title: Obstetrics and gynaecology

text: Although the ACOG has called upon OB-GYN care providers to provide gender-affirming and inclusive care for all individuals, that doesn't mean there hasn't been resistance, particularly because there is no formal legislation mandating the inclusion of LGBTQ+ healthcare in OB-GYN curricula.


title: Obstetrics and gynaecology

text: Many OB-GYN providers do not currently feel comfortable offering care to LGBTQ+ patients, either because of their personal beliefs or due to a lack of education on LGBTQ+ healthcare. One study of approximately 100 Illinois OB-GYN residents found that 50% of residents felt unprepared to care for lesbian or bisexual patients, and 76% of residents felt unprepared to offer care to transgender patients. The two main areas the residents identified as preventing the implementation of LGBTQ+ healthcare training were curricular crowding, 85%, and lack of experienced faculty, 91%. However, 92% of residents wanted to receive more education on how to offer care to LGBTQ+ patients.


title: Giuseppe Conte

text: Giuseppe Conte (; born 8 August 1964) is an Italian jurist, academic, and politician who served as prime minister of Italy from June 2018 to February 2021. He has been the president of the Five Star Movement (M5S) since August 2021.


title: Giuseppe Conte

text: Conte spent the greater part of his career as a private law professor and was also a member of the Italian Bureau of Administrative Justice from 2013 to 2018. Following the 2018 Italian general election, he was proposed as the independent leader of a coalition government between the M5S and the League, despite his having never held any political position before. After both parties agreed on a programme of government, he was sworn in as Prime Minister on 1 June by President Sergio Mattarella, appointing the M5S and League leaders as his joint deputies. In August 2019, the League filed a motion of no confidence in the coalition government and Conte offered to resign as Prime Minister; the M5S and the Democratic Party agreed to form a new government, with Conte remaining at its head. This made Conte the first Prime Minister to lead two separate Italian governments made up of right-wing and left-wing coalition partners.


title: Giuseppe Conte

text: Despite having begun his political career as a technocrat, appointed to implement the government programme of M5S and the League, during the final months of his first cabinet and throughout his second one Conte became an increasingly influential and popular figure in Italian politics. During his premiership, he introduced important reforms including the introduction of a guaranteed minimum income, a constitutional reform to reduce the number of parliamentarians, nationalizations of ASPI (Italy's highway company), Alitalia (the Italian flag carrier), and Ilva (Italy's largest steel company), as well as a stricter policy towards illegal immigration. In 2020, Italy became one of the countries worst affected by the COVID-19 pandemic. His government was the first in the Western world to implement a national lockdown to stop the spread of the disease. Despite being widely approved by public opinion, the lockdown was also described as the largest suppression of constitutional rights in the history of the Italian Republic. Conte's extensive use of prime ministerial decrees to impose restrictions aimed at containing the pandemic gave rise to criticism from journalists, political analysts, and opposition politicians. The economic impact of the COVID-19 pandemic was especially severe in Italy. In July 2020, to assist with the COVID-19 recession, Conte and other European leaders approved the Next Generation EU package, by which Italy will receive 209 billion euros in grants and loans from the European Recovery Fund.


title: Giuseppe Conte

text: When Matteo Renzi's Italia Viva withdrew its support for Conte's government, it started the 2021 Italian government crisis in January. Although Conte was able to win confidence votes in Parliament in the subsequent days, he chose to resign after failing to reach an absolute majority in the Senate. When negotiations to form Conte's third cabinet failed, the former president of the European Central Bank, Mario Draghi was asked to form a national unity government.


title: Giuseppe Conte

text: Conte was the fifth Prime Minister appointed without prior political experience, after Carlo Azeglio Ciampi, Silvio Berlusconi, Lamberto Dini, and Mario Monti, as well as the first from Southern Italy since Ciriaco De Mita in 1989. Conte was also the longest-serving independent prime minister in the history of Italy, even though he was widely seen as close to the M5S. Because of his leadership style, Conte has often been considered one of the leading examples of techno-populism, while his first cabinet was described by many publications, such as "The New York Times" and "la Repubblica", as the "first modern populist government in Western Europe". Conte has often been called "the people's lawyer" ("l'avvocato del popolo"), as he described himself during his first speech as Prime Minister.


title: Giuseppe Conte

text: Conte was born on 8 August 1964 into a middle-class family at Volturara Appula, near Foggia. His father Nicola was a public employee in the local municipality, while his mother Lillina Roberti was an elementary school teacher.


title: Giuseppe Conte

text: After his family moved to San Giovanni Rotondo, Conte attended the Classical Lyceum "Pietro Giannone" in San Marco in Lamis and then studied law at the Sapienza University of Rome, where he graduated in 1988, with honors. In 1992, he formally qualified as a lawyer, before, for a short term, studying abroad. In the same year, he moved to the United States to study at Yale Law School and Duquesne University, and at the International Culture Institute in Vienna in 1993. He later researched or lectured at Sorbonne University in 2000, Girton College, Cambridge in 2001 and New York University in 2008.


title: Giuseppe Conte

text: He began his academic career during the 1990s when he taught at Roma Tre University, at LUMSA University in Rome, at the University of Malta, and at the University of Sassari in Sardinia. Conte is currently professor of private law at the University of Florence and at Rome's LUISS. He sits on the board of trustees of John Cabot University in Rome. Conte's claim to have completed studies at New York University has been questioned, with the institution stating that "A person by this name does not show up in any of our records as either a student or faculty member."


title: Giuseppe Conte

text: In 2010 and 2011, Conte served on the board of directors of the Italian Space Agency (ASI) and in 2012 he was appointed by the Bank of Italy as a member of the "Banking and Financial Arbitrage" commission. He served also in scientific committee of the Italian Foundation of Notaries.


title: Giuseppe Conte

text: On 18 September 2013, he was elected by the Chamber of Deputies as a member of the Bureau of Administrative Justice, the self-governing body of administrative magistrates, on which he also served as vice president.


title: Giuseppe Conte

text: In February 2018, Conte was suggested by Luigi Di Maio, leader of the Five Star Movement (M5S), as a possible Minister of the Public Administration in his potential cabinet following the 2018 Italian general election; the election resulted in a hung parliament, as M5S became the party with the largest number of votes and of parliamentary seats, while the centre-right coalition, led by Matteo Salvini's League and other right-wing parties, emerged with a plurality of seats, receiving more votes together but without an absolute majority, in the Chamber of Deputies and in the Senate. The centre-left coalition led by former Prime Minister Matteo Renzi came in third.


title: Giuseppe Conte

text: On 9 May, following weeks of political deadlock and the failure of various attempts of forming cabinets both between M5S and the centre-right and the Democratic Party (PD), Di Maio and Salvini responded to President Sergio Mattarella's ultimatum to put together a neutral technocratic caretaker-led government by officially requesting that he give them 24 more hours to achieve a governing agreement between their two parties. In the evening of that same day, Silvio Berlusconi publicly announced that Forza Italia would not support a M5S–League government on a vote of confidence, but he would still back the centre-right alliance, thus opening the doors to a possible majority government between the two parties.


title: Giuseppe Conte

text: On 13 May, M5S and the League reached an agreement in principle on a government programme, possibly clearing the way for the formation of a governing coalition between the two parties but could not reach agreement on the members of a governing cabinet, most importantly the Prime Minister. M5S and League leaders met with President Sergio Mattarella on 14 May to shape a new government. At their meeting with President Mattarella, both parties asked for an additional week of negotiations to agree a detailed government programme and a Prime Minister to lead their joint government. Both M5S and the League announced their intention to ask their respective members to vote on the government agreement by the weekend.


title: Giuseppe Conte

text: On 21 May, Conte was proposed by Di Maio and Salvini for the role of Prime Minister in the 2018 Italian government, despite reports in the Italian press suggesting that President Mattarella still had significant reservations about the direction of the new government. On 23 May, Conte was invited to the Quirinal Palace to receive the presidential mandate to form a new cabinet. In the traditional statement after the appointment, Conte said that he would be the "defense lawyer of the Italian people".


title: Giuseppe Conte

text: On 27 May, Conte resigned his office because of disagreements between Salvini and President Mattarella. Salvini proposed the university professor Paolo Savona as Minister of Economy and Finances, but Mattarella strongly opposed him, considering Savona too Eurosceptic and anti-German. In his speech after Conte's resignation, Mattarella declared that the two parties wanted to bring Italy out of the Eurozone and, as the guarantor of the Italian Constitution and the country's interest and stability, he could not allow this.


title: Giuseppe Conte

text: On the following day, Mattarella gave Carlo Cottarelli, a former director of the International Monetary Fund, the task of forming a new government. On 28 May, the Democratic Party (PD) announced that it would abstain from a vote of confidence in Cottarelli, while the M5S and the center-right parties Forza Italia (FI), Brothers of Italy (FdI) and the League, said they would vote against him.


title: Giuseppe Conte

text: Cottarelli was expected to submit his list of ministers for approval to President Mattarella on 29 May. On that and the following day, he held only informal consultations with the President, waiting for the formation of a "political government". Meanwhile, Salvini and Di Maio announced their willingness to restart the negotiations to form a political government and Giorgia Meloni, leader of FdI, gave her support to this initiative. On 31 May, M5S and the League declared they had reached an agreement to form a new government without Savona as Finance Minister (he would become Minister of European Affairs) and with Conte at its head.


title: Giuseppe Conte

text: On 1 June 2018, Conte officially succeeded the Democrat Paolo Gentiloni as the head of the Italian government and was sworn in as the new prime minister. His cabinet was predominantly composed of members of the M5S and the League, but also of prominent independent technocrats like the Minister of Foreign Affairs Enzo Moavero Milanesi, who previously served as the Minister of European Affairs in the government of Mario Monti, the university professor Giovanni Tria as the minister of economy and finances and economist Paolo Savona, who served in the cabinet of Carlo Azeglio Ciampi in the 1990s and is currently known for his Eurosceptic views, who became the new Minister of European Affairs.


title: Giuseppe Conte

text: Party leaders Salvini and Di Maio were both appointed Deputy Prime Ministers. While Salvini became Minister of the Interior, with the main aim of drastically reducing the number of illegal immigrants, Di Maio served as Minister of Economic Development, Labour and Social Policies responsible for introducing the universal basic income.


title: Giuseppe Conte

text: The coalition of the two populist parties which Conte led was also known as the Government of Change, because of a document that summarized the electoral programmes of the two parties, which was called "Contract for the Government of Change".


title: Giuseppe Conte

text: During his speech before the investiture vote in the Italian Senate on 5 June, Conte stressed his wish to reduce illegal immigration and increase the pressure on human traffickers and smugglers. He also advocated a fight against political corruption, the introduction of a law which regulates the conflict of interests, a new bill which expands the right of self-defense, a reduction in taxes and a drastic cut in money going to elected politicians and government bureaucrats. Conte also proposed to lift the international sanctions against Russia.


title: Giuseppe Conte

text: The Senate backed the confidence vote in the Chamber of Deputies, voting 171 in favor and 117 against, with 25 abstentions. The cabinet was supported by M5S, Lega, two senators from Associative Movement Italians Abroad (MAIE) and two independents while the Democratic Party (PD), Forza Italia (FI), Free and Equal (LeU) and other small leftist parties voted against it. The far-right Brothers of Italy (FdI) and another ten independent senators abstained. On the following day, he received 350 votes in favor out of 630 in the Chamber of Deputies, 236 votes against and 35 abstained. As in the Senate, in the Chamber of Deputies PD, FI and LeU voted against the government, while FdI abstained. Besides M5S and League, Conte received two votes from independent deputies and one vote from Vittorio Sgarbi, a notable and controversial member of Forza Italia who has always heavily criticised M5S, but decided to support the cabinet in support of Salvini, and with the hope that a M5S government could lead to the party's failure.


title: Giuseppe Conte

text: On 5 February 2019, Conte became acting Minister of European Affairs after the resignation of Paolo Savona, who was elected President of the Companies and Exchange Commission (CONSOB). He held the "ad interim" office until 10 July 2019, when he appointed Lorenzo Fontana as the new minister.


title: Giuseppe Conte

text: In August 2019, after growing tensions within the majority, Deputy Prime Minister Salvini entered a motion of no confidence against Conte. Many political analysts believe the no confidence motion was an attempt to force early elections to improve the Lega's standing in Parliament, to enable Salvini to become the next Prime Minister. On 20 August, following a parliamentary debate in the Senate, in which Conte accused Salvini of being a political opportunist who "had triggered the political crisis only to serve his personal interest", he said: "this government ends here". The Prime Minister resigned his post to President Mattarella.


title: Giuseppe Conte

text: Subsequently, during a round of consultations between Mattarella and the parliamentary groupings, a possible new majority emerged between the Five Star Movement and the Democratic Party. On 28 August, at the Quirinal Palace, the PD leader Nicola Zingaretti announced his support for keeping Giuseppe Conte as the head of the new government. Mattarella then summoned Conte to the Quirinal Palace on 29 August to ask him to form a new cabinet. On 4 September, Conte announced the ministers of his new cabinet, which was sworn in at the Quirinal Palace the following day. On 9 September 2019, the Chamber of Deputies expressed its confidence in the new government with 343 votes in favor, 263 against and 3 abstentions. On 10 September 2019, in the second vote of confidence in the Senate, 169 voted in favour of the Conte government and 133 against.


title: Giuseppe Conte

text: On 16 September, a few days from the investiture vote, in an interview with "la Repubblica", former Prime Minister Matteo Renzi announced his intention to leave the PD, launching a new centrist and liberal party named Italia Viva (IV). In the interview he confirmed also the support to Conte's government. Two ministers and one undersecretary followed Renzi to his new movement.


title: Giuseppe Conte

text: In December 2019, the Minister of Education, Universities and Research Lorenzo Fioramonti resigned after disagreements with the rest of the cabinet over the recently approved 2020 budget bill. Fioramonti considered the share of funds dedicated to education and research to be insufficient. Conte took the ministerial role "ad interim", and announced his decision to split the Ministry of Education, University and Research into two: a Ministry of Public Education led by former undersecretary Lucia Azzolina (M5S), and a Ministry of University and Research led by the dean of the University of Naples Federico II Gaetano Manfredi (Independent), who were sworn in on 10 January.


title: Giuseppe Conte

text: Between December 2020 and January 2021, discussions arose within the government coalition between Conte and Matteo Renzi, former Prime Minister and leader of Italia Viva. Renzi called for radical changes to the government's economic recovery plans after the COVID-19 pandemic, and also demanded that Conte cede his mandate over the secret services coordination task. During his end-of-year press conference, Conte declined Renzi's requests, asserting that he still had a majority in the Parliament.


title: Giuseppe Conte

text: During a press conference on 13 January, Renzi announced the resignation of IV's two ministers, effectively triggering the collapse of Conte's government. Conte was soon backed by many members of his cabinet, like Dario Franceschini, Luigi Di Maio, Roberto Speranza, Stefano Patuanelli, Alfonso Bonafede, Vincenzo Spadafora and Riccardo Fraccaro. On the following day, Conte took the "ad interim" roles of Minister of Agriculture and Minister for Family.


title: Giuseppe Conte

text: On 18 January 2021, the government won the vote of confidence in the Chamber of Deputies with 321 votes in favour, 259 against and 27 abstentions. On the following day, Conte won a vote of confidence in the Senate too, with 156 votes in favor, 140 against and 16 abstentions; however, despite being externally supported by two dissident members of Forza Italia and three senators for life, the government was not able to reach an absolute majority in the upper house. On 26 January, after a few days of inconclusive negotiations with centrist and independent senators, Conte resigned as Prime Minister. In a statement posted on his Facebook page, he stated: "We have been going through a phase of real emergency. The widespread suffering of citizens, deep social unrest and economic difficulties require a clear perspective and a government that has a wider and more secure majority." The Prime Minister also demanded the formation of a national salvation government.


title: Giuseppe Conte

text: At the end of the consultations, President Mattarella gave the President of the Chamber Roberto Fico the task of verifying the possibility of a new government with the same majority of the previous one, composed by M5S, PD, IV and LeU. However, on 2 February, Italia Viva broke away from the majority due to disagreements on both platform and cabinet members, leading Fico to head back to Mattarella with a negative outcome. Following the unsuccessful government formation, Mattarella gave Mario Draghi, former president of the European Central Bank, the task of forming a new cabinet. On the following day, Conte met Draghi. On 4 February, during a brief declaration in front of Chigi Palace, Conte officially endorsed Draghi, asking M5S, PD and LeU to support the former ECB President and join his government. Conte also presented himself as a possible leader of the M5S–PD–LeU coalition which, according to him, must continue to cooperate, even after the end of his government.


title: Giuseppe Conte

text: On economic and fiscal issues, one of the main proposals of his first government was a reform of the Italian tax system, with the introduction of a 15% rate flat tax for small entrepreneurs and self-employed with an amount of annual revenues less than €65,000. Though this "flat regime" was a proposal from the right-wing League, it was also confirmed by Conte's second government, which had a centre-left bias.


title: Giuseppe Conte

text: During his first cabinet, Conte's government rolled out what is known as the citizens' income (), a system of social welfare provision that provides a basic income and assistance in finding a job to help poor people and families. The income was set at a maximum of €780 per month, and in its first year the programme had almost 2.7 million applications. The bill was later confirmed by Conte's second cabinet.


title: Giuseppe Conte

text: In September 2019, at the head of his second government, Conte launched a "Green New Deal", named after the analogous US proposed legislation that aimed to address climate change and economic inequality. In the same period, he praised students who protested against climate change, saying: "The images from the squares during the Fridays for Future are extraordinary, with so many young people participating with such passion. On the part of the government there is the utmost commitment to translate this request for change into concrete solutions. We all have a great responsibility for this."


title: Giuseppe Conte

text: In February 2020, Conte appointed Mariana Mazzucato as his economic counselor. Mazzucato, a professor at University College London, is considered one of the most prominent supporters of state intervensionism.


title: Giuseppe Conte

text: In April 2020, amid the COVID-19 pandemic in Europe, Conte became the most vocal supporter of issuing Eurobonds to assist with the crisis, describing the European Stability Mechanism (ESM) as "completely inadequate". Conte found key allies in France, Spain, Belgium, Ireland, Portugal, Greece, Slovenia and Luxembourg, which demanded more be done to cope with the COVID-19 pandemic; while Germany, the Netherlands, Austria, Finland and Estonia strongly opposed the eurobonds. Conte, during an interview with German weekly "Die Zeit", questioned: "What do we want to do in Europe? Does each member state want to go its own way?", He also added: "If we are a union, now is the time to prove it." On 8 April, he stated "we should loosen the European fiscal rules, otherwise we would have to cancel Europe and everyone will go their own way." On 23 April, the European Council agreed on a ESM without conditionality to sustain direct and indirect healthcare costs and the implementation of the a recovery fund to help with post-COVID reconstruction.


title: Giuseppe Conte

text: On 13 May, the Council of Ministers approved the so-called "Relaunch decree", with a budget of nearly €55 billion. This decree included "emergency income" for lower-income families, self-employed workers and economics aids to businesses.


title: Giuseppe Conte

text: From 13 to 21 June 2020, Prime Minister Conte organized a conference called "Progettiamo il Rilancio" ("We Plan the Relaunch"), better known as "estates general", in Villa Doria Pamphili in Rome, with the aim of "forging a coherent and well-funded plan for Italy's economic recovery from the coronavirus crisis". The government invited prominent international politicians including Paolo Gentiloni, David Sassoli and Ursula von der Leyen, economists such as Christine Lagarde, Ignazio Visco, Kristalina Georgieva, Olivier Jean Blanchard, Esther Duflo and Tito Boeri, and top managers like Vittorio Colao. The three main trade unions of the country, CGIL, CISL and UIL, and the Italian industrial employers' confederation, Confindustria, also took part in this estates general. The Prime Minister also invited also the opposition leaders; however, on 10 June, Matteo Salvini, Giorgia Meloni and Antonio Tajani said they would not take part in the conference.


title: Giuseppe Conte

text: From 17 to 21 July, Giuseppe Conte took part in one of the longest European Councils in history. After days of harsh confrontations, especially between Conte and Dutch Prime Minister Mark Rutte, the European leaders agreed on a new proposal by the President of the Council, Charles Michel, which provided a budget of €750 billion for the Recovery Fund, composed of €390 billion in grants and €360 billion in loans. Italy would benefit from nearly €82 billion in grants and €127 billion in loans. Prime Minister Conte described the deal as an "historic day for Italy and Europe".


title: Giuseppe Conte

text: When Conte became Prime Minister in 2018, he acted quickly to deliver on promises to the government's anti-immigration base through strict controls on immigration to Italy. Since 2013, Italy had absorbed over 700,000 African migrants arriving by boat from Libya. During his premiership, Conte and his Interior Minister Matteo Salvini promoted stricter policies regarding immigration and public security.


title: Giuseppe Conte

text: After Conte's approval on 10 June 2018, Salvini announced the closure of Italian ports to vessels rescuing immigrants in the Mediterranean Sea. On 24 September 2018, the Council of Ministers approved the "Salvini decree", which contained a series of hardline measures that saw the Italian government abolish key forms of protection for migrants and make it easier for them to be deported. The decree also suspend the refugee application process of those who are considered "socially dangerous" or who have been convicted of a crime. The decree was abolished in December 2020.


title: Giuseppe Conte

text: On 23 September 2019, Italy and other four European countries, Germany, France, Malta and Finland, agreed on a draft deal to present to other EU countries on how to manage the migrant crisis and distribute those saved from the Mediterranean. This agreement was considered a victory for Conte and his new interior minister, Luciana Lamorgese.


title: Giuseppe Conte

text: On 8 April 2020, amid the coronavirus pandemic, the government closed all Italian ports until 31 July, stating that they cannot ensure the necessary requirements for the classification and definition of "safe place", established by the Hamburg Rules on maritime search and rescue."


title: Giuseppe Conte

text: On 14 August 2018, during a torrential rainstorm over the city of Genoa, a section of the Ponte Morandi collapsed. Between 30 and 35 cars and three trucks were reported to have fallen from the bridge, with the deaths of 43 people.


title: Giuseppe Conte

text: The day after the collapse, Conte declared a state of emergency for the Liguria region, which would last for a year. After few days, Conte appointed Marco Bucci, the elected mayor of Genoa, as extraordinary commissioner for bridge reconstruction. In addition, the government put pressure on the managers of the Italian highway company, Autostrade per l’Italia (ASPI), which is part of the Benetton family owned Atlantia. The M5S asked the revocation of license to Benetton family and the nationalization of ASPI. Despite bitter controversies, the revocation was not immediately implemented.


title: Giuseppe Conte

text: The last two cable-stayed pillars of the bridge were removed through explosive demolition on 28 June 2019. The complete bridge was scheduled to be removed, along with many damaged residential buildings in the surrounding area. The reconstruction of a replacement bridge, designed by famous Italian architect Renzo Piano, began on 25 June 2019 and was completed on 28 April 2020.


title: Giuseppe Conte

text: On 3 August 2020, the new bridge, named Saint George Bridge, after the patron saint of the Republic of Genoa, was inaugurated by Conte and President Mattarella and opened to motor vehicles after a few days.


title: Giuseppe Conte

text: In July 2020, Paola De Micheli, the Minister of Infrastructure and Transport, announced that the bridge-operation license would be temporarily assigned to previous operators ASPI. This gave rise to harsh criticism both from the right-wing opposition and the M5S. On 13 July, Conte stepped in to halt any possible prorogation of the license to ASPI, commenting that the company's proposal "was totally unacceptable", and he added: "The members of the Benetton family have not yet understood that this government will not sacrifice the good of the public on the altar of their interests."


title: Giuseppe Conte

text: On 15 July, the government and Atlantia reached an agreement which brought about the nationalization of the national highway company ASPI, with the state holding a majority participation through Cassa Depositi e Prestiti, while Atlantia would keep only 10% of the company's stock. In a second phase, a listing is planned, aiming to create a company with a widespread shareholder base.


title: Giuseppe Conte

text: Under Conte's governments, the Italian Parliament approved what is known as the "Fraccaro Reform", from the name of the M5S deputy who was the bill's first signatory. The reform was finally approved by the Parliament, with the fourth and final vote in the Chamber of Deputies on 8 October, with 553 votes in favor and 14 against. In the final vote, the bill was supported both by the majority and the opposition; only the liberal party More Europe (+Eu) and other small groups voted against. The reform called for a cut in the number of MPs, which would shrink from 630 to 400 deputies and from 315 to 200 senators.


title: Giuseppe Conte

text: After the proposal's approval, Conte said: "The reduction in parliamentarians is a reform that will bring a greater efficiency of parliamentary jobs. Now, citizens will be closer to the institutions. It is an historical passing that, together with other projected reform, will be a prelude to greater efficiency of our parliamentary system."


title: Giuseppe Conte

text: The referendum to approve the reform was scheduled on 29 March. However it was postponed to 20–21 September due to the coronavirus pandemic which hit Italy hard. In September, Italians largely approved the reform, with nearly 70% voting in favor.


title: Giuseppe Conte

text: In February 2020, Italy became one of the world's main centres for confirmed cases of COVID-19, a respiratory disease caused by the SARS-CoV-2 virus that originated in China.


title: Giuseppe Conte

text: In late January, the government banned all flights from and to China, becoming the first European country to adopt this measure. On 22 February, the Council of Ministers announced a bill to contain the COVID-19 outbreak, quarantining more than 50,000 people from 11 different municipalities in Northern Italy. Prime Minister Conte stated: "In the outbreak areas, entry and exit will not be provided. Suspension of work activities and sport events has already been ordered in those areas." After few days, schools and universities closed in the whole country.


title: Giuseppe Conte

text: On 8 March 2020, Prime Minister Conte extended the quarantine to all of Lombardy and 14 other northern provinces, putting more than a quarter of the national population under lockdown. On the following day, he announced in a press conference that all measures previously applied only in the so-called "red zones" had been extended to the whole country, putting "de facto" 60 million people in lockdown. He later proceeded to officially sign the executive decree. This measure was described as the largest lockdown in human history.


title: Giuseppe Conte

text: The lockdown measures, despite being widely approved by public opinion, were also described as the largest suppression of constitutional rights in the history of the republic. Nevertheless, Article 16 of the Constitution states that travel restrictions may be established by law for reasons of health or security.


title: Giuseppe Conte

text: On 20 March, the Ministry of Health ordered tighter regulations on free movement. While on the following day, Conte announced further restrictions within the nationwide lockdown, by halting all non-essential production, industries and businesses, following the rise in the number of new cases and deaths in the previous days.


title: Giuseppe Conte

text: On 24 March, in a live-streamed press conference, Conte announced a new decree approved by the Council of Ministers. The decree imposed higher fines for the violation of the restrictive measures, and a regulation of the relationship between government and Parliament during the emergency. It included also the possibility of reducing or suspending public and private transport, and gave the regional governments power to impose additional restrictive regulations in their Regions for a maximum of seven days before being confirmed by national decree. On 1 April, Conte's government extended the period of lockdown until 13 April.


title: Giuseppe Conte

text: On 10 April, Conte made further announcements extending the lockdown until 3 May, allowing some specific businesses, like bookstores and silviculture activities, to reopen under specific safe measures. On the same day, he appointed a task force to relaunch Italy after the crisis; the team was led by Vittorio Colao and composed by a total of nineteen members, chosen among university professors, managers and public administration officers, which notably included Mariana Mazzucato and Enrico Giovannini.


title: Giuseppe Conte

text: On 26 April, the Prime Minister announced the so-called "Phase 2", that would start from 4 May. Movements across regions were still forbidden, while the ones between municipalities and provinces were allowed only for work and health reasons as well as for visit relatives. Moreover, he allowed the re-opening of closed factories, but schools, bars, restaurants and barbers were still closed.


title: Giuseppe Conte

text: On 18 May, the lockdown officially ended and the government allowed the re-openings of bars, restaurants, barbers and gyms. However, travels across regions were still limited.


title: Giuseppe Conte

text: On 28 and 29 July, the Parliament approved the extension of the state of emergency until October 2020, proposed by the government. The state of emergency, which was firstly introduced in January 2020, gave greater powers to the prime minister and the government in facing the crisis. The extension created criticism both from the opposition and the liberal wing of the government. The right-wing leader Giorgia Meloni accused the government of pursuing a "dangerous liberticidal drift", asserting that the emergency was already over. Conte described Meloni's accusations as "dangerous and false", adding that the extension of the emergency was a "legitimate and inevitable measure", which became necessary because "the virus continues to circulate in the country". On 16 August, after an increase in the daily number of new COVID-19 cases, the government closed all the discos and night clubs, and imposed to wear a mask outdoors in some areas considered at risk of crowding.


title: Giuseppe Conte

text: In October 2020, the confirmed cases continued to grow, reaching the daily record since the beginning of the pandemic. On 7 October, the Parliament postponed the end of the state of emergency to 31 January 2021. On 13 October, the Council of Ministers approved a new decree concerning further restrictions for bars and restaurants as well as the mandatory use of protection mask outdoors. On 18 October, Conte announced further restrictions, including limitations to the opening hours of bars and restaurants, as well as a suspension of amateur contact sports, local festivals and conferences. On 25 October, the government introduced new restrictions, imposing the closing of gyms, swimming pools, theatres and cinemas, as well as the closing of bars and restaurants by 6 pm.


title: Giuseppe Conte

text: On 4 November 2020, Prime Minister Conte announced a new lockdown, dividing the country into three zones depending on the severity of the pandemic, corresponding to red, orange and yellow zones. Moreover, a national curfew from 10 pm to 5 am was implemented, as well as compulsory weekend closing for shopping malls, and online education in high schools. Conte described the situation as "particularly critical", asserting that the virus was moving at a "strong and even violent" pace. In red zones, lockdown measures were similar to the ones which were implemented from March to May 2020, such as compulsory closing for shops, restaurants and other activities, online education for schools except for kindergartens, elementary schools and sixth-grade classes, and no movements allowed except for working or necessity reasons. In orange zones, restrictions included compulsory closing of restaurants and online education for high schools only, while movement within the home-town territory was still allowed. In yellow zones, the only restrictions included compulsory closing for restaurant and bar activities at 6 pm, and online education for high schools only.


title: Giuseppe Conte

text: On 2 December, a further movement restriction was implemented by the government to prevent an increase in cases during the Christmas holidays period, forbidding movement between regions from 21 December to 6 January. To prevent people from gathering during Christmas, Saint Stephen's Day and New Year's day, travel between different "comuni" was also restricted, and the curfew for New Year's Eve was extended to 7 am. On 18 December, Conte announced that the whole country will be declared "red zone" on Christmas Day and on the other festivities.


title: Giuseppe Conte

text: Since the beginning of his term as prime minister, Conte's foreign policy has been characterized by a lenient approach to Russia. For example, he pressed for the repeal of international sanctions against Russia, which according to him "damage the Italian economy". He also considered Russia a strategic partner in the fight against Islamic terrorism. However, Conte stressed that under his leadership Italy will remain an active member of NATO and a close ally of the United States. During the COVID-19 pandemic in March 2020, after a phone call with Conte, Russian president Vladimir Putin arranged the Russian army to send military medics, special disinfection vehicles and other medical equipment to Italy, which was the European country hardest hit by coronavirus.


title: Giuseppe Conte

text: During his premiership, Conte built a close relationship with U.S. President Donald Trump. Since the beginning of Conte's government, Trump considered him a key ally during international meetings as well as his "privileged interlocutor" in Europe. On 8 and 9 June, Conte participated in his first G7 summit, hosted by Prime Minister Justin Trudeau in Canada. During the summit, he was the only leader to back President Trump and his proposal to readmit Russia into the G7. However, he later assumed a more pro-European view, shared by the other five leaders, condemning Trump tariffs on steel and aluminium exported by the European Union. On the following day, Conte was thanked for his positions on Russia and his populist stance by President Trump, who invited him to the White House. On 28 June, Conte participated in his first European Council meeting and blocked a joint EU trade and defense statement criticizing Trump's tariff policy.


title: Giuseppe Conte

text: In June 2018, Trump praised Conte, describing him as a "really great leader" and "very strong on immigration". Trump also endorsed Conte during the 2019 government crisis, hoping that he could remain Prime Minister. In 2019, Conte authorized the US Attorney General, William Barr, to discuss with the Italian intelligence services about a possible plot against President Trump amid the investigations on the Russian interferences in the 2016 presidential election. This event arose criticism, especially within his own majority coalition, with the Democratic Party and Italia Viva, which asked the Prime Minister to clarify it. Conte stated that the meeting with Barr was "legal and fair", adding that he had never talked about this matter with President Trump.


title: Giuseppe Conte

text: On 31 March 2020, President Trump announced that the United States would send 100 million dollars of medical aids to Italy, in response to the COVID-19 pandemic which was affecting the country. After few days, during an interview at the NBC, Conte described Trump as "Italy's most true and loyal friend". On 11 April, Trump issued an executive order in which he allowed U.S. militaries deployed in Italy to assist Italian law enforcement in facing the crisis.


title: Giuseppe Conte

text: His close relation with Trump generated some tensions and journalistic speculations after Trump's defeat to Joe Biden in the November 2020 presidential election. Conte was the last leader of a G7 member to congratulate Biden for his victory; moreover, he was the last leader among the European G7 members to be phone called by the new President-elect. During the call, the two leaders expressed their will to cooperate in major global challenges like the COVID-19 pandemic and climate change.


title: Giuseppe Conte

text: During his cabinet, Conte built a friendly relation with the Spanish prime minister Pedro Sánchez. The two leaders organized several bilateral meetings and often shared the same positions during European Council meetings especially on economics, immigration policies and climate change. Moreover, Conte and Sánchez advocated for anti-austerity measures and for an increase in the European Union's budget. During the COVID-19 pandemic, they were among the main proponents of Next Generation EU. In November 2020, commenting on the relation with his Spanish counterpart, Conte stated: "With my friend Sánchez, we have reaffirmed the alliance between our countries, as well as a common view on the main European and international issues. Together we are a power."


title: Giuseppe Conte

text: At the beginning of his political career, Conte was described as a populist and Eurosceptic politician, openly critical towards the European Union, whose economic and financial rules were described as "old and outdated"; however, he later toned down his Eurosceptic rhetoric, whilst still remaining a vocal anti-austerity leader, as it became evidence during the COVID-19 pandemic, which severely affected Europe.


title: Giuseppe Conte

text: In March 2019, Conte and the Chinese President Xi Jinping signed in Rome 29 economic and institutional agreements amounting to 2.5 billion euros, including a memorandum of understanding on the Belt and Road Initiative investments program. Prime Minister Conte's position on the Chinese investments programme was criticized by the other major Western powers.


title: Giuseppe Conte

text: In August 2019, amid a serious government crisis, Conte took part, as caretaker prime minister, in the 45th G7 summit in Biarritz, in what it was believed to be his last summit as head of government. The main topics of the summit included global trade, climate change, taxing technology companies, but also Iran nuclear deal, and 2019 Amazon wildfires.


title: Giuseppe Conte

text: Conte criticized the 2019 Turkish offensive into north-eastern Syria. He stated that the offensive "puts the region's civilians and stability in jeopardy".


title: Giuseppe Conte

text: In January 2020, the situation of the Libyan Civil War became increasingly worrying, with the troops of field marshal Khalifa Haftar approaching Tripoli. During the crisis, Prime Minister Conte had a series of bilateral meetings in Rome both with Haftar and Fayez al-Sarraj, the chairman of the Presidential Council of Libya, who are considered two of the main contenders in the civil war. After pressures from the international community, on 12 January Haftar announced a ceasefire.


title: Giuseppe Conte

text: In November 2018, Silvia Romano, a 23-year-old Italian aid worker, was kidnapped in Kenya by a group of terrorists linked to Al-Shabaab. On 9 May 2020, Conte announced her liberation in a tweet. Immediately after the announcement, speculations rose about the ransom paid to the kidnappers, which according to some sources stood at around €4 million. Moreover, Romano became the target of a hate campaign by the right-wing opposition due to her conversion to Islam, occurred during the captivity. During a discussion in the Chamber of Deputies, Alessandro Pagano, a member of the League, called her a "neo-terrorist".


title: Giuseppe Conte

text: On 1 September 2020, two Italian fishing boats were detained by the Libyan Coast Guard, along with their crews of eighteen members total, while allegedly fishing in Libya's territorial waters in the Southern Mediterranean. Prime Minister Conte asked for the immediately release, but the Libyan commander Khalifa Haftar denied it, demanding a prisoner exchange. On 17 December 2020, Conte announced that the eighteen fishermen were freed.


title: Giuseppe Conte

text: In November 2020, an investigation conducted by Italian magistrates on the murder of Giulio Regeni, an Italian graduate student who was tortured to death in Egypt in 2016, resulted in the conviction of five agents of the Egyptian National Security Agency. On 21 November, Conte gave a two-weeks ultimatum to Egyptian President Abdel Fattah el-Sisi to cooperate with Italian authorities, stating: "We need answers on Regeni's murder. The time is over." The Prime Minister also threatened to withdraw the ambassador if the Egyptian government will not cooperate. On 11 December, the Italian magistrates officially denounced four Egyptian officers.


title: Giuseppe Conte

text: On 28 February 2021, after a few days from the end of his premiership, Conte joined the Five Star Movement (M5S). In later February, the founder and so-called Guarantor of the M5S, Beppe Grillo, gave Conte the task of writing a new party statute and announced that Conte would become the new political leader. In the following months, however, tensions grew between the two politicians. In June, Grillo accused Conte of aiming at creating a one-man party and of being "without a political vision". The former Prime Minister threatened to found his own political movement, stating that Grillo "can not stop this useful political project". In July 2021, Conte and Grillo found a compromise on the new statute and leadership elections were called on 5 August. On 4 August, party members largely approved the new statute with 87.6% of votes. On the following day, Conte easily won the election with 92.8% of votes, becoming the party's new president.


title: Giuseppe Conte

text: In 2022, tensions grew within the M5S between Conte and Luigi Di Maio; the two main representatives of the movement clashed many times regarding the policies promoted by the government as well as in the run-up of the 2022 presidential election, during which Conte briefly supported, along with Salvini, the candidacy of Elisabetta Belloni, opposed by Di Maio. In June 2022, Conte became particularly critical of the government's approach to the war in Ukraine and the deployment of military aids to Kyiv's government, on the other hand, Di Maio strongly defended it. Di Maio also labeled the new party's leadership as "immature", while Conte and his closer allies threatened to expel Di Maio from the movement. On 21 June, Di Maio, along with several deputies and senators, exited from the M5S, founding their own political group, known as Together for the Future.


title: Giuseppe Conte

text: On 13 July 2022, Conte announced that the M5S would revoke its support to the national unity government of Mario Draghi regarding the so-called "decreto aiuti", a decree on economic stimulus to contrast the ongoing energy crisis, opening a political crisis within the majority. On the following day, the M5S abstained, not voting the confidence vote to the government, and Draghi, despite having largely won the vote, officially resigned as prime minister; however, the resignation was rejected by president Sergio Mattarella. On 21 July, Draghi resigned again after a new confidence vote in the Senate failed to pass with an absolute majority, following the defections of M5S, Lega, and Forza Italia; President Mattarella accepted Draghi's resignation and asked Draghi to remain in place to handle current affairs. A snap election was called for 25 September 2022.


title: Giuseppe Conte

text: In the election, Conte's M5S gained 15.4% of votes, being the third most-voted party. However, it was able to elect only 52 deputies and 28 senators.


title: Giuseppe Conte

text: Conte has been described by journalists and political analysts as a populist politician. His leadership style has been considered one of the most prominent examples of the so-called techno-populism. During his first cabinet, Conte has often been labeled as a neo-nationalist leader; since September 2019, when he became the head of a centre-left coalition government, he slightly toned down his nationalist rhetoric, while he continued to use various instances of the so-called banal nationalism. Despite being labeled as a post-ideological leader, who governed both with the political right and the political left, Conte described his political ideal as "new humanism". In September 2019, he described himself as a leftist within the Christian-democratic tradition.


title: Giuseppe Conte

text: During an interview in 2018, Conte said he used to vote for the centre-left coalition (The Olive Tree) and once for a centrist party but never for Forza Italia or National Alliance, and then the Democratic Party until 2013, when he began approaching the M5S. He also added that "the ideological schemes of the 20th century are no longer adequate to represent the current political system" and it should be "more important and correct to evaluate the work of a political force on how it is positioned on the respect of fundamental rights and freedoms".


title: Giuseppe Conte

text: In his inaugural speech at the Senate of the Republic on 5 June 2018, in response to attacks on government political forces accused of being populist and anti-establishment, Conte replied that "if populism is the attitude of the ruling class to listen to the people's needs ... and if anti-establishment means aiming at introducing a new system able to remove old privileges and encrusted power, well, these political forces deserve both these epithets".


title: Giuseppe Conte

text: Conte opposed the "hypertrophy of Italian laws", advocating the repeal of useless laws and supported a simplification of bureaucracy. As a professor, he strongly opposed the school reform legislation promoted by Matteo Renzi's government in 2015, known as "The Good School", which, according to him, must be completely revised. Contrasts with Renzi became evident during Conte's second government. Despite the cabinet being supported by Renzi's Italia Viva, among others, the former Prime Minister has often accused Conte of being a populist politician, threatening to withdraw his party's support.


title: Giuseppe Conte

text: According to public opinion surveys, Conte's approval rating was always above 50% during all his first cabinet, then it dropped to 40% in the early months of his second government. In March 2020, amid the COVID-19 crisis, his approval rating rose above 70%, one of the highest ever ratings for an Italian prime minister. In January 2021, 56% of Italians wanted Conte to remain as Prime Minister. According to Ipsos, Conte's approval rating at the end of his second government in February 2021 was still around 65%. Moreover, with more than 3.7 million followers, Conte is one of the most followed European leaders on Facebook.


title: Giuseppe Conte

text: Conte married Valentina Fico, a lawyer from Rome and daughter of a former director of the Santa Cecilia conservatory, with whom he has a child, Niccolò, born in 2007; however, they divorced after a few years. By 2018, Conte was engaged with Olivia Paladino, daughter of the Roman entrepreneur Cesare Paladino and the Swedish actress Ewa Aulin.


title: Giuseppe Conte

text: Conte is an avid supporter of A.S. Roma, a passion that arose when he studied in Rome at the Sapienza University. He is a Roman Catholic and a follower of Padre Pio of Pietrelcina. In addition to his native Italian, Conte also speaks English.


title: Giuseppe Conte

text: On 21 May 2018, when Conte was proposed to President Mattarella as candidate for prime minister, "The New York Times" questioned his summer stays at New York University (NYU) listed in his official curriculum vitae in an article asserting that a NYU spokeswoman could not find Conte in university "records as either a student or faculty member". Similar doubts arose concerning his study period in France at the Sorbonne University.


title: Giuseppe Conte

text: The following day, the Associated Press reported in an article published also by "The New York Times" that the NYU spokeswoman added that "while Mr. Conte had no official status at NYU, he was granted permission to conduct research in the NYU Law library" during the period listed in his official curriculum vitae. Similarly, the Duquesne University of Pittsburgh and the University of Malta found no record of him in their archives, although it was confirmed that Conte held lectures at the old university building in Valletta, Malta, for the Foundation for International Studies. Yale University, contacted by another newspaper, confirmed that he was a visiting scholar there for three months.


title: Giuseppe Conte

text: Moreover, Conte stated in his CV that he had worked for his legal studies at the Kulturinstitut in Vienna, Austria, but this is a language school, not a law school.


title: Giuseppe Conte

text: In June 2020, then Prime Minister Conte approved the sale of two military ships to Egypt. This move was heavily criticised both by opposition and government allies, due to the ongoing tensions between Italy and Egypt, following the murder of Giulio Regeni, an Italian PhD student tortured to death in 2016.


title: Pheochromocytoma

text: Pheochromocytoma (PHEO or PCC) is a rare tumor of the adrenal medulla composed of chromaffin cells, also known as pheochromocytes. When a tumor composed of the same cells as a pheochromocytoma develops outside the adrenal gland, it is referred to as a paraganglioma. These neuroendocrine tumors are capable of producing and releasing massive amounts of catecholamines, metanephrines, or methoxytyramine, which result in the most common symptoms, including hypertension (high blood pressure), tachycardia (fast heart rate), and diaphoresis (sweating). However, not all of these tumors will secrete catecholamines. Those that do not are referred to as biochemically silent, and are predominantly located in the head and neck. While patients with biochemically silent disease will not develop the typical disease manifestations described above, the tumors grow and compress the surrounding structures of the head and neck, and can result in pulsatile tinnitus (ringing of the ear), hearing loss, aural fullness, dyspnea (difficulty breathing), and hoarseness. While tumors of the head and neck are parasympathetic, their sympathetic counterparts are predominantly located in the abdomen and pelvis, particularly concentrated at the organ of Zuckerkandl.


title: Pheochromocytoma

text: The signs and symptoms of a pheochromocytoma are those related to sympathetic nervous system hyperactivity. The classic triad includes headaches (likely related to elevated blood pressure, or hypertension), tachycardia/elevated heart rate, and diaphoresis (excessive sweating, particularly at night, also known as hyperhidrosis). However, patients are unlikely to experience continuous symptoms. Due to the paroxysmal nature of catecholamine synthesis and release, patients may experience "attacks" or "spells" where they are suddenly overwhelmed with signs and symptoms of their tumor. Attacks can occur spontaneously (without warning) or may be triggered by a variety of pharmaceutical agents, foods, intraoperative tumor manipulation, intubation, or during anesthetic induction.


title: Pheochromocytoma

text: While the above symptoms are classic, other common clinical manifestations have been reported and include (in no particular order)


title: Pheochromocytoma

text: While the symptoms of a pheochromocytoma are quite common, the disease has been referred to as "the great mimic". Literature reports that just 0.1% of patients with hypertension are diagnosed with this rare endocrine disorder and symptomatic patients are often mistaken for much more common diseases. As symptoms are often paroxysmal (episodic/sporadic), patients may not immediately seek treatment as the problem "disappears on its own." Furthermore, when pictured in the ideal clinical scenario (an older woman in her mid-50s), the spontaneous attacks of flushing, sweating, and a racing heart may be mistaken for pre-menopausal related hot-flashes. Unmanaged pheochromocytoma is dangerous and can lead to serious complications, including death. The cardiovascular system is the most commonly involved.


title: Pheochromocytoma

text: In pregnancy, pheochromocytoma is associated with significant maternal and fetal mortality, mainly due to hypertensive crisis in the mother and intrauterine growth restriction in the fetus.


title: Pheochromocytoma

text: Multiple organ dysfunction syndrome (MODS): Caused by an elevated inflammatory response, multiple organ dysfunction is a severe, life-threatening emergency with increasing mortality based on the number of systems involved. Pheochromocytoma-related MODS is associated with multiple organ failure, hyperthermia > 40 degrees Celsius, neurologic manifestations, and cardiovascular instability resulting in either hypo or hypertension. In contrast to a hypertensive crisis, pheochromocytoma-associated MODS may not respond to traditional alpha-receptor agents and may require emergent surgical excision if clinical stability is not achieved.


title: Pheochromocytoma

text: Current estimates predict that upwards of 40% of all pheochromocytomas are related to an inherited germline susceptibility mutation. Of the remaining 60% of tumors, more than 30% are associated with a somatic mutation. Given the high association with genetic inheritance, the United States Endocrine Society recommends that all patients diagnosed with a pheochromocytoma undergo an evaluation with a genetic counselor to consider genetic testing. The most recent data indicates that there are 25 pheochromocytoma susceptibility genes; however, just 12 are recognized as part of a well-known syndrome. Determining the genetic status of a pheochromocytoma patient is crucial – each gene is inherited in a different pattern, associated with specific disease characteristics, and may respond more favorably to certain treatment options. Furthermore, early identification can guide physicians on screening recommendations for first degree relatives of patients with pheochromocytoma. There is no current consensus for how and when asymptomatic carriers (individual who has a genetic variant associated with pheochromocytoma, but no current evidence of disease) should be evaluated. Conversations should occur at an individual level with the patient and their provider to develop a personalized screening plan that alternates between a biochemical (blood work) evaluation and whole-body imaging to monitor disease progression.


title: Pheochromocytoma

text: Additional practices may help maintain the emotional and psychological well-being of the minor. Screening includes a multidisciplinary team (endocrinologist, oncologist, psychologist, geneticist, parent, and child) where the primary focus is supporting the child.


title: Pheochromocytoma

text: The following table(s) detail the clinical characteristics of the well-known hereditary pheochromocytoma gene variants


title: Pheochromocytoma

text: MEN2 (Multiple Endocrine Neoplasia-2); VHL (von-Hippel Lindau); NF1 (Neurofibromatosis-1); NET (Neuroendocrine Tumor); CNS (Central Nervous System)


title: Pheochromocytoma

text: There have been several published case reports of other, rare pheochromocytoma-associated susceptibility genes:


title: Pheochromocytoma

text: Several additional gene variants have been described, but the provided information is inconsistent and a consensus has not been reached in the community if these mutations are truly pheochromocytoma susceptibility genes.


title: Pheochromocytoma

text: If a patient has the characteristic signs and symptoms of a pheochromocytoma and the decision is made to pursue additional biochemical (blood work) evaluation, the differential diagnosis is important as it is more likely to be something other than a pheochromocytoma given the relative frequency of 0.8 per 100,000 person-years.


title: Pheochromocytoma

text: Elevated plasma free metanephrines is considered the gold standard diagnosis for pheochromocytoma. Over 10 studies have confirmed that the sensitivity and specificity of this test is 97% and 93% respectively; however, there is still concern for false positive results in the correct clinical scenario. When interpreting a biochemical analysis for pheochromocytoma, the provider must pay close attention to the (1) conditions of the collection, (2) "all" medications the patient is taking, and (3) their diet.


title: Pheochromocytoma

text: While the above (3) conditions are likely to contribute to false-positive results if not controlled for, any value greater than 3 to 4 times the upper reference limit of normal should be considered diagnostic for a pheochromocytoma.


title: Pheochromocytoma

text: Twenty-four hour urinary metanephrines are an acceptable alternative if the plasma test is unavailable. Other additional biomarkers can be helpful to aid in the diagnosis of pheochromocytoma as well, most notable is Chromogranin A. In comparison to the specificity of elevated catecholamines in the pheochromocytoma patient, chromogranin A is a non-specific polypeptide that is high in a variety of neuroendocrine tumors. However, a 2006 report from Italy found that over 90% of studied pheochromocytoma patients demonstrated elevated chromogranin A levels. If metanephrine values are equivocal, chromogranin A can be used as an adjunct marker to predict the presence of a tumor.


title: Pheochromocytoma

text: Borderline elevated metanephrines present a diagnostic challenge to the physician - the first step is to repeat the labs, taking extra precautions to follow the gold standard diagnosis described above, including the conditions of collection, pharmaceutical interference, and any potential diet and lifestyle habits that could alter the results. If the offending medications cannot be discontinued or repeated labs remained the same, consider administering a clonidine suppression test. In the 1970s, the drug clonidine hydrocloride swept the market as a novel agent for hypertension; however, the reported side-effects (nausea, vomiting, drowsiness, dryness of the eyes and mouth, constipation, and generalized weakness) limit compliance and have vastly diminished prescriptions. While the adverse side-effects with clonidine are inconvenient, the most dangerous aspect of clonidine is withdrawal rebound hypertension - that is, when the medicine is abruptly discontinued, blood pressure may rapidly return or surpass the original value. However, a one-time, weight-based dose can be utilized in limited settings to help determine disease status. After fasting overnight, patient's will present to their testing site for a baseline metanephrines blood draw and clonidine administration. They will remain supine for (3) hours and a repeat blood draw will be taken. A positive result (indicating a pheochromocytoma) will occur if the plasma metanephrine levels remain elevated after clonidine is given. If the results are the same or fall, the test is negative and the patient does not have a pheochromocytoma. It is important to note that if a patient "does not" have a pheochromocytoma, they may become extremely hypotensive following clonidine. Patients should not depend on themselves for transport following this test.


title: Pheochromocytoma

text: Plasma methoxytyramine is a breakdown product of the catecholamine, dopamine. Paragangliomas of the head and neck commonly secrete dopamine, but are referred to as "biochemically silent" because they do not cause the characteristic symptoms associated with a pheochromocytoma. However, methoxytyramine can be utilized to detect the tumors of the head and neck. Further research indicates that the biomarker is also a useful indicator of metastatic disease - which is the only current biochemical evidence of metastases to date.


title: Pheochromocytoma

text: While diagnostic, laboratory values can also provide physician's with important information about the type, location, size, and associated tumor genotype. There are (3) major, well-recognized biochemical phenotypes that can be used by health care providers to direct patient care.


title: Pheochromocytoma

text: Across both an adrenergic and a noradrenergic phenotype, the greater the sum of plasma or urinary concentrations of metanephrine and normetanephrine, the larger the expected tumor diameter.


title: Pheochromocytoma

text: Anatomic imaging refers to computed tomography (CT) [CAT scan] or magnetic resonance imaging (MR) scans. These imaging modalities serve to initially locate the tumor and provide detailed information about size, morphology, and structural relation to adjacent internal structures. Traditionally, a patient presents to their physician for symptoms concerning for a pheochromocytoma, which prompts a biochemical evaluation. If the results are positive, the patient is referred for anatomic imaging with a CT or MR scan. However, as anatomic imaging becomes more readily available, patients are referred to an endocrinologist after an incidental (unanticipated finding) adrenal nodule is found on a scan ordered for another reason. For example, "Patient M" presents to his local emergency room for abdominal pain and a CT is ordered to rule-out appendicitis; however, the radiologist notes there is a 3.5 centimeter right adrenal mass.


title: Pheochromocytoma

text: While there has not been a consensus on if CT or MR is the preferred imaging modality in pheochromocytoma, each method has its associated strengths and weaknesses. As CT expose the patient to ionizing radiation, MR is preferred in children and pregnant women. Furthermore, the intravenous contrast used in CT can cause kidney damage and should therefore be avoided in patients with pre-existing damage. However, patients who struggle with being in confined spaces for extended periods of time (claustrophobia) cannot often tolerate an MR as the machine is close-ended compared to the open-ended design of a CT. When patients become anxious and begin to move in the machine, this causes motion artifact, which occurs less in CT-based images.


title: Pheochromocytoma

text: Compared to CT and MR, ultrasound is not a preferred imaging modality and should be avoided in the pheochromocytoma patient. However, in specific patient populations where avoid ionizing radiation is the top priority (children, pregnant women), ultrasound can be used as an adjunct method when MR may be unavailable or the patient is unable to complete the scan. Furthermore, if an acute adrenal hemorrhage is suspected in a pheochromocytoma patient, ultrasound is a quick, painless, radiation-less, and cheap modality for a "first-pass" before the above imaging modalities or surgery is used to confirm the diagnosis.


title: Pheochromocytoma

text: The imaging modalities discussed below are for tumor characterization, confirmation of metastatic disease, and treatment planning - they are not used to discern tumor location or help the surgical team prepare for excision. For most pheochromocytoma patients, functional imaging will follow a CT or MR. If anatomic imaging only demonstrates an adrenal tumor without evidence of disease anywhere else in the body and the metanephrine levels are overtly elevated, functional imaging can be foregone in favor of prompt surgical excision. Over the last decade, there have been five functional techniques used to evaluate the pheochromocytoma patient (1) 18F-fluorodeoxyglucose positron emission tomography (F-FDG PET), commonly referred to as the PET scan, (2) iodine-123 meta-iodobenzylguanadine (I-MIBG), (3) 18F-flurodihydroxyphenylalanine (F-FDOPA),(4) 68Ga-DOTA coupled somatostatin analogs (Ga-DOTA),(5) 11C-Hydroxy ephedrine(HED-PET). From this point forward, these imaging modalities will be referred to in their abbreviated names found in parentheses.


title: Pheochromocytoma

text: The first functional imaging technique utilized in pheochromocytoma patients was I-MIBG scintigraphy (Image Right). Given the compounds similar structure to the catecholamine norepinephrine (secreted by pheochromocytomas), MIBG was well-suited for uptake by most neuroendocrine tumors. Furthermore, if a patient was found to be positive on an MIBG scan, they were eligible for MIBG treatment, offering additional avenues for those with widespread metastatic disease. However, further investigation revealed that while MIBG excelled with adrenal lesions, it was far less superior in patients with extra-adrenal paragangliomas, particularly with specific genetic variants like succinate dehydrogenase subunit X ("SDHx)." As the positron emission tomography scans were developed, MIBG has slowly loss its favor for the pheochromocytoma patient.


title: Pheochromocytoma

text: Of the four above mentioned modalities, F-FDG PET is the most common and readily available functional imaging technique at most hospital systems, but the least-specific to neuroendocrine tumors (Image Left). In 2012, over 200 patients participated in a trial that compared the current gold standard of the time (MIBG/CT/MRI) to the novel FDG PET. Compared to its functional counterpart, FDG outperformed MIBG in detecting soft-tissue and bone metastases with higher specificity in patients with biochemically active tumors.


title: Pheochromocytoma

text: Following the development of FDG-PET, neuroendocrine-specific PET scans began to emerge. One of the first favorable imaging modalities was F-FDOPA, which demonstrated a high sensitivity in detecting head and neck paragangliomas as well as non-metastatic disease outside of the head and neck. Unfortunately, in cases of metastatic disease, particularly related to succinate dehydrogenase subunit B ("SDHB)" mutations, F-FDOPA fell inferior to the traditional FDG-PET. However, for patients with genetic variants in other pheochromocytoma-susceptibility genes ("NF1, VHL, RET)" F-FDOPA has become the preferred radiopharmaceutical agent.


title: Pheochromocytoma

text: The newest PET modality involves somatostatin receptor type two receptor imaging with Ga-DOTA analogues. Over the last decade, further research continues to indicate the superiority of this functional imaging modality in a wide range of clinical scenarios, even surpassing anatomic imaging (CT/MR) in pediatric patients with succinate dehydrogenase ("SDHx)" mutations. While FDOPA inconsistently detected metastatic disease, Ga-DOTA analogues have demonstrated superior localization of metastatic pheochromocytoma. When directly compared in one head-to-head study in 2019, Ga-DOTA analogues outperformed FDOPA, particularly in the detection of metastatic bone lesions. An additional benefit of the DOTA analogues is the ability for treatment with peptide receptor radionuclide therapy, which will be discussed in the treatment section below.


title: Pheochromocytoma

text: Also, HED-PET has shown to be an accurate tool to diagnose and rule out pheochromocytoma in complex clinical scenarios and to characterise equivocal adrenal tumours.


title: Pheochromocytoma

text: Surgical resection is the only curative option for pheochromocytoma as of 2019. A successful excision is a multidisciplinary effort involving the endocrinologist and the patient pre-operatively (discussed below) and the surgical team and anesthesiologist intraoperatively. Without frequent and adequate communication between all of the above-mentioned teams, a favorable outcome is much more difficult. The United States Endocrine Society 2014 Clinical Practice Guideline for pheochromocytoma recommend a laparoscopic adrenalectomy (minimally invasive technique) for most adrenal tumors, unless they are invasive or are larger than 6.0 centimeters. It is important to note that larger tumors can be attempted with a minimally invasive approach, but the team should be prepared to convert to an open procedure if necessary. An open procedure (traditional surgical technique) is currently preferred for extra-adrenal disease, unless the tumor is small, non-invasive, and in an easy to maneuver location. While previous data indicated the need for a minimally invasive approach with malignant and/or metastatic disease, current research indicates a successful operation is feasible and results in a shorter hospital stay. Literature within the last decade has also demonstrated that the robotic technique may be successfully utilized for adrenal tumors.


title: Pheochromocytoma

text: Typically, complete or total adrenalectomy is performed; however, a technique referred to as "cortical-sparing" can leave a remnant (piece) of the adrenal gland in hopes of avoiding life-long steroid replacement if the left and right adrenal glands need to be removed. The issue is particularly important in patients with "MEN" and "VHL-"related disease, which has a higher chance of bilateral pheochromocytomas. The risk of leaving adrenal tissue is recurrent disease (tumor comes back). A 2019 cohort study reported that despite a 13% recurrent rate in patients who underwent a cortical-sparing adrenalectomy for pheochromocytoma, there was no decreased survival compared to their total adrenalectomy counterparts.


title: Pheochromocytoma

text: Arguably, the most important part of a pheochromocytoma surgical plan is an adequate pre-operative blockade. Excess catecholamines have been described as a dormant volcano, ready to erupt at any time, wreaking catastrophic havoc on the body. While an eruption can occur at any time, two of the most common triggers are anesthesia and direct tumor manipulation, making surgery one of the most dangerous times for a pheochromocytoma patient if not properly prepared. In order to help circumvent a catecholamine-crisis, the United States Endocrine Society recommends that all patients with functional (hormonally active) tumors be started on a pre-operative alpha-adrenoceptor blockade a minimum of seven days prior to surgery. There are several medication options depending on the clinical scenario, each with their own associated strengths and weaknesses.


title: Pheochromocytoma

text: If the patient's blood pressure is moderately elevated, a selective, short-acting alpha-1 adrenoceptor antagonist (doxazosin, prazosin, terazosin) is the preferred agent. However, the patient should be warned about the potential side-effect known as "the first-dose phenomenon." When patients are initially exposed to one of the above agents, they may become lightheaded, dizzy, and nauseous, particularly when transferring from a seated to standing position due to a rapid decrease in blood pressure. These effects will decrease with time, but providers can try to avoid them by starting at a low-dose and slowly increasing until they reach their desired amount. In patient's with uncontrolled hypertension, the non-selective alpha-1 and 2 adrenoceptor antagonist (phenoxybenzamine) should be utilized. Unfortunately, compared to the selective agents listed above, phenoxybenzamine is much more expensive and may not be readily available to some patients. Common side-effects include dry mouth, nasal congestion, and impaired male ejaculation, all of which do not cease with time and may limit patient compliance. While uncommon, patients may have a hormonally-active pheochromocytoma and a normal blood pressure. One comparison from 2014 found that a small dose of a calcium-channel blocker (such as amlodipine) may be used pre-operatively in some people. This will not drastically lower the patients blood pressure and make them hypotensive, but it will assist the surgical and anesthesia teams if there is hemodynamic instability during the operation.


title: Pheochromocytoma

text: An elevated heart rate (tachycardia) and the feeling of a racing heart (palpitations) may follow after initiating an alpha-adrenoceptor antagonist. If that is the case, a beta-adrenoceptor antagonist is then prescribed to control the heart rate. Just as with the alpha antagonists, there are selective (beta-1) and non-selective (beta-1 and beta-2) adrenoceptor antagonists. The selective agents (atenolol, metoprolol) are preferred to the non-selective agents (propranolol). There are several (labetalol, carvedilol) combined alpha-beta-adrenoceptor antagonists. These agents should be avoided whenever possible as there is upwards of seven times more beta-adrenoceptor antagonism than alpha, which can worsen hypertension and lead to a catecholamine crisis.


title: Pheochromocytoma

text: Beta-adrenoceptor antagonists should not be given alone in a pheochromocytoma patient - this can lead to severe consequences. In 1995, a team of physicians from London described the death of a person who had been recently diagnosed pheochromocytoma after initiation of propranolol, a non-selective beta blocker. She quickly developed a hypertensive crisis leading to shock, myocardial infarction, heart failure, and dense right hemiplegia. Despite attempts at resuscitation, the person died several days later. This complication is related to the impact that alpha and beta-adrenoceptor antagonists have on blood vessels combined with the actions of catecholamines. The normal blood vessel is open, allowing for adequate blood flow. When catecholamines activate the alpha receptor, the vessel constricts (gets smaller), which results in hypertension. However, when catecholamines active the beta receptor, the blood vessel dilates (gets larger) and allows for increased blood flow, reducing the blood pressure. If a pheochromocytoma patient is only started on a beta-adrenoceptor antagonist, this reverses the protective vasodilation and worsens the patients hypertension.


title: Pheochromocytoma

text: While the pre-operative alpha and beta blockade discussed above is overwhelmingly recognized as the standard of care, particularly in the United States, there has been discussion at the international level if a blockade is necessary. In 2017, a team of researchers from Germany published an observational case series that called into question the current recommendations for a blockade. The study examined the intraoperative maximal systolic arterial pressure in people with and without alpha-adrenoceptor blockade and found no difference in complications between the two groups. The following year, a group from France published a similar article with a warning against waiting an entire week to begin alpha-blockade. The French researchers called for immediate surgical intervention and consideration of steps to mitigate any intraoperative catecholamine crisis. These articles resulted in rebuttals from research teams in the United States, but an international consensus has not yet been reached.


title: Pheochromocytoma

text: Excess catecholamines cause a decrease in the total blood volume, making a patient vulnerable to hypotension during the operation. Therefore, a high-sodium diet with adequate fluid intake should be encouraged prior to surgery. Some institutions in the United States will even admit patients the night prior to surgery for intravenous fluid replacement starting at midnight until the time of the operation. However, a small trial from 2009 reported no difference in mortality in patients treated with preoperative intravenous fluids compared to those who did not.


title: Pheochromocytoma

text: In a 2010 survey of 40 endocrinologists by researchers at the Cedars-Sinai Medical Center in Los Angeles, California, nearly all indicated the importance of preoperative volume resuscitation (having the patient take in plenty of fluids prior to surgery). However, after reviewing their patient data, over 60% of the same physicians failed to discuss salt-loading and adequate hydration. When the patients were stratified by age, those that were younger received the advice to hydrate, but older patients did not. It was hypothesized that the providers chose to forego volume repletion in the older patient population for fear of their potential comorbidities (heart failure) where excess fluid is dangerous. While there is still no recognized consensus or gold standard, providers should individualize the decision based on the patient's perceived nutritional standing, volume status, comorbidities, and ability to self-hydrate.


title: Pheochromocytoma

text: There have been many other reported complications (renal failure, heart failure, intestinal pseudo-obstruction) following tumor resection. However, the above are more likely to be encountered, which is why their management has been specifically outlined here in this article.


title: Pheochromocytoma

text: Metastatic pheochromocytoma is defined as the presence of tumor cells (chromaffin tissue) where they are not normally found. Patients with a paraganglioma are more likely to develop metastases than those with a pheochromocytoma. The most common extra-adrenal sites of metastases are the lymph nodes, lung, liver, and bone. There have been several studied risk factors associated with the development of metastatic disease - while the patients genetic background plays an important role, the initial age of presentation and size of the tumor lead to negative outcomes. Of all the genetic variants, succinate dehydrogenase subunit B "(SDHB)" mutations have the highest rates of developing metastatic disease. Another study has reported increased mortality associated with male sex and synchronous metastases. Metastases are divided into synchronous and metachronous; those that are synchronous have developed within several months of the primary tumor, while metachronous metastases do not appear for a significant period of time.


title: Pheochromocytoma

text: Laparoscopic approach to the original disease, especially in big tumors, has been appointed as an important risk factor for tumoral seeding.


title: Pheochromocytoma

text: Despite all of the below potential treatment options, recent literature highlights that (for most patients) metastatic pheochromocytoma is slow-growing. In patients with minimal disease burden, a "watch and wait" approach with frequent imaging to monitor disease is favorable, withholding treatment until evidence of progression is visualized.


title: Pheochromocytoma

text: Metastatic pheochromocytoma is best managed with a multidisciplinary team of oncologists, surgeons, radiologists, nuclear medicine physicians, and endocrinologists. There are several treatment options available to patients depending on the amount and location of disease:


title: Pheochromocytoma

text: "Surgery -" Normally, the goal of surgery is complete cytoreductive surgery; leave no remnant of disease. However, with widespread metastatic disease, this is not always feasible. Therefore, a surgical debulking procedure is performed (removing as much of the cancerous tissue as possible) in order to reduce patient symptoms by removing the source of catecholamines, improve response to chemo or radionuclide therapy, or simply decrease the size of the tumor. Unfortunately, the intended relief from the procedure is often short-lived, especially if the patient has disease outside the abdomen. A 2013 study from the National Institutes of Health reported that a majority of patients with recurrent biochemical evidence of disease within one year of the operation and less than 30% continued to be biochemically free of disease after five years.


title: Pheochromocytoma

text: In contrast to an operation for non-metastatic disease, an open procedure may be preferred over a minimally invasive technique in order to circumvent potential tumor spread. This also aids surgical visualization and offers the best opportunity to identify and remove metastatic lymph nodes. Reports have also indicated the utility of administering a radionuclide agent like iodine-123 meta-iodobenzylguanadine (I-MIBG) prior to surgery and then scanning the patient intraoperatively with a probe to detect disease that may be missed with the naked eye.


title: Pheochromocytoma

text: "Radiation Therapy -" With regard to pheochromocytoma, radiation techniques are primarily used for pain control, specifically with regards to bone metastases, local control of the disease, and to limit spinal cord compression. A multidisciplinary team from the Mayo Clinic retrospectively reviewed all of their patients who underwent external beam radiation therapy from 1973 to 2015 and reported that 94% of patients acknowledged symptomatic improvement and over 80% of patients showed no evidence of recurrent disease 5-years post-therapy. Another report from the same institution looked at almost two decades of patients who underwent radiofrequency ablation, cryoablation, or percutaneous ethanol injection for metastatic pheochromocytoma and reported that local control was achieved in over 85% of targeted lesions and that 92% of procedures were associated with reduced pain and/or symptoms of catecholamine excess.


title: Pheochromocytoma

text: "Chemotherapy -" The most common chemotherapy regimen for metastatic pheochromocytoma is cyclophosphamide, vincristine, and dacarbazine, collectively known as CVD. Response to therapy is measured by a reduction in total tumor volume as well as symptomatic relief, reported by the patient. A systematic review and meta-analysis of unstratified pheochromocytoma patients who underwent CVD therapy showed that 37% of patients had a significant reduction in tumor volume, while 40% of patients experienced lower catecholamine burden. While there was no difference in overall survival between patients whose tumors shrunk versus those without a response (no reduction in tumor burden via imaging), even in non-responders, patients reported feeling better, blood pressure was lower, and some patients were even able to undergo surgery following disease stabilization with CVD. When patients are studied by various categories, research has suggested that females are less likely to have extended survival with CVD chemotherapy compared to their male counterparts. Genetic status has been shown to greatly impact response to CVD. A team of researchers from the National Institutes of Health reported that patient's with succinate dehydrogenase subunit B "(SDHB)" mutations are not only more likely to initially respond to CVD, but that they also experienced over 30 months of progression free survival (time until tumor returned) with continued administration.


title: Pheochromocytoma

text: However, CVD is not the only proven chemotherapeutic regimen in the pheochromocytoma patient. A 2018 report demonstrated the remarkable response of two "SDHB" patients who failed CVD chemotherapy (disease progressed despite medication), but were then treated with temozolomide (TMZ) and had progression free survival of 13 and 27 months, indicating that TMZ can be considered as an alternative treatment regimen in those who have progressed on CVD. Several studies have since reported successful responses with TMZ, particularly in the "SDHB" sub-population.


title: Pheochromocytoma

text: According to the National Cancer Institute, prognosis is defined as the likely outcome of a disease OR, the chance of recovery or a recurrence. This is an extremely difficult question when it comes to pheochromcytoma, and the answer depends on the patients genetic status, presence of metastatic disease, and the location of their primary tumor. An article about prognosis published in 2000 reported a 91% 5-year survival rate in their patient population; however, it is important to note that over 86% of their patients had sporadic tumors (no known genetic mutation), which commonly have low malignant potential. In 2019, a consortium of almost twenty European medical centers looked at the prognosis of malignant pheochromocytoma and the data starkly varies from the report of sporadic, single tumors, with a median survival of 6.7 years. Overall survival improved if the patient had (1) disease of the head and neck compared to abdomen, (2) less than 40 years of age, (3) and if their biochemistry was less than five times the upper reference limit of normal.


title: Pheochromocytoma

text: Recent literature has detailed several factors that predict accelerated progression of disease and higher mortality rates, including patients who choose to forego surgical resection of their primary tumor, larger tumors at initial presentation, older age at initial diagnosis, and a shortened time from primary tumor to presence of metastases. The actual location of the metastases can also indicate prognosis, with osseous lesions (bone) faring better than their soft-tissue (lung, liver) counterparts.


title: Pheochromocytoma

text: According to the North American Neuroendocrine Tumor Society, the prevalence of pheochromocytoma is between 1:2500 and 1:6500, meaning that for every 2,500 – 6,500 people, there is (on average) one person with pheochromocytoma. In the United States, this equates to an annual incidence (new cases per year) of 500 to 1600 cases. However, approximations in the early 2000s reported that upwards of 50% of pheochromocytoma diagnoses are at autopsy; therefore, the above estimations may be lower than expected. In a 50-year autopsy case series, the Mayo Clinic reviewed 54 pheochromocytoma cases between 1928–1977 and discovered that just 24% of the patients were correctly diagnosed prior to their death. Outside of the United States, several countries have documented their own epidemiological studies and compared them to what is known in North America. In the first national, epidemiological population-based study in Asia utilizing Korean National Health Insurance Service data, the prevalence of a pheochromocytoma was reported at 2.13 per 100,000 persons with an incidence of 0.18 per 100,000 person-years. This is lower than the occurrence reported from Rochester, Minnesota (0.8 per 100,000 person-years) in a study conducted from 1950 to 1979. However, the Netherlands also conducted a study using a nationwide registry and reported incidence results of 0.57 per 100,000 person-years from 2011 to 2015, which was a significant increase from their 0.37 cases per 100,000 person-years reported from 1995 to 1999. Current hypotheses for why the incidence of pheochromocytoma is growing in the Dutch population point to the advent of modern imaging evaluation and the ability to detect these tumors prior to death. While each of the above studies reported varying incidence and prevalence values, all have indicated that the average age at initial diagnosis is between the third to fifth decade of life. When younger patients are diagnosed with a pheochromocytoma, there should be a high suspicion for hereditary disease, as genetic anticipation (earlier disease onset with each generation) is associated with some mutations.


title: Pheochromocytoma

text: Despite the prominence in many respected textbooks, these guidelines have since been established as inaccurate and are not used in current epidemiological discussions.


title: Pheochromocytoma

text: As suggested above, incidental imaging has become a major player in the diagnosis of patients with pheochromocytoma, with current estimates between 10 and 49% of all cases diagnosed after imaging was obtained for another reason. When an adrenal nodule (potential tumor) is discovered on computed tomography or magnetic resonance imaging, there is between a 5 and 10% chance the lesion is a pheochromocytoma. The incidence of adrenal tumors is found in the infographic above, with pheochromocytoma noted in yellow in the top right corner.


title: Pheochromocytoma

text: In 1800, an Irish physician (Charles Sugrue) penned a case report to the London Medical and Physical Journal describing the peculiar case of an 8-year-old male patient who had had seemingly random fits of pain concentrated in the abdomen accompanied by "a hectic flush distinctly marked on each cheek" with a "constant profuse and universal perspiration." Following his death, a group of physicians performed an autopsy to determine cause of death and discovered a six-inch oblong tumor composed of an unknown "yellow-ish coloured substance" coming from the capsula renalis (what is now known as the adrenal gland). This would become the first known clinical description of a pheochromocytoma, but as no features of the tumor itself were described, complete credit is given to the German Felix Fraenkel, who provided a clinical and morphologic picture of this tumor. While various physicians were recognizing symptoms and treating patients, Czech biologist Alfred Kohn reported his discovery of the paraganglia system, which would later become crucial to the diagnosis of these tumors. Furthermore, he also introduced the term "chromaffin," allowing pathologists to recognize tumors that arose from the adrenal gland.


title: Pheochromocytoma

text: In 1908, two pathologists, Henri Alezais and Felix Peyron, introduced the scientific community to "paraganglioma" after they discovered extra-adrenal tissue that reacted to chromium salts, which mimicked the reaction of the adrenal medulla. Just four years later, German pathologist Ludwig Pick coined the term "pheochromocytoma" after he observed the consistent color change in tumors associated with the adrenal medulla. Many surgeons attempted to remove these tumors over the next decade, but their patients died intraoperatively from shock. In 1926, Charles Mayo (a founder of the Mayo Clinic) became the first physician to successfully excise a pheochromocytoma. However, Mayo was likely unaware of the diagnosis prior to the operation. Not until 1929 was a pheochromocytoma recognized preoperatively. Throughout the early 1900s, the operative mortality rate for a pheochromocytoma ranged from 30 to 45%. Retrospective series have postulated that these alarmingly high death rates were due to the lack of a pre-operative blockade with alpha and beta-adrenoceptor antagonist and the need for modern anesthesia practices. From this point forward, physician-scientists have been recognizing patterns in patients with pheochromocytoma and identifying genetic associations and various syndromes.


title: Pheochromocytoma

text: While a rare disease, there have been several references to pheochromocytoma in popular culture and the media, specifically medical television dramas. Additionally, there is a strong online patient advocacy community that works to connect patients with rare diseases and allows them to meet other individuals who are experiencing similar diagnoses and treatment strategies.


title: Pheochromocytoma

text: In the medical community, students are often taught "when you hear hoofbeats, think horses, not zebras." In other words, common diagnoses are common, so healthcare professionals should first rule out what is most expected (the horses) before diving into the rare etiologies that are far less likely to be correct (the zebras). However, the symbol of the zebra has become increasingly powerful to the rare disease community and resulted in several organizations, societies, and special events (Rare Disease Day) to draw attention to the least common option sometimes being the correct diagnosis.


title: Pheochromocytoma

text: The National Organization for Rare Disorders is a United States-based advocacy parent organization with the goal of promoting awareness and research opportunities to cure rare diseases. Groups such as these encourage patients to become their own advocates and change agents in their healthcare decision-making processes.


title: Pheochromocytoma

text: In July 2012, an actual pheochromocytoma patient, Tannis Brown, former vice-president of the PheoPara Troopers, was featured on the Discovery Fit & Health Network program "Diagnosis: Dead or Alive." The show highlighted her personal struggle with misdiagnosed disease as many physicians felt her episodic headaches and hypertension (high blood pressure) were related to stress.


title: Pheochromocytoma

text: In the seventh and eighth seasons of "Greys Anatomy," series regular Henry has a Von Hippel-Lindau "(VHL)" mutation that has resulted in a pheochromocytoma. The story arc was met with mixed opinions from the rare disease community. Then executive Director of the VHL Alliance was happy with the portrayal of a VHL patient in mainstream media, but pointed out that of the four scripts she knew of with a VHL patient, three involved a pheochromocytoma, which actually occurs in less than a fifth of all VHL patients.


title: Pheochromocytoma

text: A case of pheochromocytoma was featured in the first episode of season 2 of "House MD". Dr. House and his team are tasked with diagnosing and treating an inmate on death row. Although the patient has a violent history of homicide, Dr. House suspects that his episodic rage and aggression may be caused by an adrenaline secreting tumor. Dr. House is able to locate the tumor and diagnoses the patient with pheochromocytoma. Dr. Foreman, one of the doctors, attempts to appeal the inmate's death penalty on the basis that he was unable to control his actions due to his tumor. This kind of legal defense is rarely successful, however.


title: Vegvísir

text: A (Icelandic for 'sign post, wayfinder') is an Icelandic magical stave intended to help the bearer find their way through rough weather. The symbol is attested in the Huld Manuscript, collected in Iceland by Geir Vigfusson in Akureyri in 1860, and does not have any earlier attestations.


title: Vegvísir

text: A leaf of the manuscript provides an image of the , gives its name, and, in prose, declares that "if this sign is carried, one will never lose one's way in storms or bad weather, even when the way is not known".