and necessary for designing a usable display. If the characters or objects being displayed cannot be discernible, the operator cannot effectively use them.


title: Human–computer interaction

text: "2. Avoid absolute judgment limits". Do not ask the user to determine the level of a variable based on a single sensory variable (e.g., color, size, loudness). These sensory variables can contain many possible levels.


title: Human–computer interaction

text: "3. Top-down processing". Signals are likely perceived and interpreted by what is expected based on a user's experience. If a signal is presented contrary to the user's expectation, more physical evidence of that signal may need to be presented to assure that it is understood correctly.


title: Human–computer interaction

text: "4. Redundancy gain". If a signal is presented more than once, it is more likely to be understood correctly. This can be done by presenting the signal in alternative physical forms (e.g., color and shape, voice and print, etc.), as redundancy does not imply repetition. A traffic light is a good example of redundancy, as color and position are redundant.


title: Human–computer interaction

text: "5. Similarity causes confusion: Use distinguishable elements". Signals that appear to be similar will likely be confused. The ratio of similar features to different features causes signals to be similar. For example, A423B9 is more similar to A423B8 than 92 is to 93. Unnecessarily similar features should be removed, and dissimilar features should be highlighted.


title: Human–computer interaction

text: "6. Principle of pictorial realism". A display should look like the variable that it represents (e.g., the high temperature on a thermometer shown as a higher vertical level). If there are multiple elements, they can be configured in a manner that looks like they would in the represented environment.


title: Human–computer interaction

text: "7. Principle of the moving part". Moving elements should move in a pattern and direction compatible with the user's mental model of how it actually moves in the system. For example, the moving element on an altimeter should move upward with increasing altitude.


title: Human–computer interaction

text: "8. Minimizing information access cost" or interaction cost. When the user's attention is diverted from one location to another to access necessary information, there is an associated cost in time or effort. A display design should minimize this cost by allowing frequently accessed sources to be located at the nearest possible position. However, adequate legibility should not be sacrificed to reduce this cost.


title: Human–computer interaction

text: "9. Proximity compatibility principle". Divided attention between two information sources may be necessary for the completion of one task. These sources must be mentally integrated and are defined to have close mental proximity. Information access costs should be low, which can be achieved in many ways (e.g., proximity, linkage by common colors, patterns, shapes, etc.). However, close display proximity can be harmful by causing too much clutter.


title: Human–computer interaction

text: "10. Principle of multiple resources". A user can more easily process information across different resources. For example, visual and auditory information can be presented simultaneously rather than presenting all visual or all auditory information.


title: Human–computer interaction

text: "11. Replace memory with visual information: knowledge in the world". A user should not need to retain important information solely in working memory or retrieve it from long-term memory. A menu, checklist, or another display can aid the user by easing the use of their memory. However, memory use may sometimes benefit the user by eliminating the need to reference some knowledge globally (e.g., an expert computer operator would rather use direct commands from memory than refer to a manual). The use of knowledge in a user's head and knowledge in the world must be balanced for an effective design.


title: Human–computer interaction

text: "12. Principle of predictive aiding". Proactive actions are usually more effective than reactive actions. A display should eliminate resource-demanding cognitive tasks and replace them with simpler perceptual tasks to reduce the user's mental resources. This will allow the user to focus on current conditions and to consider possible future conditions. An example of a predictive aid is a road sign displaying the distance to a certain destination.


title: Human–computer interaction

text: "13. Principle of consistency". Old habits from other displays will easily transfer to support the processing of new displays if they are designed consistently. A user's long-term memory will trigger actions that are expected to be appropriate. A design must accept this fact and utilize consistency among different displays.


title: Human–computer interaction

text: Social computing is an interactive and collaborative behavior considered between technology and people. In recent years, there has been an explosion of social science research focusing on interactions as the unit of analysis, as there are a lot of social computing technologies that include blogs, emails, social networking, quick messaging, and various others. Much of this research draws from psychology, social psychology, and sociology. For example, one study found out that people expected a computer with a man's name to cost more than a machine with a woman's name. Other research finds that individuals perceive their interactions with computers more negatively than humans, despite behaving the same way towards these machines.


title: Human–computer interaction

text: In human and computer interactions, a semantic gap usually exists between human and computer's understandings towards mutual behaviors. Ontology, as a formal representation of domain-specific knowledge, can be used to address this problem by solving the semantic ambiguities between the two parties.


title: Human–computer interaction

text: In the interaction of humans and computers, research has studied how computers can detect, process, and react to human emotions to develop emotionally intelligent information systems. Researchers have suggested several 'affect-detection channels'. The potential of telling human emotions in an automated and digital fashion lies in improvements to the effectiveness of human–computer interaction. The influence of emotions in human–computer interaction has been studied in fields such as financial decision-making using ECG and organizational knowledge sharing using eye-tracking and face readers as affect-detection channels. In these fields, it has been shown that affect-detection channels have the potential to detect human emotions and those information systems can incorporate the data obtained from affect-detection channels to improve decision models.


title: Human–computer interaction

text: A brain–computer interface (BCI), is a direct communication pathway between an enhanced or wired brain and an external device. BCI differs from neuromodulation in that it allows for bidirectional information flow. BCIs are often directed at researching, mapping, assisting, augmenting, or repairing human cognitive or sensory-motor functions.


title: Human–computer interaction

text: Security interactions are the study of interaction between humans and computers specifically as it pertains to information security. Its aim, in plain terms, is to improve the usability of security features in end user applications.


title: Human–computer interaction

text: Unlike HCI, which has roots in the early days of Xerox PARC during the 1970s, HCISec is a nascent field of study by comparison. Interest in this topic tracks with that of Internet security, which has become an area of broad public concern only in very recent years.


title: Human–computer interaction

text: Traditionally, computer use was modeled as a human–computer dyad in which the two were connected by a narrow explicit communication channel, such as text-based terminals. Much work has been done to make the interaction between a computing system and a human more reflective of the multidimensional nature of everyday communication. Because of potential issues, human–computer interaction shifted focus beyond the interface to respond to observations as articulated by D. Engelbart: "If ease of use were the only valid criterion, people would stick to tricycles and never try bicycles."


title: Human–computer interaction

text: How humans interact with computers continues to evolve rapidly. Human–computer interaction is affected by developments in computing. These forces include:


title: Human–computer interaction

text: One of the main conferences for new research in human–computer interaction is the annually held Association for Computing Machinery's (ACM) "Conference on Human Factors in Computing Systems", usually referred to by its short name CHI (pronounced "kai", or "Khai"). CHI is organized by ACM Special Interest Group on Computer-Human Interaction (SIGCHI). CHI is a large conference, with thousands of attendants, and is quite broad in scope. It is attended by academics, practitioners, and industry people, with company sponsors such as Google, Microsoft, and PayPal.


title: Human–computer interaction

text: There are also dozens of other smaller, regional, or specialized HCI-related conferences held around the world each year, including:


title: Mosasaur

text: Mosasaurs (from Latin "Mosa" meaning the 'Meuse', and Greek "" meaning 'lizard') comprise a group of extinct, large marine reptiles from the Late Cretaceous. Their first fossil remains were discovered in a limestone quarry at Maastricht on the Meuse in 1764. They belong to the order Squamata, which includes lizards and snakes.


title: Mosasaur

text: Mosasaurs probably evolved from an extinct group of aquatic lizards known as aigialosaurs in the Earliest Late Cretaceous with 42 described genera. During the last 20 million years of the Cretaceous period (Turonian–Maastrichtian ages), with the extinction of the ichthyosaurs and pliosaurs, mosasaurs became the dominant marine predators. They themselves became extinct as a result of the K-Pg event at the end of the Cretaceous period, about 66 million years ago.


title: Mosasaur

text: Mosasaurs breathed air, were powerful swimmers, and were well-adapted to living in the warm, shallow inland seas prevalent during the Late Cretaceous period. Mosasaurs were so well adapted to this environment that they most likely gave birth to live young, rather than returning to the shore to lay eggs as sea turtles do.


title: Mosasaur

text: The smallest-known mosasaur was "Dallasaurus turneri", which was less than long. Larger mosasaurs were more typical, with many species growing longer than . "Mosasaurus hoffmannii", the largest known species reached up to , but it has been considered to be probably overestimated by Cleary "et al." (2018). Currently, the largest publicly exhibited mosasaur skeleton in the world is on display at the Canadian Fossil Discovery Centre in Morden, Manitoba. The specimen, nicknamed "Bruce", is just over long, but this might be an overestimate as the skeleton was assembled for display prior to a 2010 reassessment of the species that found its original number of vertebrae to be exaggerated, implying that the actual size of the animal was likely smaller.


title: Mosasaur

text: Mosasaurs had a body shape similar to that of modern-day monitor lizards (varanids), but were more elongated and streamlined for swimming. Their limb bones were reduced in length and their paddles were formed by webbing between their long finger and toe bones. Their tails were broad, and supplied their locomotive power.


title: Mosasaur

text: Until recently, mosasaurs were assumed to have swum in a method similar to the one used today by conger eels and sea snakes, undulating their entire bodies from side to side. However, new evidence suggests that many advanced mosasaurs had large, crescent-shaped flukes on the ends of their tails, similar to those of sharks and some ichthyosaurs. Rather than use snake-like undulations, their bodies probably remained stiff to reduce drag through the water, while their tails provided strong propulsion. These animals may have lurked and pounced rapidly and powerfully on passing prey, rather than chasing after it.


title: Mosasaur

text: Early reconstructions showed mosasaurs with dorsal crests running the length of their bodies, which were based on misidentified remains of tracheal cartilage. By the time this error was discovered, depicting mosasaurs with such crests in artwork had already become a trend.


title: Mosasaur

text: Mosasaurs had double-hinged jaws and flexible skulls (much like those of snakes), which enabled them to gulp down their prey almost whole. A skeleton of "Tylosaurus proriger" from South Dakota included remains of the diving seabird "Hesperornis", a marine bony fish, a possible shark, and another, smaller mosasaur ("Clidastes"). Mosasaur bones have also been found with shark teeth embedded in them.


title: Mosasaur

text: One of the food items of mosasaurs were ammonites, molluscs with shells similar to those of "Nautilus", which were abundant in the Cretaceous seas. Holes have been found in fossil shells of some ammonites, mainly "Pachydiscus" and "Placenticeras". These were once interpreted as a result of limpets attaching themselves to the ammonites, but the triangular shape of the holes, their size, and their presence on both sides of the shells, corresponding to upper and lower jaws, is evidence of the bite of medium-sized mosasaurs. Whether this behaviour was common across all size classes of mosasaurs is not clear.


title: Mosasaur

text: Virtually all forms were active predators of fish and ammonites; a few, such as "Globidens", had blunt, spherical teeth, specialized for crushing mollusk shells. The smaller genera, such as "Platecarpus" and "Dallasaurus", which were about long, probably fed on fish and other small prey. The smaller mosasaurs may have spent some time in fresh water, hunting for food. The largest mosasaur "Mosasaurus hoffmannii" was the apex predator of the Late Cretaceous oceans, reaching more than in length and weighing up to in body mass.


title: Mosasaur

text: Despite the many mosasaur remains collected worldwide, knowledge of the nature of their skin coverings remains in its early stages. Few mosasaurid specimens collected from around the world retain fossilized scale imprints. This lack may be due to the delicate nature of the scales, which nearly eliminates the possibility of preservation, in addition to the preservation sediment types and the marine conditions under which the preservation occurred. Until the discovery of several mosasaur specimens with remarkably well-preserved scale imprints from late Maastrichtian deposits of the Muwaqqar Chalk Marl Formation of Harrana in Jordan, knowledge of the nature of mosasaur integument was mainly based on very few accounts describing early mosasaur fossils dating back to the upper Santonian–lower Campanian, such as the famous "Tylosaurus" specimen (KUVP-1075) from Gove County, Kansas.


title: Mosasaur

text: Material from Jordan has shown that the bodies of mosasaurs, as well as the membranes between their fingers and toes, were covered with small, overlapping, diamond-shaped scales resembling those of snakes. Much like those of modern reptiles, mosasaur scales varied across the body in type and size. In Harrana specimens, two types of scales were observed on a single specimen: keeled scales covering the upper regions of the body and smooth scales covering the lower. As ambush predators, lurking and quickly capturing prey using stealth tactics, they may have benefited from the nonreflective, keeled scales. Additionally, mosasaurs had large pectoral girdles, and such genera as "Plotosaurus" may have used their front flippers in a breaststroke motion to gain added bursts of speed during an attack on prey.


title: Mosasaur

text: More recently, a fossil of "Platecarpus tympaniticus" has been found that preserved not only skin impressions, but also internal organs. Several reddish areas in the fossil may represent the heart, lungs, and kidneys. The trachea is also preserved, along with part of what may be the retina in the eye. The placement of the kidneys is farther forward in the abdomen than it is in monitor lizards, and is more similar to those of cetaceans. As in cetaceans, the bronchi leading to the lungs run parallel to each other instead of splitting apart from one another as in monitors and other terrestrial reptiles. In mosasaurs, these features may be internal adaptations to fully marine lifestyles.


title: Mosasaur

text: In 2005, a case study by A.S. Schulp, E.W.A Mulder, and K. Schwenk outlined the fact that mosasaurs had paired fenestrae in their palates. In monitor lizards and snakes, paired fenestrae are associated with a forked tongue, which is flicked in and out to detect chemical traces and provide a directional sense of smell. They therefore proposed that mosasaurs probably also had a sensitive forked tongue.


title: Mosasaur

text: A study published in 2016 by T. Lyn Harrell, Alberto Pérez-Huerta and Celina Suarez showed that mosasaurs were endothermic. The study contradicted findings published in 2010 indicating mosasaurs were ectothermic. The 2010 study did not use warm-blooded animals for comparison but analogous groups of common marine animals. Based on comparisons with modern warm-blooded animals and fossils of known cold-blooded animals from the same time period, the 2016 study found mosasaurs likely had body temperatures similar to those of contemporary seabirds and were able to internally regulate their temperatures to remain warmer than the surrounding water.


title: Mosasaur

text: The coloration of mosasaurs was unknown until 2014, when the findings of Johan Lindgren of Lund University and colleagues revealed the pigment melanin in the fossilized scales of a mosasaur. Mosasaurs were likely countershaded, with dark backs and light underbellies, much like a great white shark or leatherback sea turtle, the latter of which had fossilized ancestors for which color was also determined. The findings were described in "Nature".


title: Mosasaur

text: Mosasaurs possessed a thecodont dentiton, meaning that the roots were cemented deeply into the jaw bone. Mosasaurs did not use permanent teeth but instead constantly shed them. Replacement teeth developed within a pit inside the roots of the original tooth called the resorption pit. This is done through a distinctively unique eight-stage process. The first stage was characterized by the mineralization of a small tooth crown developed elsewhere that descended into the resorption pit by the second stage. In the third stage, the developing crown firmly cemented itself within the resorption pit and grew in size; by the fourth stage, it would be of the same size as the crown in the original tooth. Stages five and six were characterized by the development of the replacement tooth's root: in stage five the root developed vertically, and in stage six the root expanded in all directions to the point that the replacement tooth became exposed and actively pushed on the original tooth. In the seventh stage, the original tooth was shed and the now-independent replacement tooth began to anchor itself into the vacancy. In the eighth and final stage, the replacement tooth has grown to firmly anchor itself.


title: Mosasaur

text: Mosasaur growth is not well understood, as specimens of juveniles are rare, and many were mistaken for hesperornithine birds when discovered 100 years ago. However, the discovery of several specimens of juvenile and neonate-sized mosasaurs unearthed more than a century ago indicate that mosasaurs gave birth to live young, and that they spent their early years of life out in the open ocean, not in sheltered nurseries or areas such as shallow water as previously believed. Whether mosasaurs provided parental care, like other marine reptiles such as plesiosaurs, is currently unknown. The discovery of young mosasaurs was published in the journal "Palaeontology".


title: Mosasaur

text: In late 2014 Guinness World Records awarded the museum with a record for Largest Publicly Displayed Mosasaur – Bruce. The record was added to the 2016 print edition of "Guinness World Records".