document_title: Tim Burton

question_text: where did tim burton got his start in the film industry

question_tokens: where did tim burton got his start in the film industry

text: Tim Burton

text: Early life[edit]

text: Burton was born in 1958, in Burbank, California, the son of Jean Burton (née Erickson), later the owner of a cat-themed gift shop, and William "Bill" Burton, a former minor league baseball player who was working for the Burbank Parks and Recreation Department.[2][3] As a preteen, Burton would make short films in his backyard on Evergreen Street using crude stop motion animation techniques or shoot them on 8 mm film without sound (one of his oldest known juvenile films is The Island of Doctor Agor, which he made when he was 13 years old). Burton attended Providencia Elementary School in Burbank. Burton went to Burbank High School, but he was not a particularly good student. He played on the water polo team at Burbank High. Burton was an introspective person and found pleasure in painting, drawing and watching movies. His future work would be heavily influenced by the works of such childhood heroes as Dr. Seuss and Roald Dahl.[4] After graduating from Burbank High School, Burton attended the California Institute of the Arts in Valencia, California, to study character animation.[5] As a student at CalArts, Burton made the shorts Stalk of the Celery Monster and King and Octopus.[6]

text: Early career: 1980s[edit]

text: Stalk of the Celery Monster attracted the attention of Walt Disney Productions' animation division, which offered Burton an animator's apprenticeship at the studio.[5] He worked as an animator, storyboard artist and concept artist on films such as The Fox and the Hound (1981), The Black Cauldron (1985) and Tron (1982). His concept art never made it into the finished films.

text: While at Disney in 1982, Burton made his first short, Vincent, a six-minute black-and-white stop motion film based on a poem written by the filmmaker, and depicting a young boy who fantasizes that he is his hero Vincent Price, with Price himself providing narration. The film was produced by Rick Heinrichs, whom Burton had befriended while working in the concept art department at Disney. The film was shown at the Chicago Film Festival and released, alongside the teen drama Tex, for two weeks in one Los Angeles cinema. This was followed by Burton's first live-action production Hansel and Gretel, a Japanese-themed adaptation of the Brothers Grimm fairy tale for the Disney Channel, which climaxes in a kung fu fight between Hansel and Gretel and the witch. Having aired once in 1983 at 10:30 pm on Halloween and promptly shelved, prints of the film are extremely difficult to locate, fueling rumors that the project did not exist. The short would finally go on public display in 2009 at the Museum of Modern Art, and again in 2011 as part of the Tim Burton art exhibit at LACMA.[7][8] It was again shown at the Seoul Museum of Art in 2012.[9]

text: Burton's next live-action short, Frankenweenie, was released in 1984. It tells the story of a young boy who tries to revive his dog after it is run over by a car. Filmed in black-and-white, it stars Barret Oliver, Shelley Duvall (with whom he would work again in 1986, directing an episode of her Faerie Tale Theatre) and Daniel Stern. After Frankenweenie was completed, Disney fired Burton, under the pretext of him spending the company's resources on doing a film that would be too dark and scary for children to see.[10]

text: Pee-wee's Big Adventure[edit]

text: Actor Paul Reubens saw Vincent[when?] and chose Burton to direct the cinematic spin-off of his popular character Pee-wee Herman. Pee-wee Herman gained mainstream popularity with a successful stage show at The Groundlings and the Roxy which was later turned into an HBO special. The film, Pee-wee's Big Adventure, was made on a budget of $8 million and grossed more than $40 million at the North American box office. Burton, a fan of the eccentric musical group Oingo Boingo, asked songwriter Danny Elfman to provide the music for the film. Since then, Elfman has scored every film that Tim Burton has directed, except for Ed Wood (because of a falling out that they had[11]), Sweeney Todd: The Demon Barber of Fleet Street (because the music was based on Stephen Sondheim's musical) and Miss Peregrine's Home for Peculiar Children.

text: Beetlejuice[edit]

text: After directing episodes for the revitalized version of '50s/'60s anthology horror series Alfred Hitchcock Presents and Shelley Duvall's Faerie Tale Theatre, Burton directed his next big project: Beetlejuice (1988), a supernatural comedy horror about a young couple forced to cope with life after death, and the family of pretentious yuppies who invade their treasured New England home. Their teenage daughter Lydia (Winona Ryder) has an obsession with death which allows her to see the deceased couple. Starring Alec Baldwin and Geena Davis, and featuring Michael Keaton as the obnoxious bio-exorcist Beetlejuice, the film grossed $80 million on a relatively low budget and won an Academy Award for Best Makeup. It would be converted into a cartoon of the same name, with Burton playing a role as executive producer, that ran on ABC and later Fox.

text: Batman[edit]

text: Burton's ability to produce hits with low budgets impressed studio executives, and he received his first big budget film, Batman. The production was plagued with problems. Burton repeatedly clashed with the film's producers, Jon Peters and Peter Guber, but the most notable debacle involved casting. For the title role, Burton chose to cast Michael Keaton as Batman following their previous collaboration in Beetlejuice, despite Keaton's average physique, inexperience with action films, and reputation as a comic actor. Although Burton won in the end, the furor over the casting provoked enormous fan animosity, to the extent that Warner Brothers' share price slumped.[citation needed] Burton had considered it ridiculous to cast a "bulked-up" ultra-masculine man as Batman, insisting that Batman should be an ordinary man who dressed up in an elaborate bat costume to frighten criminals. Burton cast Jack Nicholson as The Joker (Tim Curry being his second choice) in a move that helped assuage fans' fears, as well as attracting older audiences not as interested in a superhero film.[citation needed]

text: When the film opened in June 1989, it was backed by the biggest marketing and merchandising campaign in film history at the time, and became one of the biggest box office hits of all time, grossing over US$250 million in the U.S. and $400 million worldwide (numbers not adjusted for inflation) and earning critical acclaim for the performances of both Keaton and Nicholson, as well as the film's production aspects, which won the Academy Award for Best Art Direction. The success of the film helped establish Burton as a profitable director, and it proved to be a huge influence on future superhero films, which eschewed the bright, all-American heroism of Richard Donner's Superman for a grimmer, more realistic look and characters with more psychological depth. It also became a major inspiration for the successful 1990s cartoon Batman: The Animated Series, in as much as the darkness of the picture and its sequel allowed for a darker Batman on television.

text: Burton claimed that the graphic novel Batman: The Killing Joke was a major influence on his film adaptation of Batman:

text: I was never a giant comic book fan, but I've always loved the image of Batman and the Joker. The reason I've never been a comic book fan – and I think it started when I was a child – is because I could never tell which box I was supposed to read. I don't know if it was dyslexia or whatever, but that's why I loved The Killing Joke, because for the first time I could tell which one to read. It's my favorite. It's the first comic I've ever loved. And the success of those graphic novels made our ideas more acceptable.[12]

text: Edward Scissorhands[edit]

text: In 1990, Burton co-wrote (with Caroline Thompson) and directed Edward Scissorhands, re-uniting with Winona Ryder from Beetlejuice. His friend Johnny Depp, a teen idol at the end of the 1980s due primarily to his work on the hit TV series 21 Jump Street, was cast in the title role of Edward, who was the creation of an eccentric and old-fashioned inventor (played by Vincent Price in one of his last screen appearances). Edward looked human, but was left with scissors in the place of hands due to the untimely death of his creator. Set in suburbia (and shot in Lakeland, Florida), the film is largely seen as Burton's autobiography of his childhood in Burbank. Depp wrote a similar comment in the foreword to Mark Salisbury's book, Burton on Burton, regarding his first meeting with Burton over the casting of the film. Edward Scissorhands is considered one of Burton's best movies by some critics.[13] Following this collaboration with Burton, Depp starred in Ed Wood, Sleepy Hollow, Charlie and the Chocolate Factory, Corpse Bride, Sweeney Todd: The Demon Barber of Fleet Street, Alice in Wonderland, and Dark Shadows.

text: In 2004, Matthew Bourne came to Burton with the idea to turn the story of Edward into a ballet. In 2005, the ballet first aired. It has toured the UK, the U.S., Canada, Australia and parts of Europe.

text: Batman Returns[edit]

text: The day Warner Brothers declined to make the more personal Scissorhands, after the success of Batman, Burton agreed to direct the sequel for Warner Brothers on the condition that he would be granted total control. The result was Batman Returns, which featured Michael Keaton returning as Batman, and a new triad of villains: Danny DeVito (as the Penguin), Michelle Pfeiffer (as Catwoman) and Christopher Walken as Max Shreck, an evil corporate tycoon and original character created for the film. Darker and considerably more personal than its predecessor, concerns were raised that the film was too scary for children. Audiences were more uncomfortable at the film's overt sexuality, personified by the sleek, fetish-inspired styling of Catwoman's costume. One critic remarked, "too many villains spoiled the Batman", highlighting Burton's decision to focus the storyline more on the villains instead of Batman. The film also polarized the fanbase, with some loving the darkness and quirkiness, while others felt it was not true to the core aspects of the source material. Burton made many changes to the Penguin which would subsequently be applied to the character in both comics and television. While in the comics, he was an ordinary man, Burton created a freak of nature resembling a penguin with webbed, flipper-like fingers, a hooked, beak-like nose, and a penguin-like body (resulting in a rotund, obese man). Released in 1992, Batman Returns grossed $282.8 million worldwide, making it financial success, though not to the extent of its predecessor.

text: The Nightmare Before Christmas[edit]

text: Burton wrote and produced, but did not direct, due to schedule constraints on Batman Returns, The Nightmare Before Christmas (1993) for Disney, originally meant to be a children's book in rhyme. The film was directed by Henry Selick and written by Caroline Thompson, based on Burton's original story, world and characters. The film received positive reviews for the stop motion animation, musical score and original storyline. It was a box office success, grossing $50 million. Burton collaborated with Selick again for James and the Giant Peach (1996), which Burton co-produced.

text: Cabin Boy[edit]

text: In 1994, Burton and frequent co-producer Denise Di Novi produced the 1994 fantasy-comedy Cabin Boy, starring comedian Chris Elliott and directed/written by Adam Resnick. Burton was originally supposed to direct the film after seeing Elliott perform on Get a Life, but handed the directing responsibility to Resnick once he was offered Ed Wood. The reception to the film was mixed. Chris Elliott won a 1995 Razzie Award for "Worst New Star" with his performance.[14] On Metacritic, the film holds a score of 21 out of 100, but has a 45% "rotten" rating on Rotten Tomatoes, indicating more mixed contemporary reviews.

text: Ed Wood[edit]

text: Burton's next film, Ed Wood (1994), was of a much smaller scale, depicting the life of Ed Wood, a filmmaker sometimes called "the worst director of all time". Starring Johnny Depp in the title role, the film is an homage to the low-budget science fiction and horror films of Burton's childhood, and handles its comical protagonist and his motley band of collaborators with surprising fondness and sensitivity. Owing to creative squabbles during the making of The Nightmare Before Christmas, Danny Elfman declined to score Ed Wood, and the assignment went to Howard Shore. While a commercial failure at the time of its release, Ed Wood was well received by critics. Martin Landau received an Academy Award in the Best Supporting Actor category for his portrayal of Bela Lugosi, and the film received the award for Best Makeup.

text: Batman Forever[edit]

text: Despite Burton's intention to still lead the Batman franchise, Warner Bros. considered Batman Returns too dark and unsafe for children. To attract the young audience, it was decided that Joel Schumacher, who had directed films like The Client, lead the third film, while Burton would only produce it in conjunction with Peter MacGregor-Scott. Following this change and the changes made by the new director, Michael Keaton resigned from the lead role and was replaced by Val Kilmer. Filming began in late 1994 with new actors: Tommy Lee Jones as Harvey Dent/Two-Face, Nicole Kidman as Dr. Chase Meridian, Chris O'Donnell as Dick Grayson/Robin and Jim Carrey as Edward Nygma/ The Riddler; the only two actors who returned were Pat Hingle as Commissioner Gordon and Michael Gough as Alfred Pennyworth. The film, a combination of the darkness that characterized the saga and colors and neon signs proposed by Schumacher, was a huge box office success, earning $336 million, in spite of the controversy over the characters and plot. Warner Bros. demanded that Schumacher delete some scenes so the film did not have the same tone as its predecessor, Batman Returns (later they were added as deleted scenes on the 2005 DVD release).

text: James and the Giant Peach[edit]

text: In 1996, Burton and Selick reunited for the musical fantasy James and the Giant Peach, based on the book by Roald Dahl. The film, a combination of live action and stop motion footage, starred Richard Dreyfuss, Susan Sarandon, David Thewlis, Simon Callow and Jane Leeves among others, with Burton producing and Selick directing. The film was mostly praised by critics, and was nominated for the Academy Award for Best Original Musical or Comedy Score (by Randy Newman).

text: Mars Attacks![edit]

text: Elfman and Burton reunited for Mars Attacks! (1996). Based on a popular science fiction trading card series, the film was a hybrid of 1950s science fiction and 1970s all-star disaster films. Coincidence made it an inadvertent spoof of the blockbuster Independence Day, which had been released five months earlier. The film boasted an all-star cast, including Jack Nicholson, Glenn Close, Annette Bening, Danny DeVito, Pierce Brosnan, Michael J. Fox, Sarah Jessica Parker, Natalie Portman, Lukas Haas, Martin Short, Rod Steiger, Christina Applegate and Jack Black.

text: Superman Lives[edit]

text: After Kevin Smith had been hired to write a new Superman film, he suggested Burton to direct.[15] Burton came on and Warner Bros. set a theatrical release date for the summer of 1998, the 60th anniversary of the character's debut in Action Comics.[16] Nicolas Cage was signed on to play Superman, Burton hired Wesley Strick to rewrite Smith's script and the film entered pre-production in June 1997. For budgetary reasons, Warner Bros. ordered another rewrite from Dan Gilroy, delayed the film and ultimately put it on hold in April 1998. Burton then left to direct Sleepy Hollow.[16] Burton has depicted the experience as a difficult one, citing differences with producer Jon Peters and the studio, stating, "I basically wasted a year. A year is a long time to be working with somebody that you don't really want to be working with."[17]

text: Sleepy Hollow[edit]

text: Sleepy Hollow, released in late 1999, had a supernatural setting and contained another offbeat performance by Johnny Depp as Ichabod Crane, a detective with an interest in forensic science rather than the schoolteacher of Washington Irving's original tale. With Sleepy Hollow, Burton paid homage to the horror films of the English company Hammer Films. Christopher Lee, one of Hammer's stars, was given a cameo role. A host of Burton regulars appeared in supporting roles (Michael Gough, Jeffrey Jones and Christopher Walken, among others) and Christina Ricci was cast as Katrina van Tassel. A well-regarded supporting cast was headed by Miranda Richardson, Michael Gambon, Richard Griffiths and Ian McDiarmid. Mostly well received by critics, and with a special mention to Elfman's gothic score, the film won an Academy Award for Best Art Direction, as well as two BAFTAs for Best Costume Design and Best Production Design. A box office success, Sleepy Hollow was also a turning point for Burton. Along with change in his personal life (separation from actress Lisa Marie), Burton changed radically in style for his next project, leaving the haunted forests and colorful outcasts behind to go on to directing Planet of the Apes which, as Burton had repeatedly noted, was "not a remake" of the earlier film.

text: Planet of the Apes[edit]

text: Planet of the Apes was a commercial success, grossing $68 million in its opening weekend. The film has received mixed reviews and is widely considered inferior to the first adaptation of the novel.

text: Big Fish[edit]

text: In 2003, Burton directed Big Fish, based on the novel Big Fish: A Novel of Mythic Proportions by Daniel Wallace. The film is about a father telling the story of his life to his son using exaggeration and color. Starring Ewan McGregor as young Edward Bloom and Albert Finney as an older Edward Bloom, the film also stars Jessica Lange, Billy Crudup, Danny DeVito, Alison Lohman and Marion Cotillard. Big Fish is also notable as Miley Cyrus' first film—she plays "Young Ruthie" credited under her birth name, Destiny Hope Cyrus. Big Fish received four Golden Globe nominations as well as an Academy Award nomination for Elfman's score. Big Fish was also the second collaboration between Burton and Helena Bonham Carter, who played the characters of Jenny and the Witch.

text: Charlie and the Chocolate Factory[edit]

text: Charlie and the Chocolate Factory (2005) is an adaptation of the book of the same name by Roald Dahl. Starring Johnny Depp as Willy Wonka, Freddie Highmore as Charlie Bucket and Deep Roy as the Oompa-Loompas, the film generally took a more faithful approach to the source material than the 1971 adaptation, Willy Wonka & the Chocolate Factory, although some liberties were taken, such as adding Wonka's issue with his father (played by Christopher Lee). Charlie and the Chocolate Factory was later nominated for the Academy Award for Best Costume Design. The film made over $207 million domestically. Filming proved difficult as Burton, Depp, and Danny Elfman had to work on this and Burton's Corpse Bride at the same time.

text: Corpse Bride[edit]

text: Corpse Bride (2005) was Burton's first full-length stop motion film as a director, featuring the voices of Johnny Depp as Victor and Helena Bonham Carter (for whom the project was specifically created) as Emily in the lead roles. In this film, Burton was able again to use his familiar styles and trademarks, such as the complex interaction between light and darkness, and of being caught between two irreconcilable worlds.

text: The Killers[edit]

text: "Bones" (2006) was the first music video Burton directed. The song "Bones" is the sixth overall single by American indie rock band The Killers, the second released from their second studio album, Sam's Town. Starring in this video were actors Michael Steger and Devon Aoki. Also featured in the video are scenes from films like Creature from the Black Lagoon, Jason and the Argonauts and Lolita.

text: The band, as well as Steger and Aoki, change temporarily into partial CG skeletal versions of themselves, before becoming complete skeletons by the end of the video. At the 2007 Shockwaves NME Awards, it won the award for Best Video.

text: Burton went to direct a second music video for The Killers, starring Winona Ryder.[18]

text: Sweeney Todd: The Demon Barber of Fleet Street[edit]

text: The DreamWorks/Warner Bros. production was released on December 21, 2007. Burton's work on Sweeney Todd won the National Board of Review Award for Best Director,[19] received a Golden Globe nomination for Best Director[20] and won an Academy Award for Best Art Direction. Helena Bonham Carter won an Evening Standard British Film Award for her portrayal of Mrs. Lovett, as well as a Golden Globe nomination. The film blends explicit gore and Broadway tunes, and was well received by critics. Johnny Depp was nominated for the Best Actor Oscar for the role of Sweeney Todd. Depp also won the Golden Globe for Best Actor in a Musical/Comedy, as well as the award for Best Villain as Todd in the 2008 MTV Awards.

text: In 2005, filmmaker Shane Acker released his short film 9, a story about a sentient rag doll living in a post-apocalyptic world who tries to stop machines from destroying the rest of his eight fellow rag dolls. The film won numerous awards and was nominated for an Academy Award for Best Animated Short Film. After seeing the short film, Tim Burton and Timur Bekmambetov, director of Wanted, showed interest in producing a feature-length adaptation of the film. Directed by Acker, the full-length film was produced by Burton, written by Acker (story) and Pamela Pettler (screenplay, co-writer of Corpse Bride) and featured the voice work of Elijah Wood, John C. Reilly, Jennifer Connelly, Christopher Plummer, Martin Landau and Crispin Glover, among others.

text: Alice in Wonderland[edit]

text: In Burton's version, the story is set 13 years after the original Lewis Carroll tales. Mia Wasikowska was cast as Alice. The original start date was May 2008.[21] Torpoint and Plymouth were the locations used for filming from September 1 – October 14, and the film remains set in the Victorian era. During this time, filming took place in Antony House in Torpoint.[22] 250 local extras were chosen in early August.[23][24] Other production work took place in London.[25] The film was originally to be released in 2009, but was pushed to March 5, 2010.[26] Johnny Depp plays the Mad Hatter, while Matt Lucas is both Tweedledee and Tweedledum; Helena Bonham Carter portrays the Red Queen; Stephen Fry is the Cheshire Cat; Anne Hathaway stars as the White Queen; Alan Rickman voices Absolem the Caterpillar, Michael Sheen voices McTwisp the White Rabbit and Crispin Glover's head and voice were added onto a CGI body to play the Knave of Hearts.

text: Tim Burton appeared at the 2009 Comic-Con in San Diego, California, to promote both 9 and Alice in Wonderland. When asked about the filmmaking process by an attendee, he mentioned his "imaginary friend" who helps him out, prompting Johnny Depp to walk on stage to the applause of the audience. The film won two Academy Awards, for Best Art Direction and Best Costume Design.

text: Dark Shadows[edit]

text: Burton's film Dark Shadows once again starred Johnny Depp and Helena Bonham Carter in leading roles. The film was based on the original Dark Shadows gothic soap opera, which aired on ABC from 1966 to 1971. Other members of the cast included Michelle Pfeiffer, Eva Green, Jackie Earle Haley, Bella Heathcote, Gulliver McGrath and Chloë Grace Moretz. Filming began in April 2011, with the film released on May 11, 2012. Danny Elfman once again composed and conducted the score and soundtrack for the film, and Colleen Atwood was the costume designer. It has received mixed reviews from critics, some of whom think it is a tongue-in-cheek gothic comedy, visually appealing and fitting as an adaptation of the melodramatic soap opera, whereas others think the film has a very loose plot, is not particularly humorous, and that Burton and Depp's collaborative efforts have worn thin.

text: Abraham Lincoln: Vampire Hunter[edit]

text: Burton co-produced Abraham Lincoln: Vampire Hunter, with Timur Bekmambetov, who also served as director (they previously worked together in 9). The film, released on June 22, 2012, was based on the novel by Seth Grahame-Smith, who also wrote the film's screenplay and also authored Pride and Prejudice and Zombies. The film starred Benjamin Walker as Abraham Lincoln, Anthony Mackie as William H. Johnson, Joseph Mawle as Lincoln's father Thomas, Robin McLeavy as Lincoln's mother Nancy and Mary Elizabeth Winstead as Lincoln's love interest (and later wife) Mary Ann Todd. It received mixed reviews.[citation needed]

text: Frankenweenie[edit]

text: Burton remade his 1984 short film Frankenweenie as a feature-length stop motion film, distributed by Walt Disney Pictures.[27] He has said, "The film is based on a memory that I had when I was growing up and with my relationship with a dog that I had."[28] The film was released on October 5, 2012, and met with positive reviews.[29]

text: Big Eyes[edit]

text: Burton directed the 2014 biographical drama film Big Eyes about American artist Margaret Keane (Amy Adams), whose work was fraudulently claimed in the 1950s and 1960s by her then-husband, Walter Keane (Christoph Waltz), and their heated divorce trial after Margaret accused Walter of stealing credit for her paintings. The script was written by the screenwriters behind Burton's Ed Wood, Scott Alexander and Larry Karaszewski. The film, pitched a few years earlier, was intended to be directed by Alexander and Karaszewski and produced by Burton, featuring Reese Witherspoon and Ryan Reynolds as its leads. Filming began in Vancouver, British Columbia, in mid-2013. The film was distributed by The Weinstein Company and released in U.S. theaters on December 25, 2014. It received generally positive reviews from critics.[30][31]

text: Alice Through the Looking Glass[edit]

text: Burton produced the sequel to Alice in Wonderland, titled Alice Through the Looking Glass (2016).[32]

text: Miss Peregrine's Home for Peculiar Children[edit]

text: Burton directed an adaptation of Ransom Riggs' book Miss Peregrine's Home for Peculiar Children, which was released in September 2016, starring Asa Butterfield and Eva Green, in her second Burton film.[33]

text: Dumbo[edit]

text: Burton is in principal production on a live action adaptation of Dumbo, with Colin Farrell, Eva Green and Michael Keaton starring.

text: Future projects[edit]

text: Around 2009, Henry Selick stated that he could make a sequel to The Nightmare Before Christmas if he and Burton could create a good story for it.[34]

text: In 2012, Shane Acker confirmed that Burton will work with Valve Corporation to create his next animated feature film, Deep. Like 9, the film will take place in a post-apocalyptic world (although set in a different universe). Deep will be another darker animated film, as Shane Acker has expressed his interest in creating more PG-13 animated films.[35]

text: In July 2012, following the release of both Dark Shadows and Abraham Lincoln: Vampire Hunter, it was reported that screenwriter and novelist Seth Grahame-Smith is working alongside Tim Burton on a potential Beetlejuice sequel. Actor Michael Keaton has also expressed interest in reprising his role as the title character along with Winona Ryder.[36][37]

text: Unrealized projects[edit]

text: On January 19, 2010, it was announced that after Dark Shadows, Burton's next project would be Maleficent, a Wicked-like film that showed the origin and the past of Sleeping Beauty's antagonist Maleficent. In an interview with Fandango published February 23, 2010, however, he denied he was directing any upcoming Sleeping Beauty film.[38] However, on November 23, 2010, in an interview with MTV, Burton confirmed that he was indeed putting together a script for Maleficent.[39] It was announced by The Hollywood Reporter on May 16, 2011, that Burton was no longer attached to Maleficent.[40]

text: It was reported that Burton would direct a 3D stop motion animation adaptation of The Addams Family, which was confirmed by Christopher Meledandri,[41] but the project was scrapped on July 17, 2013.[42] On July 19, 2010, he was announced as the director of the upcoming film adaptation of Monsterpocalypse.[43]

text: In 2011, it reported that Burton was working on a live-action adaptation of The Hunchback of Notre-Dame, featuring Josh Brolin, who would also be co-producing. The project did not move forward.[44][45]

text: Personal life[edit]

text: Burton was married to Lena Gieseke, a German-born artist. Their marriage ended in 1991 after four years.[46] He went on to live with model and actress Lisa Marie; she acted in the films he made during their relationship from 1992 to 2001, most notably in Ed Wood and Mars Attacks!. Burton developed a romantic relationship with English actress Helena Bonham Carter, whom he met while filming Planet of the Apes. Marie responded in 2005 by holding an auction of personal belongings that Burton had left behind, much to his dismay.[47]

text: Burton and Bonham Carter have two children: a son, Billy Raymond, named after his and Bonham Carter's fathers, born in 2003; and a daughter, Nell, born in 2007.[48] Bonham Carter's representative said in December 2014 that Bonham Carter and Burton had broken up amicably earlier that year.[49]

text: Close friend Johnny Depp is a godfather of both of Burton's children. In Depp's introduction to Burton on Burton, he writes, "What more can I say about him? He is a brother, a friend, my godson's father. He is a unique and brave soul, someone that I would go to the ends of the earth for, and I know, full and well, he would do the same for me."

text: On March 15, 2010, Burton received the insignia of Chevalier of Arts and Letters from then-Minister of Culture Frédéric Mitterrand.[50]

text: Burton was the President of the Jury for the 63rd annual Cannes Film Festival, held from May 12 to 24, 2010 in Cannes, France.[51]

text: Burton has stated that his favorite films are Dracula A.D. 1972, The Wicker Man, The Golden Voyage of Sinbad, The War of the Gargantuas and The Omega Man.[52]

text: Frequent collaborators[edit]

text: Burton often casts certain actors in multiple directing projects.

text: Exhibitions[edit]

text: From November 22, 2009, to April 26, 2010, Burton had a retrospective at the MoMA in New York with over 700 "drawings, paintings, photographs, storyboards, moving-image works, puppets, maquettes, costumes and cinematic ephemera", including many from the filmmaker's personal collection.[53] The show also included his amateur and student films, music videos, commercials and digital slide shows, as well as a complete set of features and shorts.[citation needed]

text: From MoMA the "Tim Burton" exhibition traveled directly to Australian Centre for the Moving Image in Melbourne. Running from June 24 to October 10, 2010, the ACMI exhibition incorporated additional material from Burton's Alice in Wonderland, which was released in March 2010.[54]

text: The exhibition was displayed at the TIFF Bell Lightbox in Toronto, Ontario, Canada from November 26, 2010, to April 17, 2011. It was accompanied by several personal appearances by Burton as well as a retrospective of his films.

text: "The Art of Tim Burton" was exhibited at the Los Angeles County Museum of Art from May 29 to October 31, 2011, in the Museum's Resnick Pavilion.[55] LACMA also featured six films of Tim Burton's idol,[56] Vincent Price, for the anniversary of what would have been the actor's 100th birthday during the closing weekend of the Exhibit.

text: "Tim Burton, the exhibition/Tim Burton, l'exposition" was exhibited at the Cinémathèque Française from March 7 to August 5, 2012, in Paris, France.[57] All Tim Burton's movies are programmed during the exhibition.

text: "Tim Burton at Seoul Museum of Art" was exhibited as a promotion of Hyundai Card at Seoul Museum of Art from December 12, 2012, to April 15, 2013, in Seoul, South Korea.[58] This exhibition featured 862 of his works including drawings, paintings, short films, sculptures, music and costumes that have been used in the making of his feature-length movies. The exhibition was divided into three parts: the first part, "Surviving Burbank", covered his younger years, from 1958 to 1976. The second, "Beautifying Burbank", covers 1977 to 1984, including his time with CalArts and Walt Disney. The last segment, "Beyond Burbank", covers 1985 onward.[59]

text: "Tim Burton and His World" was exhibited at the Stone Bell House from March 3 to August 8, 2014, in Prague, Czech Republic.[60]

text: The exhibition later premiered at the Museu da Imagem e do Som in São Paulo, Brazil, on February 4, 2016, and lasted until June 5.[61]

text: The exhibition later held in Artis Tree in Taikoo Place, Hong Kong, from 5 November 2016 to 23 January 2017.[62]

text: Filmography[edit]

text: Awards[edit]

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text: Academy Awards[edit]

text:
Year
Nominated work
Category
Result
Ref.

2006
Corpse Bride
Best Animated Feature
Nominated

2013
Frankenweenie
Nominated

text: Golden Globe Awards[edit]

text:
Year
Nominated work
Category
Result
Ref.

2008
Sweeney Todd: The Demon Barber of Fleet Street
Best Director – Motion Picture
Nominated

Best Motion Picture – Musical or Comedy
Won

2011
Alice in Wonderland
Nominated

2013
Frankenweenie
Best Animated Film
Nominated

text: BAFTA Awards[edit]

text:
British Academy of Film Awards

Year
Nominated work
Category
Result
Ref.

2004
Big Fish
Best Direction
Nominated

Best Film
Nominated

2013
Frankenweenie
Best Animated Film
Nominated

text:
British Academy Children's Awards

Year
Nominated work
Category
Result
Ref.

2005
Charlie and the Chocolate Factory
Best Feature Film
Nominated

text: Emmy Award

text: (1990) Won—Outstanding Children's Animated Program / Beetlejuice

text: Cannes Film Festival

text: (1994) Nominated—Palme d'Or / Ed Wood

text: Saturn Awards

text:
(1990) Nominated—Best Director / Beetlejuice
(1993) Nominated—Best Director / Batman Returns
(1997) Nominated—Best Director / Mars Attacks!
(2000) Nominated—Best Director / Sleepy Hollow
(2008) Nominated—Best Director / Sweeney Todd: The Demon Barber of Fleet Street
(2013) Won—Best Animated Film / Frankenweenie

text: National Board of Review Awards

text: (2008) Won – Best Director / Sweeney Todd: The Demon Barber of Fleet Street

text: Chicago Film Critics Association Awards

text: (2004) Nominated—Best Director / Big Fish

text: Producers Guild of America Awards

text:
(2006) Nominated—Animated Motion Picture / Corpse Bride
(2008) Honored—Scream Awards: Scream Immortal Award, for his unique interpretation of horror and fantasy
(2009) Won—Best Producer / 9

text: 64th Venice International Film Festival

text: (2007) Honored—Golden Lion for Lifetime Achievement

text: Lacanian Psychoanalysis Prize

text: (2010) Won—Alice in Wonderland[63]

text: The Order of the Arts and Letters

text: (2010) Knighted by Culture Minister of France

text: Moscow International Film Festival

text: (2012) "Golden George" for his contribution to world cinema.

text: Reception[edit]

text: Critical, public and commercial reception to films Burton has directed as of February 2017.

text:
Year
Film
Rotten Tomatoes[64]
Metacritic[65]
CinemaScore[66]
Budget
Box office[67]

1985
Pee-wee's Big Adventure
89% (44 reviews)
(7.8/10)
47 (14 reviews)
N/A
$7 million
$40.9 million
(domestic)

1988
Beetlejuice
81% (43 reviews)
(7/10)
67 (13 reviews)
B
$15 million
$73.7 million
(domestic)

1989
Batman
72% (68 reviews)
(6.6/10)
69 (21 reviews)
A
$35 million
$411.3 million

1990
Edward Scissorhands
89% (56 reviews)
(7.7/10)
74 (19 reviews)
A–
$20 million
$86 million

1992
Batman Returns
80% (71 reviews)
(6.7/10)
68 (23 reviews)
B
$80 million
$266.8 million

1994
Ed Wood
92% (60 reviews)
(8/10)
70 (19 reviews)
B+
$18 million
$5.9 million
(domestic)

1996
Mars Attacks!
52% (63 reviews)
(5.9/10)
52 (19 reviews)
B
$70 million
$101.4 million

1999
Sleepy Hollow
67% (126 reviews)
(6.3/10)
65 (35 reviews)
B–
$100 million
$206.1 million

2001
Planet of the Apes
45% (156 reviews)
(5.5/10)
50 (34 reviews)
B–
$100 million
$362.2 million

2003
Big Fish
77% (214 reviews)
(7.2/10)
58 (42 reviews)
B+
$70 million
$122.9 million

2005
Charlie and the Chocolate Factory
83% (221 reviews)
(7.2/10)
72 (40 reviews)
A–
$150 million
$475 million

2005
Corpse Bride
83% (187 reviews)
(7.2/10)
83 (35 reviews)
B+
$40 million
$117.2 million

2007
Sweeney Todd: The Demon Barber of Fleet Street
86% (222 reviews)
(7.7/10)
83 (39 reviews)
N/A
$50 million
$152.5 million

2010
Alice in Wonderland
52% (262 reviews)
(5.7/10)
53 (38 reviews)
A–
$150–200 million
$1.02 billion

2012
Dark Shadows
37% (233 reviews)
(5.3/10)
55 (42 reviews)
B–
$150 million
$245.5 million

2012
Frankenweenie
87% (200 reviews)
(7.6/10)
74 (38 reviews)
B+
$40 million
$81.5 million

2014
Big Eyes
72% (166 reviews)
(6.6/10)
62 (40 reviews)
N/A
$10 million
$29.3 million

2016
Miss Peregrine's Home for Peculiar Children
64% (199 reviews)
(5.9/10)
57 (43 reviews)
B+
$110 million
$295.3 million

text: Books[edit]

text:
Burton on Burton, edited by Mark Salisbury (1995, revised editions 2000, 2006)
The Melancholy Death of Oyster Boy & Other Stories (1997)
The Art of Tim Burton, written by Leah Gallo (2009)
The Napkin Art of Tim Burton: Things You Think About in a Bar, edited by Holly Kempf and Leah Gallo (2015)


document_title: Menstrual cycle

question_text: what are the two parts of the menstrual cycle

question_tokens: what are the two parts of the menstrual cycle

root

text: Menstrual cycle

text: Onset and frequency[edit]

text: The average age of menarche is 12–15.[5][11] They may occasionally start as early as eight, and this onset may still be normal.[6] This first period often occurs later in the developing world than the developed world.[7]

tag: p

text: The average age of menarche is approximately 12.5 years in the United States,[12] 12.7 in Canada,[13] 12.9 in the UK[14] and 13.1 years in Iceland.[15] Factors such as genetics, diet and overall health can affect timing.[16]

text: The cessation of menstrual cycles at the end of a woman's reproductive period is termed menopause. The average age of menopause in women is 52 years, with anywhere between 45 and 55 being common. Menopause before age 45 is considered premature in industrialised countries.[17] Like the age of menarche, the age of menopause is largely a result of cultural and biological factors;[18] however, illnesses, certain surgeries, or medical treatments may cause menopause to occur earlier than it might have otherwise.[19]

text: The length of a woman's menstrual cycle typically varies somewhat, with some shorter cycles and some longer cycles. A woman who experiences variations of less than eight days between her longest cycles and shortest cycles is considered to have regular menstrual cycles. It is unusual for a woman to experience cycle length variations of more than four days. Length variation between eight and 20 days is considered as moderately irregular cycles. Variation of 21 days or more between a woman's shortest and longest cycle lengths is considered very irregular. [20]

text: The average menstrual cycle lasts 28 days. The variability of menstrual cycle lengths is highest for women under 25 years of age and is lowest, that is, most regular, for ages 25 to 39.[21] Subsequently, the variability increases slightly for women aged 40 to 44.[21]

text: The luteal phase of the menstrual cycle is about the same length in most individuals (mean 14.13 days, standard deviation 1.41 days)[22] whereas the follicular phase tends to show much more variability (log-normally distributed with 95% of individuals having follicular phases between 10.3 and 16.3 days).[23] The follicular phase also seems to get significantly shorter with age (geometric mean 14.2 days in women aged 18–24 vs. 10.4 days in women aged 40–44).[23]

text: Health effects[edit]

text: Some women with neurological conditions experience increased activity of their conditions at about the same time during each menstrual cycle. For example, drops in estrogen levels have been known to trigger migraines,[24] especially when the woman who suffers migraines is also taking the birth control pill. Many women with epilepsy have more seizures in a pattern linked to the menstrual cycle; this is called "catamenial epilepsy".[25] Different patterns seem to exist (such as seizures coinciding with the time of menstruation, or coinciding with the time of ovulation), and the frequency with which they occur has not been firmly established. Using one particular definition, one group of scientists found that around one-third of women with intractable partial epilepsy has catamenial epilepsy.[25][26][27] An effect of hormones has been proposed, in which progesterone declines and estrogen increases would trigger seizures.[28] Recently, studies have shown that high doses of estrogen can cause or worsen seizures, whereas high doses of progesterone can act like an antiepileptic drug.[29] Studies by medical journals have found that women experiencing menses are 1.68 times more likely to attempt suicide.[30]

text: Mice have been used as an experimental system to investigate possible mechanisms by which levels of sex steroid hormones might regulate nervous system function. During the part of the mouse estrous cycle when progesterone is highest, the level of nerve-cell GABA receptor subtype delta was high. Since these GABA receptors are inhibitory, nerve cells with more delta receptors are less likely to fire than cells with lower numbers of delta receptors. During the part of the mouse estrous cycle when estrogen levels are higher than progesterone levels, the number of delta receptors decrease, increasing nerve cell activity, in turn increasing anxiety and seizure susceptibility.[31]

text: Estrogen levels may affect thyroid behavior.[32] For example, during the luteal phase (when estrogen levels are lower), the velocity of blood flow in the thyroid is lower than during the follicular phase (when estrogen levels are higher).[33]

text: Among women living closely together, it was once thought that the onsets of menstruation tend to synchronize. This effect was first described in 1971, and possibly explained by the action of pheromones in 1998.[34] Subsequent research has called this hypothesis into question.[35]

text: Research indicates that women have a significantly higher likelihood of anterior cruciate ligament injuries in the pre-ovulatory stage, than post-ovulatory stage.[36]

text: Fertility[edit]

text: The most fertile period (the time with the highest likelihood of pregnancy resulting from sexual intercourse) covers the time from some 5 days before until 1 to 2 days after ovulation.[38] In a 28‑day cycle with a 14‑day luteal phase, this corresponds to the second and the beginning of the third week. A variety of methods have been developed to help individual women estimate the relatively fertile and the relatively infertile days in the cycle; these systems are called fertility awareness.

text: There are many fertility testing methods, including urine test kits that detect the LH surge that occurs 24 to 36 hours before ovulation; these are known as ovulation predictor kits (OPKs).[39] Computerized devices that interpret basal body temperatures, urinary test results, or changes in saliva are called fertility monitors. Fertility awareness methods that rely on cycle length records alone are called calendar-based methods.[40] Methods that require observation of one or more of the three primary fertility signs (basal body temperature, cervical mucus, and cervical position)[41] are known as symptoms-based methods.[40]

text: A woman's fertility is also affected by her age.[42] As a woman's total egg supply is formed in fetal life,[43] to be ovulated decades later, it has been suggested that this long lifetime may make the chromatin of eggs more vulnerable to division problems, breakage, and mutation than the chromatin of sperm, which are produced continuously during a man's reproductive life. However, despite this hypothesis, a similar paternal age effect has also been observed.

text: As measured on women undergoing in vitro fertilization, a longer menstrual cycle length is associated with higher pregnancy and delivery rates, even after age adjustment.[44] Delivery rates after IVF have been estimated to be almost doubled for women with a menstrual cycle length of more than 34 days compared with women with a menstrual cycle length shorter than 26 days.[44] A longer menstrual cycle length is also significantly associated with better ovarian response to gonadotropin stimulation and embryo quality.[44]

text: Mood and behavior[edit]

text: The different phases of the menstrual cycle correlate with women's moods. In some cases, hormones released during the menstrual cycle can cause behavioral changes in females; mild to severe mood changes can occur.[45] The menstrual cycle phase and ovarian hormones may contribute to increased empathy in women. The natural shift of hormone levels during the different phases of the menstrual cycle has been studied in conjunction with test scores. When completing empathy exercises, women in the follicular stage of their menstrual cycle performed better than women in their midluteal phase. A significant correlation between progesterone levels and the ability to accurately recognize emotion was found. Performances on emotion recognition tasks were better when women had lower progesterone levels. Women in the follicular stage showed higher emotion recognition accuracy than their midluteal phase counterparts. Women were found to react more to negative stimuli when in midluteal stage over the women in the follicular stage, perhaps indicating more reactivity to social stress during that menstrual cycle phase.[46] Overall, it has been found that women in the follicular phase demonstrated better performance in tasks that contain empathetic traits.

text: Fear response in women during two different points in the menstrual cycle has been examined. When estrogen is highest in the preovulatory stage, women are significantly better at identifying expressions of fear than women who were menstruating, which is when estrogen levels are lowest. The women were equally able to identify happy faces, demonstrating that the fear response was a more powerful response. To summarize, menstrual cycle phase and the estrogen levels correlates with women’s fear processing.[47]

text: However, the examination of daily moods in women with measuring ovarian hormones may indicate a less powerful connection. In comparison to levels of stress or physical health, the ovarian hormones had less of an impact on overall mood.[48] This indicates that while changes of ovarian hormones may influence mood, on a day-to-day level it does not influence mood more than other stressors do.

text: Sexual feelings and behaviors change during the menstrual cycle. Before and during ovulation, high levels of estrogen and androgens result in women having an increased interest in sexual activity.[49] Unlike other animal species, women show interest in sex across all days of the menstrual cycle, regardless of fertility.[50] It appears that when women are most fertile, they tend to avoid situations that may result in sexual harassment or sexual assault.[51]

text: Mate choice[edit]

text: Behavior towards potential mating partners changes during different phases of the menstrual cycle.[52][53][54] Near ovulation, women may have increased physical attraction and interest in attending social gatherings with men.[51] During the fertile phase of the cycle, women appear to prefer males who are more masculine.[55] The intensity of mate guarding differs across the phases of the cycle, with increased mate guarding occurring when woman are fertile.[54][56][57]

text: During the fertile phase, many women experience more attraction, fantasies and sexual interest for extra pair men but not for the primary partner.[51][54][58] They also engage in extra-pair flirtations and demonstrate a preference for extra pair copulation.[51][58]

text: Voice[edit]

text: Preferences for voice pitch change across the cycle.[58] When seeking a short term mating partner, women may prefer a male with a low voice pitch, particularly during the fertile phase.[58] During the late follicular phase, it is common for women demonstrate a preference for mates with a masculine, deep voice.[59] Research has also been conducted on the attractiveness of the female voice throughout the cycle.[60] During their most fertile phase of the menstrual cycle, there is some evidence that female voices are rated as significantly more attractive.[60] This effect is not found with women on the birth control pill.[60]

text: Smell[edit]

text: Women's preference for male's body odor can change across the menstrual cycle.[61] Males who score highly on dominance have been rated as sexier by females during the fertile phase of the menstrual cycle. Additionally, during their most fertile phase of the menstrual cycle, women may show preference for the odor of symmetrical men.[54] This effect is not found for women on the birth control pill.[62] Also, during the late follicular and ovulatory phases, women prefer the scent of masculine men.[58] The scent of androsterone (responsible for testosterone levels) is highly preferred by women during the peak of their fertility in the menstrual cycle.[58] Moreover, women may demonstrate preference for men with a scent that indicates developmental stability.[58]

text: With regard to women's smell across the cycle, some evidence indicates that men use olfactory cues in order to know if a woman is ovulating.[61] Using a rating of women's odors, women who are ovulating have been rated as more attractive by men.[61] Men demonstrate preferences for the scent of fertile women.[61]

text: Body[edit]

text: Preferences for facial features in mates can also change across the cycle.[58] There has been no difference found in preference for long-term mating partners during the menstrual cycle; however, those seeking a short-term relationship were more likely to choose a partner with more masculine features than usual.[51][59] This was found to be the case especially during the woman's high conception risk stage and when salivary testosterone was high.[63] However, when women are in the luteal (non-fertile) phase, they tend to prefer men (and females) with more feminine faces.[59] A preference is also shown for self-resembling faces and apparent health in faces during the luteal phase of the cycle.[64] Apparent health preferences were found to be strongest when progesterone levels were high.[64] Additionally, during the fertile phase, many women show a preference for men with darker skin pigmentation.[58] Research on facial symmetry is mixed.[65]

text: Preferences for body features can change during the fertile phase of the cycle. Women seeking a short-term partner demonstrate a preference for taller and muscular males.[58] Women also show preferences of males with masculine bodies at peak fertility.[58][63] Mixed research has been found regarding body symmetry preferences throughout different phases of the cycle.[58]

text: Personality[edit]

text: In short term mates, during the fertile phase, women may show more attraction to dominant men who display social presence.[58] For long-term mates, shifts in desired trait preferences do not occur throughout the cycle.[58]

text: Eating behavior[edit]

text: Females have been found to experience different eating habits at different stages of their menstrual cycle, with food intake being higher during the luteal phase than the follicular phase.[66][67] Food intake increases by approximately 10% during the luteal phase compared to the follicular phase.[67]

text: Various studies have shown that during the luteal phase woman consume more carbohydrates, proteins and fats and that 24-hour energy expenditure shows increases between 2.5-11.5%.[68] The increasing intake during the luteal phase may be related to higher preferences for sweet and fatty foods, which occurs naturally and is enhanced during the luteal phases of the menstrual cycle.[68] This is due to the higher metabolic demand during this phase.[69] In particular, women tend to show a cravings for chocolate, with higher cravings during the luteal phase.[68]

text: Females with premenstrual syndrome (PMS) report  changes in appetite across the menstrual cycle more than non-sufferers of PMS, possibly due to their oversensitivity to changes in hormone levels.[67] In women with PMS, food intake is higher in the luteal phase than follicular.[70] The remaining symptoms of PMS, including mood changes and physical symptoms, also occur during the luteal phase. No difference for preference of food types has been found between PMS sufferers and non-sufferers.[66]

text: The different levels of ovarian hormones at different stages of the cycle have been used to explain eating behaviour changes. Progesterone has been shown to promote fat storage, causing a higher intake of fatty foods during the luteal phase when progesterone levels are higher.[67] Additionally, with a high estrogen level dopamine is ineffective in converting to noradrenaline, a hormone which promotes eating, therefore decreasing appetite.[67] In humans, the level of these ovarian hormones during the menstrual cycle have been found to influence binge eating.[71]

text: It is theorized that the use of birth control pills should affect eating behaviour as they minimise or remove the fluctuations in hormone levels.[66] The neurotransmitter serotonin is also thought to play a role in food intake. Serotonin is responsible for inhibiting eating and controlling meal size,[72] among other things, and is modulated in part by ovarian hormones.[73]

text: A number of factors affect whether dieting will affect these menstrual processes: age, weight loss and the diet itself. First, younger women are likely to experience menstrual irregularities due to their diet. Second, menstrual abnormalities are more likely with more weight loss. For example, anovulatory cycles can occur as a result of adopting a restricted diet, as well as engaging in a high amount of exercise.[67] Finally, the cycle is affected more by a vegetarian diet compared to a non-vegetarian diet.[74]

text: Substance abuse[edit]

text: Studies investigating effects of the menstrual cycle on alcohol consumption have found mixed evidence.[75] However, some evidence suggests that individuals consume more alcohol during the luteal stage, especially if these individuals are heavy drinkers or have a family history of alcohol abuse.[69]

text: The level of substance abuse increases with PMS, mostly with addictive substances such as nicotine, tobacco and cocaine.[69] One theory behind this suggests this higher level of substance abuse is due to decreased self-control as a result of the higher metabolic demands during the luteal phase.[69]

text: Menstrual disorders[edit]

text: Infrequent or irregular ovulation is called oligoovulation.[76] The absence of ovulation is called anovulation. Normal menstrual flow can occur without ovulation preceding it: an anovulatory cycle. In some cycles, follicular development may start but not be completed; nevertheless, estrogens will be formed and  stimulate the uterine lining. Anovulatory flow resulting from a very thick endometrium caused by prolonged, continued high estrogen levels is called estrogen breakthrough bleeding. Anovulatory bleeding triggered by a sudden drop in estrogen levels is called withdrawal bleeding.[77] Anovulatory cycles commonly occur before menopause (perimenopause) and in women with polycystic ovary syndrome.[78]

text: Very little flow (less than 10 ml) is called hypomenorrhea. Regular cycles with intervals of 21 days or fewer are polymenorrhea; frequent but irregular menstruation is known as metrorrhagia. Sudden heavy flows or amounts greater than 80 ml are termed menorrhagia.[79] Heavy menstruation that occurs frequently and irregularly is menometrorrhagia. The term for cycles with intervals exceeding 35 days is oligomenorrhea.[80] Amenorrhea refers to more than three[79] to six[80] months without menses (while not being pregnant) during a woman's reproductive years.

text: Cycles and phases[edit]

text: The menstrual cycle can be described by the ovarian or uterine cycle. The ovarian cycle describes changes that occur in the follicles of the ovary whereas the uterine cycle describes changes in the endometrial lining of the uterus.  Both cycles can be divided into three phases.  The ovarian cycle consists of the follicular phase, ovulation, and the luteal phase, whereas the uterine cycle consists of menstruation, proliferative phase, and secretory phase.[1]

text: Ovarian cycle[edit]

text: Follicular phase[edit]

text: The follicular phase is the first part of the ovarian cycle. During this phase, the ovarian follicles mature and get ready to release an egg.[1] The latter part of this phase overlaps with the proliferative phase of the uterine cycle.

text: Through the influence of a rise in follicle stimulating hormone (FSH) during the first days of the cycle, a few ovarian follicles are stimulated.[81] These follicles, which were present at birth[81] and have been developing for the better part of a year in a process known as folliculogenesis, compete with each other for dominance. Under the influence of several hormones, all but one of these follicles will stop growing, while one dominant follicle in the ovary will continue to maturity. The follicle that reaches maturity is called a tertiary, or Graafian, follicle, and it contains the ovum.[81]

text: Ovulation[edit]

text: Ovulation is the second phase of the ovarian cycle in which a mature egg is released from the ovarian follicles into the oviduct.[82] During the follicular phase, estradiol suppresses release of luteinizing hormone (LH) from the anterior pituitary gland. When the egg has nearly matured, levels of estradiol reach a threshold above which this effect is reversed and estrogen stimulates the production of a large amount of LH. This process, known as the LH surge, starts around day 12 of the average cycle and may last 48 hours.[83]

text: The exact mechanism of these opposite responses of LH levels to estradiol is not well understood.[84] In animals, a gonadotropin-releasing hormone (GnRH) surge has been shown to precede the LH surge, suggesting that estrogen's main effect is on the hypothalamus, which controls GnRH secretion.[84] This may be enabled by the presence of two different estrogen receptors in the hypothalamus: estrogen receptor alpha, which is responsible for the negative feedback estradiol-LH loop, and estrogen receptor beta, which is responsible for the positive estradiol-LH relationship.[85] However, in humans it has been shown that high levels of estradiol can provoke abrupt increases in LH, even when GnRH levels and pulse frequencies are held constant,[84] suggesting that estrogen acts directly on the pituitary to provoke the LH surge.

text: The release of LH matures the egg and weakens the wall of the follicle in the ovary, causing the fully developed follicle to release its secondary oocyte.[81] The secondary oocyte promptly matures into an ootid and then becomes a mature ovum. The mature ovum has a diameter of about 0.2 mm.[86]

text: Which of the two ovaries—left or right—ovulates appears essentially random; no known left and right co-ordination exists.[87] Occasionally, both ovaries will release an egg;[87] if both eggs are fertilized, the result is fraternal twins.[88]

text: After being released from the ovary, the egg is swept into the fallopian tube by the fimbria, which is a fringe of tissue at the end of each fallopian tube. After about a day, an unfertilized egg will disintegrate or dissolve in the fallopian tube.[81]

text: Fertilization by a spermatozoon, when it occurs, usually takes place in the ampulla, the widest section of the fallopian tubes. A fertilized egg immediately begins the process of embryogenesis, or development. The developing embryo takes about three days to reach the uterus and another three days to implant into the endometrium.[81] It has usually reached the blastocyst stage at the time of implantation.

text: In some women, ovulation features a characteristic pain called mittelschmerz (German term meaning middle pain).[89] The sudden change in hormones at the time of ovulation sometimes also causes light mid-cycle blood flow.[90]

text: Luteal phase[edit]

text: The luteal phase is the final phase of the ovarian cycle and it corresponds to the secretory phase of the uterine cycle. During the luteal phase, the pituitary hormones FSH and LH cause the remaining parts of the dominant follicle to transform into the corpus luteum, which produces progesterone. The increased progesterone in the adrenals starts to induce the production of estrogen. The hormones produced by the corpus luteum also suppress production of the FSH and LH that the corpus luteum needs to maintain itself. Consequently, the level of FSH and LH fall quickly over time, and the corpus luteum subsequently atrophies.[81] Falling levels of progesterone trigger menstruation and the beginning of the next cycle. From the time of ovulation until progesterone withdrawal has caused menstruation to begin, the process typically takes about two weeks, with 14 days considered normal. For an individual woman, the follicular phase often varies in length from cycle to cycle; by contrast, the length of her luteal phase will be fairly consistent from cycle to cycle.[91]

text: The loss of the corpus luteum is prevented by fertilization of the egg.  The syncytiotrophoblast, which is the outer layer of the resulting embryo-containing structure (the blastocyst) and later also becomes the outer layer of the placenta, produces human chorionic gonadotropin (hCG), which is very similar to LH and which preserves the corpus luteum.  The corpus luteum can then continue to secrete progesterone to maintain the new pregnancy.  Most pregnancy tests look for the presence of hCG.[81]

text: Uterine cycle[edit]

text: The uterine cycle has three phases: menses, proliferative, secretory.[92]

text: Menstruation[edit]

text: Menstruation (also called menstrual bleeding, menses, catamenia or a period) is the first phase of the uterine cycle. The flow of menses normally serves as a sign that a woman has not become pregnant. (However, this cannot be taken as certainty, as a number of factors can cause bleeding during pregnancy; some factors are specific to early pregnancy, and some can cause heavy flow.)[93][94][95]

text: Eumenorrhea denotes normal, regular menstruation that lasts for a few days (usually 3 to 5 days, but anywhere from 2 to 7 days is considered normal).[89][96] The average blood loss during menstruation is 35 milliliters with 10–80 ml considered normal.[97] Women who experience Menorrhagia are more susceptible to iron deficiency than the average person.[98] An enzyme called plasmin inhibits clotting in the menstrual fluid.[99]

text: Painful cramping in the abdomen, back, or upper thighs is common during the first few days of menstruation. Severe uterine pain during menstruation is known as dysmenorrhea, and it is most common among adolescents and younger women (affecting about 67.2% of adolescent females).[100] When menstruation begins, symptoms of premenstrual syndrome (PMS) such as breast tenderness and irritability generally decrease.[89] Many sanitary products are marketed to women for use during their menstruation.

text: Proliferative phase[edit]

text: The proliferative phase is the second phase of the uterine cycle when estrogen causes the lining of the uterus to grow, or proliferate, during this time.[81] As they mature, the ovarian follicles secrete increasing amounts of estradiol, and estrogen. The estrogens initiate the formation of a new layer of endometrium in the uterus, histologically identified as the proliferative endometrium. The estrogen also stimulates crypts in the cervix to produce fertile cervical mucus, which may be noticed by women practicing fertility awareness.[101]

text: Secretory phase[edit]

text: The secretory phase is the final phase of the uterine cycle and it corresponds to the luteal phase of the ovarian cycle. During the secretory phase, the corpus luteum produces progesterone, which plays a vital role in making the endometrium receptive to implantation of the blastocyst and supportive of the early pregnancy, by increasing blood flow and uterine secretions and reducing the contractility of the smooth muscle in the uterus;[102] it also has the side effect of raising the woman's basal body temperature.[103]

text: Ovulation suppression[edit]

text: Birth control[edit]

text: While some forms of birth control do not affect the menstrual cycle, hormonal contraceptives work by disrupting it. Progestogen negative feedback decreases the pulse frequency of gonadotropin-releasing hormone (GnRH) release by the hypothalamus, which decreases the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by the anterior pituitary. Decreased levels of FSH inhibit follicular development, preventing an increase in estradiol levels. Progestogen negative feedback and the lack of estrogen positive feedback on LH release prevent a mid-cycle LH surge. Inhibition of follicular development and the absence of a LH surge prevent ovulation.[104][105][106]

text: The degree of ovulation suppression in progestogen-only contraceptives depends on the progestogen activity and dose. Low dose progestogen-only contraceptives—traditional progestogen only pills, subdermal implants Norplant and Jadelle, and intrauterine system Mirena—inhibit ovulation in about 50% of cycles and rely mainly on other effects, such as thickening of cervical mucus, for their contraceptive effectiveness.[107] Intermediate dose progestogen-only contraceptives—the progestogen-only pill Cerazette and the subdermal implant Nexplanon—allow some follicular development but more consistently inhibit ovulation in 97–99% of cycles. The same cervical mucus changes occur as with very low-dose progestogens. High-dose, progestogen-only contraceptives—the injectables Depo-Provera and Noristerat—completely inhibit follicular development and ovulation.[107]

text: Combined hormonal contraceptives include both an estrogen and a progestogen. Estrogen negative feedback on the anterior pituitary greatly decreases the release of FSH, which makes combined hormonal contraceptives more effective at inhibiting follicular development and preventing ovulation. Estrogen also reduces the incidence of irregular breakthrough bleeding.[104][105][106] Several combined hormonal contraceptives—the pill, NuvaRing, and the contraceptive patch—are usually used in a way that causes regular withdrawal bleeding. In a normal cycle, menstruation occurs when estrogen and progesterone levels drop rapidly.[103] Temporarily discontinuing use of combined hormonal contraceptives (a placebo week, not using patch or ring for a week) has a similar effect of causing the uterine lining to shed. If withdrawal bleeding is not desired, combined hormonal contraceptives may be taken continuously, although this increases the risk of breakthrough bleeding.

text: Breastfeeding[edit]

text: Breastfeeding causes negative feedback to occur on pulse secretion of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH). Depending on the strength of the negative feedback, breastfeeding women may experience complete suppression of follicular development, but no ovulation, or normal menstrual cycle may resume.[108] Suppression of ovulation is more likely when suckling occurs more frequently.[109] The production of prolactin in response to suckling is important to maintaining lactational amenorrhea.[110] On average, women who are fully breastfeeding whose infants suckle frequently experience a return of menstruation at fourteen and a half months postpartum. There is a wide range of response among individual breastfeeding women, however, with some experiencing return of menstruation at two months and others remaining amenorrheic for up to 42 months postpartum.[111]

text: Society and culture[edit]

text: Etymological[edit]

text: The word "menstruation" is etymologically related to "moon". The terms "menstruation" and "menses" are derived from the Latin mensis (month), which in turn relates to the Greek mene (moon) and to the roots of the English words month and moon.[112]

text: The Moon[edit]

text: Even though the average length of the human menstrual cycle is similar to that of the lunar cycle, in modern humans there is no relation between the two.[113] The relationship is believed to be a coincidence.[114][115] Light exposure does not appear to affect the menstrual cycle in humans.[10] A meta-analysis of studies from 1996 showed no correlation between the human menstrual cycle and the lunar cycle.[116][117][118]

text: Dogon villagers did not have electric lighting and spent most nights outdoors, talking and sleeping, so they were apparently an ideal population for detecting a lunar influence; none was found.[119]

text: Work[edit]

text: In a number of countries, mainly in Asia, legislation or corporate practice has introduced formal menstrual leave to provide women with either paid or unpaid leave of absence from their employment while they are menstruating.[120] Countries with policies include Japan, Taiwan, Indonesia, and South Korea.[120] The practice is controversial due to concerns that it bolsters the perception of women as weak, inefficient workers,[120] as well as concerns that it is unfair to men.[121][122]


document_title: Liver cancer

question_text: which type of hepatitis is responsible for 50 to 76 of all patients with liver cancer

text: Liver cancer

text: Classification[edit]

text: The most frequent liver cancer, accounting for approximately 75% of all primary liver cancers, is hepatocellular carcinoma (HCC) (also named hepatoma, which is a misnomer because adenomas are usually benign). HCC is a cancer formed by liver cells, known as hepatocytes, that become malignant. Another type of cancer formed by liver cells is hepatoblastoma, which is specifically formed by immature liver cells.[9] It is a rare malignant tumor that primarily develops in children, and accounts for approximately 1% of all cancers in children and 79% of all primary liver cancers under the age of 15. Most hepatoblastomas form in the right lobe.[10]

text: Liver cancer can also form from other structures within the liver such as the bile duct, blood vessels and immune cells. Cancer of the bile duct (cholangiocarcinoma and cholangiocellular cystadenocarcinoma) account for approximately 6% of primary liver cancers.[9] There is also a variant type of HCC that consists of both HCC and cholangiocarcinoma.[11] Tumors of the blood vessels (angiosarcoma and hemangioendothelioma, embryonal sarcoma and fibrosarcoma are produced from a type of connective tissue known as mesenchyme. Cancers produced from muscle in the liver are leiomyosarcoma and rhabdomyosarcoma. Other less common liver cancers include carcinosarcomas, teratomas, yolk sac tumours, carcinoid tumours and lymphomas.[9] Lymphomas usually have diffuse infiltration to liver, but It may also form a liver mass in rare occasions.

text: Many cancers found in the liver are not true liver cancers, but are cancers from other sites in the body that have spread to the liver (known as metastases). Frequently, the site of origin is the gastrointestinal tract, since the liver is close to many of these metabolically active, blood-rich organs near to blood vessels and lymph nodes (such as pancreatic cancer, stomach cancer, colon cancer and carcinoid tumors mainly of the appendix), but also from breast cancer, ovarian cancer, lung cancer, renal cancer, prostate cancer.

text: Signs and symptoms[edit]

text: Because liver cancer is an umbrella term for many types of cancer, the signs and symptoms depend on what type of cancer is present. Cholangiocarcinoma is associated with sweating, jaundice, abdominal pain, weight loss and liver enlargement.[12] Hepatocellular carcinoma is associated with abdominal mass, abdominal pain, emesis, anemia, back pain, jaundice, itching, weight loss and fever.[13]

text: Causes[edit]

text: Viral infection[edit]

text: Viral infection with either hepatitis C virus (HCV) or Hepatitis B virus (HBV) is the chief cause of liver cancer in the world today, accounting for 80% of hepatocellular carcinoma (HCC).[14][15][16] The viruses cause HCC because massive inflammation, fibrosis and eventual cirrhosis occurs within the liver. HCC usually arises after cirrhosis, with an annual incidence of 1.7% in cirrhotic HCV-infected individuals.[17] Around 5-10% of individuals that become infected with HBV become chronic carriers, and around 30% of these acquire chronic liver disease, which can lead to HCC.[14] HBV infection is also linked to cholangiocarcinoma.[18] The role of viruses other than HCV or HBV in liver cancer is much less clear, although there is some evidence that co-infection of HBV and hepatitis D virus may increase the risk of HCC.[19]

text: Many genetic and epigenetic changes are formed in liver cells during HCV and HBV infection, which is a major factor in the production of the liver tumors. The viruses induce malignant changes in cells by altering gene methylation, affecting gene expression and promoting or repressing cellular signal transduction pathways. By doing this the viruses can prevent cells from undergoing a programmed form of cell death (apoptosis) and promote viral replication and persistence.[14][17]

text: HBV and HCV also induce malignant changes by causing DNA damage and genomic instability. This is by creating reactive oxygen species, express proteins that interfere with DNA repair enzymes, and HCV causes activation of a mutator enzyme.[20][21]

text: Cirrhosis[edit]

text: In addition to virus-related cirrhosis described above, other causes of cirrhosis can lead to HCC. Alcohol intake correlates with risk of HCC, and the risk is far greater in individuals with an alcohol-induced cirrhotic liver. There are a few disorders that are known to cause cirrhosis and lead to cancer, including hereditary hemochromatosis and primary biliary cirrhosis.[22]

text: Aflatoxin[edit]

text: Aflatoxin exposure can lead to the development of HCC. The aflatoxins are a group of chemicals produced by the fungi Aspergillus flavus (the name comes from A. flavus toxin) and A. parasiticus. Food contamination by the fungi leads to ingestion of the chemicals, which are very toxic to the liver. Common foodstuffs contaminated with the toxins are cereals, peanuts and other vegetables. Contamination of food is common in Africa, South-East Asia and China. Concurrent HBV infection and aflatoxin exposure increases the risk of liver cancer to over three times that seen in HBV infected individuals without aflatoxin exposure. The mechanism by which aflatoxins cause cancer is through genetic mutation of a gene required for the prevention of cancer: p53.[23][24]

text: Other causes in adults[edit]

text:
High grade dysplastic nodules are precancerous lesions of the liver. Within 2 years, there is a risk of cancer arising from these nodules of 30-40%.[25]
Obesity has emerged as an important risk factor as it can lead to steatohepatitis.[16][24]
Diabetes increases the risk of HCC.[24]
Smoking increases the risk of HCC compared to non-smokers and previous smokers.[24]
There is around 5-10% lifetime risk of cholangiocarcinoma in people with primary sclerosing cholangitis.[26]
Liver fluke infection increases the risk of cholangiocarcinoma, and is the reason Thailand has particularly high rates of this cancer.[27]

tag: ul

text: Children[edit]

text: Increased risk of liver cancer in children can be caused by Beckwith-Wiedemann Syndrome (associated with hepatoblastoma),[28][29] familial adenomatous polyposis (associated with hepatoblastoma),[29] low birth weight (associated with hepatoblastoma),[10] Progressive familial intrahepatic cholestasis (associated with HCC)[30] and Trisomy 18 (associated with hepatoblastoma).[29]

text: Diagnosis[edit]

text: Many imaging modalities are used to aid in the diagnosis of primary liver cancer. For HCC these include sonography (ultrasound), computed tomography (CT) and magnetic resonance imaging (MRI). When imaging the liver with ultrasound, a mass greater than 2 cm has more than 95% chance of being HCC. The majority of cholangiocarcimas occur in the hilar region of the liver, and often present as bile duct obstruction. If the cause of obstruction is suspected to be malignant, endoscopic retrograde cholangiopancreatography (ERCP), ultrasound, CT, MRI and magnetic resonance cholangiopancreatography (MRCP) are used.[31]

text: Tumor markers, chemicals sometimes found in the blood of people with cancer, can be helpful in diagnosing and monitoring the course of liver cancers. High levels of alpha-fetoprotein (AFP) in the blood can be found in many cases of HCC and intrahepatic cholangiocarcinoma. Cholangiocarcinoma can be detected with these commonly used tumor markers: carbohydrate antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA) and cancer antigen 125 (CA125). These tumour markers are found in primary liver cancers, as well as in other cancers and certain other disorders.[32][33]

text: Prevention[edit]

text: Prevention of cancers can be separated into primary, secondary, and tertiary prevention. Primary prevention preemptively reduces exposure to a risk factor for liver cancer. One of the most successful primary liver cancer preventions is vaccination against hepatitis B. Vaccination against the hepatitis C virus is currently unavailable. Other forms of primary prevention are aimed at limiting transmission of these viruses by promoting safe injection practices, screening blood donation products, and screening high-risk asymptomatic individuals. Aflatoxin exposure can be avoided by post-harvest intervention to discourage mold, which has been effective in west Africa. Reducing alcohol abuse, obesity, and diabetes would also reduce rates of liver cancer. Diet control in hemochromatosis could decrease the risk of iron overload, decreasing the risk of cancer.[34]

text: Secondary prevention includes both cure of the agent involved in the formation of cancer (carcinogenesis) and the prevention of carcinogenesis if this is not possible. Cure of virus-infected individuals is not possible, but treatment with antiviral drugs such as interferon can decrease the risk of liver cancer. Chlorophyllin may have potential in reducing the effects of aflatoxin.[34]

text: Tertiary prevention includes treatments to prevent the recurrence of liver cancer. These include the use of chemotherapy drugs and antiviral drugs.[34]

text: Treatment[edit]

text: Hepatocellular carcinoma[edit]

text: This section needs to be updated. Please update this article to reflect recent events or newly available information. (June 2017)

tag: table

text: Partial surgical resection is the optimal treatment for hepatocellular carcinoma (HCC) when patients have sufficient hepatic function reserve. Increased risk of complications such as liver failure can occur with resection of cirrhotic (i.e. less-than-optimally functional) livers. 5-year survival rates after resection have massively improved over the last few decades and can now exceed 50%. However, recurrence rates after resection can exceed 70%, whether due to spread of the initial tumor or formation of new tumors .[35] Liver transplantation can also be considered in cases of HCC where this form of treatment can be tolerated and the tumor fits specific criteria (such as the Milan criteria). In general, patients who are being considered for liver transplantation have multiple hepatic lesions, severe underlying liver dysfunction, or both. Less than 30-40% of individuals with HCC are eligible for surgery and transplant because the cancer is often detected at a late stage. Also, HCC can progress during the waiting time for liver transplants, which can prevent transplant due to the strict criteria.

text: Percutaneous ablation is the only non-surgical treatment that can offer cure. There are many forms of percutaneous ablation, which consist of either injecting chemicals into the liver (ethanol or acetic acid) or producing extremes of temperature using radio frequency ablation, microwaves, lasers or cryotherapy. Of these, radio frequency ablation has one of the best reputations in HCC, but the limitations include inability to treat tumors close to other organs and blood vessels due to heat generation and the heat sink effect, respectively.[36][37] In addition, long-term of outcomes of percutaneous ablation procedures for HCC have not been well studied. In general, surgery is the preferred treatment modality when possible.

text: Systemic chemotherapeutics are not routinely used in HCC, although local chemotherapy may be used in a procedure known as transarterial chemoembolization. In this procedure, cytotoxic drugs such as doxorubicin or cisplatin with lipiodol are administered and the arteries supplying the liver are blocked by gelatin sponge or other particles. Because most systemic drugs have no efficacy in the treatment of HCC, research into the molecular pathways involved in the production of liver cancer produced sorafenib, a targeted therapy drug that prevents cell proliferation and blood cell growth. Sorafenib obtained FDA approval for the treatment of advanced hepatocellular carcinoma in November 2007.[38] This drug provides a survival benefit for advanced HCC.[37]

text: Radiotherapy is not often used in HCC because the liver is not tolerant to radiation. Although with modern technology it is possible to provide well-targeted radiation to the tumor, minimizing the dose to the rest of the liver. Dual treatments of radiotherapy plus chemoembolization, local chemotherapy, systemic chemotherapy or targeted therapy drugs may show benefit over radiotherapy alone.[39]

text: Cholangiocarcinoma[edit]

text: Resection is an option in cholangiocarcinoma, but fewer than 30% of cases of cholangiocarcinoma are resectable at diagnosis. After surgery, recurrence rates are up to 60%.[40][41] Liver transplant may be used where partial resection is not an option, and adjuvant chemoradiation may benefit some cases.[26]

text: 60% of cholangiocarcinomas form in the perihilar region and photodynamic therapy can be used to improve quality of life and survival time in these unresectable cases. Photodynamic therapy is a novel treatment that utilitizes light activated molecules to treat the tumor. The compounds are activated in the tumor region by laser light, which causes the release of toxic reactive oxygen species, killing tumor cells.[40][42]

text: Systemic chemotherapies such as gemcitabine and cisplatin are sometimes used in inoperable cases of cholangiocarcinoma.[26]

text: Radio frequency ablation, transarterial chemoembolization and internal radiotherapy (brachytherapy) all show promise in the treatment of cholangiocarcinoma.[41]

text: Radiotherapy may be used in the adjuvant setting or for palliative treatment of cholangiocarcinoma.[43]

text: Hepatoblastoma[edit]

text: Removing the tumor by either surgical resection or liver transplant can be used in the treatment of hepatoblastoma. In some cases surgery can offer a cure. Chemotherapy may be used before and after surgery and transplant.[44]

text: Chemotherapy, including cisplatin, vincristine, cyclophosphamide, and doxorubicin are used for the systemic treatment of hepatoblastoma. Out of these drugs, cisplatin seems to be the most effective.[45]

text: Epidemiology[edit]

text: Globally, as of  2010[update], liver cancer resulted in 754,000 deaths, up from 460,000 in 1990, making it the third leading cause of cancer death after lung and stomach.[46] In 2012, it represented 7% of cancer diagnoses in men, the 5th most diagnosed cancer that year.[47] Of these deaths 340,000 were secondary to hepatitis B, 196,000 were secondary to hepatitis C, and 150,000 were secondary to alcohol.[46] HCC, the most common form of liver cancer, shows a striking geographical distribution. China has 50% of HCC cases globally, and more than 80% of total cases occur in sub-Saharan Africa or in East-Asia due to hepatitis B virus.[27][48] Cholangiocarcinoma also has a significant geographical distribution, with Thailand showing the highest rates worldwide due to the presence of liver fluke.[27][49]

text: UK[edit]

text: Liver cancer is the eighteenth most common cancer in the UK (around 4,300 people were diagnosed with liver cancer in the UK in 2011), and it is the twelfth most common cause of cancer death (around 4,500 people died of the disease in 2012).[50]

text: India[edit]

text: The number of new cases of hepatocellular carcinoma per year in India in males is about 4.1 and for females 1.2 per 100,000. It typically occurs between 40 and 70 years of age.[51]

text: Research[edit]

text: Hepcortespenlisimut-L is an oral immunotherapy that is going through a phase 3 clinical trial for HCC.[52]